Disclaimer
This information collection is a core HTA, i.e. an extensive analysis
of one or more health technologies using all nine domains of the HTA Core Model.
The core HTA is intended to be used as an information base for local
(e.g. national or regional) HTAs.
UPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX compared to Standard of care in selecting treatment for Breast cancer recurrence in females
(See detailed scope below)
Background
Given its high impact on the healthcare service, the management of breast cancer is a relevant issue for all European Union (EU) countries. The three tests assessed in this core health technology assessment (HTA)— uPA/PAI-1 (FEMTELLE®, American Diagnostica) based on immunostaining techniques and MammaPrint® (Agendia) and Oncotype DX® (Genomic Health), based on gene expression profiling—measure multiple markers within the tumour that may indicate how the tumour is likely to develop. The potential clinical utility of the tests lies in their ability to discriminate between patients who will benefit to a greater or lesser extent from a therapeutic intervention. The assessment of technologies of this type could be of interest to all the EU member states.
The uPA/PAI-1, MammaPrint and Oncotype DX tests are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient, which may reduce the number of women receiving chemotherapy and experiencing the associated side-effects. Specifically, the uPA/PAI-1 test is intended for women with newly diagnosed lymph node-negative breast cancer. MammaPrint is intended as a prognostic test for women with lymph node-negative and lymph node-positive breast cancer with a tumour size of 5 cm or less, or for women who are 61 years of age or less, with oestrogen receptor-positive or oestrogen receptor-negative, lymph node-negative breast cancer. The Oncotype DX assay is intended for use for women with newly diagnosed lymph node-negative or lymph node-positive, oestrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer.
Results
Safety of the technology (SAF)
The three tests under evaluation share general safety concerns about aspects of environmental safety and surgical pathology practice, such as sample contamination, delays in transfer of samples to the testing laboratory, incorrect labelling and other features that may affect the reliability of the result and thus patient safety. There is insufficient evidence, from the 12 included studies, of possible anxiety or other psychosocial harms caused to the patients by the tests.
Effectiveness of the technology (EFF)
Studies assessing the prognostic/predictive accuracy of the tests were excluded. The 15 poor quality observational studies included did not provide any comparative direct evidence on the effects of treatment with and without the use of the index test. They assessed issues such as quality of life, anxiety and patient satisfaction. There is a clear need for manufacturers to communicate at an early stage with the European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and health technology assessment (HTA) bodies to obtain so-called “early scientific advice” when designing randomised controlled trials (RCTs).
Costs, economic evaluation of the technology (ECO)
If dominance of the prognostic tests for breast cancer recurrence (PTBCRs) were to be shown in prospective independent comparative studies, introduction of these tests might avoid unnecessary use of expensive chemotherapy with its associated adverse effects for women who would derive little or no benefit from it. The tests might reduce the mortality rate in high-risk women who would have benefitted from chemotherapy. However, the key effectiveness data needed to draw conclusions about cost-effectiveness ratios is missing. The generation of appropriate effectiveness data should make the estimation of such ratios possible in the future.
Ethical aspects of the technology (ETH)
Direct evidence of improved outcomes is lacking for all three tests, but studies of components of clinical utility might provide indirect evidence. There is encouraging indirect evidence for Oncotype DX, and plausibility for potential use of MammaPrint and, possibly, the uPA/PAI-1 test. It seems plausible that more women will benefit (i.e. avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefitted from chemotherapy), possibly resulting in breast cancer recurrence or death. Currently, there are insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine what proportion of women with moderate to high risk, based on conventional risk assessments, will have a “low enough” score to affect their decision about chemotherapy. The use of the tests raises the question of the extent to which patients are prepared to participate in informed decision making about their care.
Organisational aspects of the technology (ORG)
The introduction of PTBCRs into the clinical pathways of women with breast cancer is unlikely to have significant organisational impacts. However attention should be paid to costs, and to communication between provider units and patients.
Social aspects of the technology (SOC)
If PTBCRs are introduced, emotional and psychological support is likely to be useful, especially if results of these prognostic tests are not in accord with those of standard clinicopathological prognostic factors analysis. Feelings of distress and anxiety are frequently reported by patients undergoing prognostic tests and are related to the consequences of the tests on treatment decisions. It remains unclear whether and how these feelings affect the social areas of the patient. Overall knowledge about some aspects of PTBCRs, such as harms, is low.
Legal aspects of the technology (LEG)
Legislation/regulation on three aspects should be developed at the European level. (1) the absence of an ad hoc European directive on medical devices—in vitro predictive tests, (2) the absence of the FEMTELLE uPA/PAI-1 test, MammaPrint and Oncotype DX from the Eudamed register (European registry) and (3) the need to ensure equitable access to these tests.
Closing Remarks
The Core Model is not intended to provide a cookbook solution to all problems but to suggest a way in which information can be assembled and structured, and to facilitate local adaptation. The information is assembled around the nine domains, each with several result cards in which questions and possible answers are reported.
The reasons for having a standardised but flexible content and layout are rooted in the way HTA is carried out in the EU HTA institutions and in the philosophy of the first EUnetHTA Joint Action (JA1) production experiment.
HTA is a complex multidisciplinary activity addressing a very complex reality – that of healthcare. Uniformly standardised evidence-based methods of conducting assessments for each domain do not exist (Corio M, Paone S, Ferroni E, Meier H, Jefferson TO, Cerbo M. – Systematic review of the methodological instruments used in Health Technology Assessment. Rome, July 2011.). There are sometimes variations across and within Member States in how things are done and which aspects of the evaluation are privileged. This is especially so for the “softer”, more context-dependent domains such as the ethical and social domains.
Currently there are only three applications of the HTA Core Model (medical and surgical interventions, diagnostic technologies, and screening technologies). In this work the HTA Core Model for diagnostic technologies was used to assess the clinical effectiveness of the three prognostic tests. However there are fundamental differences between diagnostic and prognostic tests. Because of these differences, a number of the HTA Core assessment element questions for diagnostic technologies are not suited to prognostic technologies. Prognostic/predictive accuracy was not assessed in this HTA Core Model.
This test would represents a useful lesson for methodological development in EUnetHTA Joint Action 2.
Objective
To produce a Core health technology assessment (HTA) assessing the effects of prognostic tests for breast cancer recurrence (PTBCRs) based on the EUnetHTA Core Model and working within the Collaborative Model 1 (COLMOD 1) organisational framework.
Methods
The work was based on the HTA Core Model on diagnostic technologies which was developed during the EUnetHTA Project 2006–2008.
The first step was the selection of the technology to be assessed using the Core Model; this phase was carried out through a three-step process that included surveys and questionnaires to WP4 partners by email. At the same time, the Collaborative Model to be used in this Core HTA was chosen by WP4 Partners.
Then there was the check of Partners’ availability to take the lead, as Primary Investigator, in one of the nine evaluation domains. At the same time, the nine Domain Teams were built up in accordance with Partners’ preferences and some general guidelines (i.e.: “each WP4/B AP should be involved in at least one domain, indicating its interest for at least one domain”).
Finally the specific work plan was shared, in accordance with the general WP4 3-year work plan and objectives. This specific work plan included the phases scheduled in the “HTA Core Model Handbook” (Production of Core HTAs and structured HTA information).
An editorial team was set up for discussion and major decisions on basic principles and solutions related to the content of the core HTA. The editorial team was chaired by Tom Jefferson (Agenas), vice-chaired by Heike Raatz (SNHTA), and composed of all the primary investigators of domains.
To allow collaboration between partners a draft protocol for Core Model use was agreed by the researchers involved. The research questions for each of the nine domains of the Core Model were formulated and the corresponding relevant assessment elements (AE) were selected.
Overlaps within domains were identified and assigned exclusively to one domain, by mutual agreement.
The research strategy was carried out by one of the domain team, collecting input from the others.
Evidence from published and manufacturer sources was identified, retrieved, assessed, and included according to pre-specified criteria and summarised to answer each AE. Each domain assessment was made by researchers from different institutions led by a primary investigator (COLMOD1); researchers from different WP4 Partners reviewed and commented on the Core HTA.
This section provides background information on the preparation and development of the Core HTA on prognostic tests for breast cancer recurrence (PTBCRs; uPA/PAI-1 [FEMTELLE®, American Diagnostica], MammaPrint® [Agendia] and Oncotype DX® [Genomic Health] ). The core HTA document was produced during the course of the first EUnetHTA Joint Action (JA1) 2010–2012.
The idea behind EUnetHTA’s Core Model is to provide a framework for structuring relevant HTA information while at the same time facilitating local use and adaptation of the information or guiding its production.
The Model is based on nine dimensions or “domains” of evaluation:
In the following nine documents the PTBCRs were assessed using the HTA Core Model Application for Diagnostic Technologies (1.1), developed during the EUnetHTA project 2006–2008.
The PTBCR Core HTA was prepared using an experimental Collaborative Model (COLMOD). The PTBCR Core HTA was prepared using COLMOD 1 in which groups of researchers from 22 different HTA Institutions (55 researchers in all) produced the domain texts. The experimental organisational model added a strong element of challenge but probably helped forge strong links across participants.
In the last months an intensive programme of interviews and consultations will elicit comments and feedback, both from those who contributed to the Core HTA and from those who read it for the first time. This validation plan includes an internal audit within the WorkPackage 4 teams during which each partner will validate the Core HTA they did not produce and the Core HTA production process (collaborative models, on-line tool, etc.).
At the same time, as scheduled in the 3-year work plan, the Core HTA will be sent to the Stakeholder Advisory Group (SAG) for review and feedback before the final Public Consultation phase, during which the Core HTAs will be published in the On-line Tool and Service.
The results from the Validation Phase and SAG consultation will help us in amending the introduction of the 2 Core HTAs and in preparing a first methodological guidance for the EUnetHTA Joint Action 2.
This process, we hope, will provide invaluable information to improve the product and will help us to understand whether our efforts have been worthwhile.
The following contributed to the preparation of the document:
Institutions:
Researchers:
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
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Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Authors: Sarah Baggaley, Massimo Gion
Breast cancer is one of the most commonly occurring cancers and incidence rates are four or five times higher in developed countries than those in developing countries. One in nine women will acquire breast cancer at some point in her life and one in thirty will die from the disease. Age is the strongest risk factor for breast cancer (the older the woman, the higher the risk) and symptoms of the disease include a lump or swelling in the armpit or the breast, bloody discharge from the nipple and pain in the breasts or armpits.
Breast cancer starts when a cell or group of cells start to grow and divide uncontrollably. The two main categories of early breast cancer are in situ disease (cancer is typically confined to one area of the breast) and invasive cancer (cancer spreads to surrounding tissues and other parts of the body). The main ways in which breast cancer can spread are by local spread to nearby tissues, or by regional or distant spread through the circulatory system or through the lymphatic system. These circulating cancer cells can go undetected until a tumour starts to form and this is one of the reasons cancer can recur after the initial treatment. Cancer can also recur if cancer cells remain after the primary tumour has been removed.
After breast cancer has been diagnosed, various tests are performed to find out if the cancer has spread and to determine the stage of the disease. The degree to which cancer has spread determines the stage of the disease and subsequent treatment. Typically, the more extensive the spread of cancer in the body is, the more aggressive the treatment and the worse the patient’s prognosis.
Two systems can be used to describe the stage of the breast cancer, the numerical system and the TNM (tumour, node, metastasis) classification system. Both systems consider the size of the tumour and whether the cancer has spread to the lymph nodes and other parts of the body. The tumour grade (appearance of cells) and receptor status of the tumour are also used to inform decisions about the most appropriate treatment for the patient and the risk of breast cancer recurrence. A number of algorithms and decision-making tools are also used in some countries to help clinicians assess the risk of breast cancer recurrence.
The treatment of cancer can cause many side-effects including significant pain, persistent fatigue, lymphoedema, osteoporosis and reduced fertility. Emotionally, a diagnosis of breast cancer and subsequent treatment can cause long-term anxiety, depression and isolation in both the individual and their relatives. Hair loss and changes to the body from a mastectomy, for example, are associated with a social stigma and can significantly impact on quality of life and reduce self-esteem.
The three prognostic tests, uPA/PAI-1 (FEMTELLE®), MammaPrint® and Oncotype DX®, are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient. All of these tests are available for use in Europe and the uPA/PAI-1 test has been recommended in two German clinical guidelines for therapy decisions in node-negative breast cancer. Survey results from clinicians suggested that all three tests were in use in Europe but there was a low response rate to the survey and this may be due to low use of the tests in European countries {Appendix COL-2}.
Breast cancer is one of the most common cancers in women in developed countries and significantly impacts healthcare services. Therefore, improvements in breast cancer management are of great interest and relevance to all EU countries. Advances in diagnostic or therapeutic technologies may offer benefits to patients and the healthcare system so new technologies are often of interest to policy makers. In this assessment three prognostic technologies, uPA/PAI-1 (FEMTELLE®), MammaPrint® and Oncotype DX®, were evaluated. These technologies are tests that aim to provide prognostic information that can be used to help the clinician predict the likelihood of breast cancer recurrence and tailor adjuvant therapy to the individual patient.
This domain outlines the health problem for which these prognostic tests are intended to be used and provides information on how breast cancer is currently diagnosed and managed. This knowledge is necessary in the assessment to provide a basic description of the situation in which the tests are intended to be used and to provide context for other domains in the assessment. This domain also provides relevant information for the assessment of the clinical and economic impact of introducing these tests or promoting their utilisation in the care pathway for breast cancer.
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
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Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
A0001 | Target Condition | Which disease/health problem/potential health problem will the technology be used for? | yes | Which disease/health problem/potential health problem will Genetic Test be used for? |
A0002 | Target Condition | What, if any, is the precise definition/ characterization of the target disease? Which diagnosis is given to the condition and according to which classification system (e.g. ICD-10)? | yes | How is the disease/health condition currently being diagnosed? Include a description of any relevant classification system |
A0003 | Target Condition | Which are the known risk factors for acquiring the condition? | yes | Which are the known risk factors for acquiring the condition? |
A0004 | Target Condition | What is the natural course of the condition? | yes | What is the natural course of the condition? |
A0005 | Target Condition | What are the symptoms of the disease? | yes | What are the symptoms of the disease? |
A0006 | Target Condition | What are the consequences of the condition? | yes | What are the consequences of the condition? |
A0007 | Target Condition | How many people belong at the moment (will belong) to the specific target group (describe according to sex, age)? | yes | How many people belong at the moment (will belong) to the specific target group (describe according to sex, age)? |
A0008 | Target Condition | What is the burden of disease (mortality, disability, life years lost)? | yes | What is the burden of disease (mortality, disability, life years lost)? |
A0009 | Target Condition | What aspects of the burden of disease are targeted by the technology, i.e. are expected to be reduced by the technology? | yes | What aspects of the burden of disease are targeted by Genetic Test, i.e. are expected to be reduced by Genetic Test? |
A0010 | Target Condition | How long is the waiting time for diagnosis and/or treatment of the specific disease? | no | Merged withA0013 |
A0011 | Utilisation | How much is the technology being used? | yes | How much is Genetic Test being used? |
A0012 | Utilisation | Describe the variations in use across countries/regions/settings, if any? | no | Merged with A0011 |
A0013 | Current Management of the Condition | How is the disease/health condition currently being diagnosed? | yes | How is the disease/health condition currently being diagnosed? |
A0014 | Current Management of the Condition | According to published algorithms/guidelines (if any), how should the condition be diagnosed? | yes | According to published algorithms/guidelines (if any), how should the condition be diagnosed? |
A0015 | Current Management of the Condition | How is the disease/health condition currently being managed? | yes | How is the disease/health condition currently being managed? |
A0016 | Current Management of the Condition | According to published algorithms/guidelines (if any), how should the condition be managed? | yes | According to published algorithms/guidelines (if any), how should the condition be managed? |
A0017 | Current Management of the Condition | What are the differences in the management for different stages of disease, if any? | no | Merged with A0015 |
A0018 | Current Management of the Condition | What are the other evidence-based alternatives to the current technology, if any? | no | Question too broad |
A0020 | Regulatory Status | Which approval status has the technology in other countries, or international authorities? | yes | Which approval status has Genetic Test in other countries, or international authorities? |
A0021 | Regulatory Status | Has the technology been included in / excluded from the benefit basket of any country? How is the coverage of the technology across countries? (e.g. full-coverage, co-payments, coverage under special circumstances/conditional coverage?) | no | More relevant to other domains and can be merged with A0011 |
A0019 | Life-Cycle | In which phase is the development of the technology (experimental, emerging, routine use, obsolete)? | no | More relevant to technical characteristics domain |
A0022 | Other | Who manufactures the technology? | no | Merged into A0009 |
The information for this domain comes from a variety of sources including national guidelines, health technology assessment (HTA) reports, a basic literature search, manufacturers’ websites, research charity websites, government agency websites, international reports and surveys sent to manufacturers, clinicians and European healthcare agencies {Appendix COL-1, COL-2 and COL-3}. No systematic review or quality assessment of the information was conducted for this domain.
The information used for this section was from other HTAs, evidence-based guidelines and the manufacturers’ websites.
Treatment of primary breast cancer usually involves surgery to remove the breast tumour and any involved lymph nodes, followed by adjuvant therapy to reduce the risk of breast cancer recurrence. Recurrence can occur when some cancer cells remain after surgery or when previously unidentified cancer cells have spread to areas around the breast or other areas of the body {1}.
Breast cancer does not recur in all cases and therefore, some patients may experience harmful side-effects of adjuvant therapy unnecessarily {2}. The uPA/PAI-1, MammaPrint and Oncotype DX tests are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient.
Specifically,
Importance: Critical
Transferability: Completely
The information used for this section was from other HTAs, a government agency website and cancer research charity websites.
The condition is breast cancer. ICD-10 code: C50
Stage of breast cancer
After breast cancer has been diagnosed, various tests are performed to find out if the cancer has spread and to determine the stage of the disease. The stage of the breast cancer can inform decisions on the most appropriate treatment and help predict the prognosis of the patient.
Two systems can be used to describe the stage of the breast cancer, the numerical system {6} and the TNM classification system {7}.
The numerical system describes the cancer stage based on four characteristics {8}:
Stage 0
Stage 0 is used to describe non-invasive breast cancers, such as ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). There is no evidence of cancer cells or pre-cancerous cells invading the surrounding healthy breast tissue.
Stage I
Stage I describes invasive breast cancer. There is evidence of cancer cells invading the surrounding healthy breast tissue. Stage I is divided into subcategories known as IA and IB:
Stage II
Stage II is also divided into two subcategories.
Stage III
Stage III is divided into three subcategories.
Cancer that has spread to the skin of the breast is inflammatory breast cancer and is considered at least stage IIIB.
Stage IIIC breast cancer is divided into operable and inoperable stage IIIC.
Stage IV
Stage IV is used to describe invasive breast cancer that has spread beyond the breast and nearby lymph nodes to other organs of the body, such as the lungs, distant lymph nodes, skin, bones, liver, or brain {6, 8}.
The TNM classification system describes the cancer stage based on three characteristics:
The T (size) category describes the primary tumour:
The higher the T number, the larger the tumour and the more it may have grown into the breast tissue.
The N (lymph node involvement) category describes whether or not the cancer has spread to the lymph nodes:
The higher the N number, the greater the extent of the lymph node involvement.
The M (metastasis) category describes whether or not the cancer has spread to other parts of the body:
Tumour grade
In addition to the stage of the cancer, another factor that is considered when making treatment decisions is the tumour grade.
The tumour grade describes the appearance of cancer cells when compared with healthy breast cells under the microscope.
Grade 1 (low grade)
Grade 1 is used to describe a tumour in which the cancer cells grow very slowly and appear similar to healthy breast cells.
Grade 2 (moderate or intermediate grade)
Grade 2 is used to describe a tumour in which the cancer cells appear abnormal and are faster growing
Grade 3 (high grade)
Grade 3 is used to describe a tumour in which the cancer cells grow rapidly and appear very different to healthy breast cells
High grade tumours are likely to be metastatic and are treated more aggressively than low grade tumours {11}.
Receptor status
The receptor status of the cancer will also be determined to inform decisions about the most appropriate treatment for the patient and the risk of breast cancer recurrence.
Some breast cancers have receptors for the hormones oestrogen and progesterone. Breast cancers that express high levels of the oestrogen receptor are considered oestrogen receptor-positive (ER+) and those that do not express the receptor are considered oestrogen receptor-negative (ER-). Generally, ER+ cancers are sensitive to treatment with hormone (endocrine) therapies.
Some breast cancers have receptors for the HER2 (human epidermal growth factor 2) protein. Those cancers expressing high levels of the HER2 receptor are considered HER2-positive (HER2+) and are sensitive to treatment with trastuzumab (Herceptin) {12}.
Importance: Important
Transferability: Completely
The information used for this section was from cancer research charity websites.
The known risk factors that affect the incidence of breast cancer include:
Age is the strongest risk factor for breast cancer (after gender): the older the woman, the higher the risk.
Women with a history of benign breast disease and women who have received treatment with radiation therapy to the breast or chest can have an increased risk of breast cancer. Women with a previous diagnosis of breast cancer have an increased risk of developing a second primary breast tumour.
Breast cancer is higher among women whose close relatives have, or have previously had, breast cancer. Having a first-degree relative (mother or sister) with breast cancer approximately doubles a woman’s risk.
It is estimated that 5–10% of breast cancers are hereditary, resulting from gene mutations inherited from a parent. Inherited mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. Women with a mutation in either gene are at high risk of developing breast cancer in their lifetime, often at a younger age and in both breasts compared with women without a BRCA mutation.
{13, 14}
Importance: Important
Transferability: Completely
The information used for this section was from an evidence-based guideline and cancer research charity websites.
Cancer begins when a cell or a group of cells start to grow and divide uncontrollably. This abnormal cell growth can occur when there are mutations in genes that are involved in cell growth or cell repair. Genes are segments of genetic code that provide the basic instructions that influence a cell’s behaviour. In healthy cells, when there is a gene mutation the cell repairs the mutation or dies. In cancer, cell repair and cell death do not occur so, as the cancer cell divides, the gene mutation(s) are passed on to the cell progeny. Some mutated genes are inherited (e.g. BRCA gene) but most mutations occur when cells divide or are created by environmental factors such as cigarette smoke {2}.
The natural progression of breast cancer differs greatly between patients. The two main categories of early breast cancer are in situ disease and invasive cancer. Breast cancer that is in situ is typically confined to the lobules (milk-producing glands) or ducts (tubes that carry the milk from the lobule to the nipple) of the breast. However, breast cancer in situ can progress from non-invasive (in situ) to invasive breast cancer and spread from the ducts or lobules, invading the surrounding tissues in the breast or other parts of the body {15}.
The main ways in which breast cancer can spread are by local spread to nearby tissues, or by regional or distant spread through the circulatory system or through the lymphatic system. In order for cancer to spread, cancer cells must become detached from the main tumour and be carried in the lymph to the lymph nodes or travel in the circulating blood until they get stuck in a capillary and invade the nearby tissue. When cancer cells spread and start to grow elsewhere in the body, the tumours are known as secondary tumours.
Circulating cancer cells can go undetected until a tumour starts to form and this is one of the reasons cancer can recur after the initial treatment. Another reason for cancer recurring is if cancer cells remain after the primary tumour has been removed.
The degree to which cancer has spread determines the stage of the disease and subsequent treatment. Typically, the more extensive the spread of cancer in the body then the more aggressive the treatment and the worse the patient’s prognosis {16}.
Importance: Important
Transferability: Completely
The information used for this section was from a cancer research charity website.
The symptoms of breast cancer are:
{17, 18}
Importance: Optional
Transferability: Completely
The information for this section was from the basic literature search and health organisation websites.
Breast cancer is one of the most common causes of death from cancer in women.
The treatment of cancer can cause many side-effects including significant pain, persistent fatigue, osteoporosis and a reduction in fertility. Emotionally, a diagnosis of breast cancer and subsequent treatment can cause long-term anxiety, depression and isolation in both the individual and their relatives. Hair loss and changes to the body from a mastectomy for example, are associated with a social stigma and can significantly impact on quality of life and reduce self-esteem.
Lymphoedema is swelling caused by a build-up of lymph fluid in the tissues of the body. This can occur after breast cancer treatment because of damage to the lymphatic system as a result of lymph node surgery or radiotherapy. Lymphoedema does not affect all those who undergo lymph node surgery but in some people it can develop soon after treatment or years later. The most common symptom is swelling of the arm, hands and fingers on the side of the body that was operated on. Swelling can also affect the breast, chest and shoulder {19}.
Axillary (armpit) lymph node surgery results in complications for 80% of women. These can include limited mobility, arm oedema and numbness or sensory loss {20}.
Importance: Critical
Transferability: Completely
The information for this section was from an international cancer research agency website and an international organisation report.
Breast cancer is one of the most commonly occurring cancers with an estimated 1.38 million women diagnosed worldwide in 2008. This accounts for nearly a quarter of all cancers diagnosed in women {21}. One in nine women will acquire breast cancer at some point in her life and one in thirty will die from the disease {22}. In 2008, the highest estimated European age-standardised rates of incidence among women was in Belgium (145 cases per 100,000) and the lowest rates were in Greece (57 cases per 100,000). In men, the rates were less than 1 per 100,000. The highest rate of breast cancer is in women aged over 70 years. Globally, incidence rates in developed countries are four or five times higher than those in developing countries. The highest incidence of breast cancer is in northern Europe, northern America, Australia and New Zealand, and the lowest incidence of breast cancer is in South Central Asia and, middle and eastern Africa {21}.
Information about the number of women with specific subtypes of breast cancer is limited. However, it is estimated that 70% of breast cancers are ER+ and that one in five women with breast cancer will have tumours that are HER2+ {12}. The receptor status of a tumour can indicate the risk of breast cancer recurrence and inform the patient prognosis.
Importance: Critical
Transferability: Completely
The information for this section was from cancer research charity websites and an international organisation report.
In 2008, it was estimated that breast cancer was the cause of 139,000 deaths in Europe and 458,000 deaths worldwide. Globally, the range of mortality rates is less than the range of incidence rates because survival rates are higher in high-incidence regions (developed countries). The Organisation for Economic Co-operation and Development (OECD) reports 5-year breast cancer survival rates of over 80% in developed countries. The most important prognostic variable is the stage of the cancer at diagnosis. Survival rates are highest in women diagnosed with breast cancer at an early stage before it has spread {22, 23}.
Breast cancer is associated with high morbidity and the treatment of breast cancer can cause significant pain, osteoporosis, a reduction in fertility and long-term anxiety and depression, which can significantly impact on quality of life {19}.
Importance: Critical
Transferability: Completely
The information used for this section was from other HTAs, evidence-based guidelines and the manufacturers’ websites.
Treatment of primary breast cancer usually involves surgery to remove the breast tumour and any involved lymph nodes, followed by adjuvant therapy to reduce the risk of breast cancer recurrence. Recurrence can occur when some cancer cells remain after surgery or when previously unidentified cancer cells have spread to areas around the breast or to other areas of the body {1}.
Breast cancer does not recur in all cases and, therefore, some patients may experience harmful side-effects of chemotherapy unnecessarily {2}. The uPA/PAI-1, MammaPrint and Oncotype DX tests are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient. Therefore, the use of these tests may reduce the number of women receiving chemotherapy and experiencing the associated side-effects unnecessarily, or increase survival rates by helping to identify patients who are at high risk of recurrence and, therefore, may need to receive more aggressive adjuvant therapy {3,4,5}.
Importance: Critical
Transferability: Completely
The information used for this section was from guidelines, manufacturer’s websites and, surveys or questions sent to European healthcare agencies, clinicians and manufacturers.
According to the manufacturer, MammaPrint is currently marketed in all European countries and the test is most widely used in Spain, the Netherlands and Italy {Appendix COL-1}. Results from the survey of healthcare agencies suggest the test is also used in Germany, Slovenia and the UK {Appendix COL-3}.
Results from the manufacturer survey reported that the FEMTELLE uPA/PAI-1test is marketed in Germany, Spain, Slovenia, France and Italy and is most widely used in France and Germany. It is estimated that 7000 patients in Germany and 2000 patients in France are routinely tested each year {Appendix COL-1}. Results from the survey of healthcare agencies reported that the FEMTELLE uPA/PAI-1test is used in Germany and Slovenia and not used in Latvia, Norway, Spain and the UK {Appendix COL-3}.
Results from the manufacturer survey reported that the Oncotype DX test is marketed in Germany, UK, France, Spain, Greece, Hungary and Ireland. The test is most widely used in UK, Germany, Spain and Ireland {Appendix COL-1}. Results from the survey of healthcare agencies reported that the Oncotype DX test is used in Germany, Ireland, Italy, Slovenia, Spain and the UK {Appendix COL-3}.
The survey from clinicians suggested that all three tests are in use in Europe and that Oncotype DX is the most widely used. However, only seven clinicians responded to the survey and this low response rate may be at least in part due to the low use of the tests in European countries {Appendix COL-2}.
The Oncotype DX assay is included in three clinical guidelines from the National Comprehensive Cancer Network (NCCN) {24}, the American Society of Clinical Oncology (ASCO) {25}, and the St Gallen Consensus guidelines {26}. All three guidelines have included the Oncotype DX assay as a test to predict the patient benefit from chemotherapy.
The FEMTELLE uPA/PAI-1 test has been recommended in clinical guidelines from the ASCO {25}, the German Working Group of Gynecological Oncology (AGO) {27} and the German Breast Cancer Society for therapy decisions in node-negative breast cancer {28}. The National Academy of Clinical Biochemistry laboratory medicine practice guidelines include the FEMTELLE uPA/PAI-1 test for use of tumour markers in breast cancer {29}.
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend for or against the use of tumour gene expression profiles (Oncotype DX and MammaPrint). It considered that until more evidence was available the use of these prognostic tests should be decided by the clinician on a case by case basis {30}.
From the evidence and surveys it is unclear how much the prognostic tests are being used in Europe. It is likely that the low survey response rate is likely at least in part due to the low use of the tests in Europe although the recommendations for the use of MammaPrint in clinical guidelines in Germany suggest that the uptake of the MammaPrint test in Germany may be higher than the evidence and surveys indicate. The use of the Oncotype DX and MammaPrint prognostic tests is recommended in a number of clinical guidelines in the USA and, therefore, it is likely that the use of these prognostic tests is higher in the USA than in Europe.
Importance: Important
Transferability: Partially
The information used for this section was from the responses received from the multiple choice survey that was sent to European healthcare agencies.
Information received from European healthcare agencies reported current clinical practice for assessing the risk of breast cancer recurrence. Ten healthcare agencies responded and described the type of information that is used:
{Appendix COL-3}
Importance: Critical
Transferability: Partially
The information used for this section was from evidence-based guidelines.
In the UK, histological examination of the breast tumour and lymph nodes following surgery provides prognostic information such as tumour grade, tumour size and nodal status. The receptor status of the tumour is also considered to predict response to specific targeted therapies. These prognostic factors, together with patient characteristics, are considered by a breast cancer multidisciplinary team when planning the treatment strategy and determining the likelihood of breast cancer recurrence.
A number of tools are used to assess prognosis and aid decisions on treatment planning. The two algorithms used in the UK are the Nottingham Prognostic Index (NPI) and Adjuvant! Online.
The NPI is used to predict survival following surgery for breast cancer. The NPI value is calculated using the size and grade of the tumour or lesion and the number of involved lymph nodes. An NPI score of greater than 5.4 indicates a poor prognosis and an NPI value less than 2.4 indicates an excellent prognosis.
The Adjuvant! Online software is designed to provide estimates of the risk of recurrence and the benefits of systemic adjuvant therapy. The estimates are based on individual patient characteristics and histological data on the tumour and lymph nodes. The software provides an estimate of the baseline risk of mortality or recurrence for patients if they do not receive adjuvant therapy {1}.
The American Society of Clinical Oncology recommends that the receptor status (e.g. HER2, ER) of the tumour, and the FEMTELLE uPA/PAI-1 and Oncotype DX tests are used to detect tumour markers and predict the risk of recurrence of breast cancer {25}.
The St. Gallen 2011 recommendations also included the receptor status of the tumour for indicating prognosis, and identified the Oncotype DX assay as potentially useful for predicting the need for adjuvant therapy in cases where other factors such as the receptor status do not help {26}.
Importance: Critical
Transferability: Partially
The information used for this section was from evidence-based guidelines and other HTAs. The responses from surveys sent to clinicians and healthcare agencies were also reviewed.
Usually, the first treatment option for invasive breast cancer is surgery to remove the tumour or breast and any involved lymph nodes. Following surgery, histological examination of the tissues removed during surgery provides prognostic information including tumour grade, nodal status and tumour size. Receptor status (e.g. ER, HER2) is also determined to predict the response to specific targeted therapies. Patient characteristics and these prognostic and predictive factors are considered by a breast cancer multidisciplinary team to assess the risk of breast cancer recurrence and determine a plan of treatment.
Most patients with early breast cancer will require treatment that involves adjuvant therapy in addition to surgery. Adjuvant therapy typically consists of radiotherapy (typically for individuals with large tumours or many involved lymph nodes), chemotherapy (for individuals at high risk of poor outcome) or endocrine therapy (for individuals with tumours that are ER+) and many patients will require a combination of these. The purpose of adjuvant systemic therapy is to reduce the risk of breast cancer recurring because circulating cancer cells (occult metastatic disease) can often go undetected at the time of diagnosis and, therefore, breast cancer can recur at a later date. Planning adjuvant therapy is complex and mostly dependent on clinical decisions, the risk of recurrence, patient choice, the availability of drugs or therapies, and the licensed indications and side-effect profiles of individual drugs or therapies {1, 2}. The availability of different drugs and therapies may vary between countries and local healthcare authorities.
One of the challenges associated with the management of breast cancer is the decision about whether or not to use adjuvant chemotherapy. The likelihood of breast cancer recurrence and death is less for individuals who receive adjuvant chemotherapy so many individuals with early-stage breast cancer are advised to undergo chemotherapy. However, chemotherapy can have severe adverse effects and not all individuals will benefit from receiving it. Some, especially those with small tumours, may remain free of breast cancer recurrence at 10 years without chemotherapy.
There are a number of algorithms and decision making tools to help clinicians assess the risk of breast cancer recurrence {2}. The prognostic tests, uPA/PAI-1 [FEMTELLE], MammaPrint and Oncotype DX are used in some countries to detect known predictive genetic or protein markers to help clinicians predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient.
The responses from the surveys did not indicate that the current management of breast cancer is different to published guidelines although the surveys were primarily focussed on the use of the prognostic tests not on the management of breast cancer.
Importance: Important
Transferability: Partially
The information used for this section was from evidence-based guidelines.
There was no evidence to suggest that current management described in CUR14 (and below) differed from the published guidelines.
Usually, the first treatment option for invasive breast cancer is surgery to remove the tumour or breast and any involved lymph nodes. Following surgery, histological examination of the tissues removed during surgery provides prognostic information including tumour grade, nodal status and tumour size. Receptor status (e.g. ER, HER2) is also determined to predict the response to specific targeted therapies. Patient characteristics and these prognostic and predictive factors are considered by a breast cancer multidisciplinary team to assess the risk of breast cancer recurrence and determine a plan of treatment.
Most patients with early breast cancer will require treatment that involves adjuvant therapy in addition to surgery. Adjuvant therapy typically consists of radiotherapy (typically for individuals with large tumours or many involved lymph nodes), chemotherapy (for individuals at high risk of poor outcome) or endocrine therapy (for individuals with tumours that are ER+) and many patients will require a combination of these. The purpose of adjuvant systemic therapy is to reduce the risk of breast cancer recurring because circulating cancer cells (occult metastatic disease) can often go undetected at the time of diagnosis and therefore, breast cancer can recur at a later date. Planning adjuvant therapy is complex and mostly dependent on clinical decisions, the risk of recurrence, patient choice, the availability of drugs or therapies and, the licensed indications and side-effect profiles of individual drugs or therapies {1, 2}. The availability of different drugs and therapies may vary between countries and local healthcare authorities.
One of the challenges associated with the management of breast cancer is the decision about whether or not to use adjuvant chemotherapy. The likelihood of breast cancer recurrence and death is less for individuals who receive adjuvant chemotherapy so many individuals with early-stage breast cancer are advised to undergo chemotherapy. However, chemotherapy can have severe adverse effects and not all individuals will benefit from receiving it. Some, especially those with small tumours, may remain free of breast cancer recurrence at 10 years without chemotherapy.
There are a number of algorithms and decision making tools to help clinicians assess the risk of breast cancer recurrence {2}. The prognostic tests, FEMTELLE (uPA/PAI-1), MammaPrint and Oncotype DX are used in some countries to detect known predictive genetic or protein markers to help clinicians predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient.
Importance: Critical
Transferability: Partially
The information used for this section was from the manufacturer’s websites and web-based searches.
The FEMTELLE test is manufactured by American Diagnostica Inc. (member of Sekisui Group) and has received the CE mark for use in Europe {3}.
MammaPrint is manufactured by Agendia and has received the CE mark for use in Europe. It is also approved for use by the US Food and Drug Administration (FDA) {4}.
The Oncotype DX assay is manufactured by Genomic Health and has received the CE mark for use in Europe. The assay is offered as a laboratory developed test and therefore, does not require FDA approval at this time {5}.
Please refer to the TEC domain for further details.
Importance: Important
Transferability: Completely
The objective of this domain was to describe breast cancer and provide information on the current use of the prognostic tests. Information on breast cancer as a condition is widely available and completely transferable for national HTA production, although there was no formal quality assessment of most of the information. HTA reports and national guidelines were critical in providing information on the current diagnosis and management of breast cancer although the information was highly context dependent and may vary depending on the country. It was difficult to find information on the use of the prognostic tests and it is likely that this is due to the low use of the tests in Europe. The survey responses from manufacturers, clinicians and healthcare agencies were very useful in broadly indicating where and how much the tests were used, and national guidelines were also useful in identifying where the tests were used. It is likely that information on the use of prognostic tests, particularly those new to market, will be difficult to find in future assessments because specific diagnostic or prognostic tests are rarely described in national guidelines and the use of such tests is rarely recorded and made available at a national or international level. Manufacturers often have data on the number of sales in different locations but frequently, this data is commercially confidential.
Authors: Pseudo169 Pseudo169, Pseudo90 Pseudo90, Pseudo154 Pseudo154, Pseudo98 Pseudo98
The three tests described in this domain (uPA/PAI-1 [FEMTELLE®], MammaPrint®, and Oncotype DX®) are actually testing services and not in vitro diagnostic (IVD) devices that can be purchased and performed everywhere. According to the manufacturer, FEMTELLE can be performed at any properly equipped laboratory, but to guarantee a given quality standard, the test should be done at “recommended laboratories” that perform the test for third parties. For all three products, results are available within 3-10 days of the sample being sent to the laboratory. The intended use of FEMTELLE, MammaPrint, and Oncotype DX is prognostic (likelihood of breast cancer recurrence) and the results should be considered together with all the other clinical and pathological factors. FEMTELLE, MammaPrint, and Oncotype DX are available in both Europe and the USA (performing laboratories for FEMTELLE are EU based; for MammaPrint there are two laboratories, one for the EU and one for the USA; the only Oncotype DX laboratory is in the USA). No special requirements are needed to use the testing service: the samples need to be processed using common and established techniques (the samples need to be formalin fixed and paraffin embedded (FFPE) or unfixed fresh frozen). Results from FEMTELLE and MammaPrint serve to stratify patients into two risk groups (high risk, low risk); results from Oncotype DX allow stratification into three risk groups (high, intermediate, and low risk). However, while cut-off values are established for all the three tests, risk values are clearly defined just for MammaPrint and Oncotype DX, while for FEMTELLE the clear definition of the risk of recurrence within a timeframe is not available.
Given its high impact on the healthcare service, the management of breast cancer is a relevant issue for all EU counties. Three tests are evaluated in this assessment. Two are based on gene expression profiling: MammaPrint® (Agendia) and Oncotype DX® (Genomic Health); one is based on immunostaining techniques (i.e. enzyme-linked immunoassay [ELISA]), FEMTELLE® (American Diagnostica). Other commercial ELISA kits for separate in-house analysis of uPA (urokinase plasminogen activator) and/or PAI-1 (plasminogen activator inhibitor 1) are available from different suppliers (these also use samples other than tissue and are also used for indications other than cancer) {1}. As processes may differ from one laboratory to another, in the present domain the FEMTELLE test is the only one described.
The three tests evaluated (FEMTELLE/MammaPrint/Oncotype DX) measure multiple markers within the tumour that may indicate how the tumour is likely to develop. Their clinical utility relates to their ability to discriminate between patients who will benefit to a greater or lesser extent from a therapeutic intervention. The assessment of this kind of technology could be of interest for all the EU member states. The purpose of this domain is to describe and review the technical characteristics of the assessed products.
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
B0001 | Features of the technology | What is this technology? | yes | What is the FEMTELLE® uPA/PAI-1 ELISA test? What is the MammaPrint® test? What is the Oncotype DX™ test? |
B0002 | Features of the technology | Why is this technology used? | yes | Why FEMTELLE®, MammaPrint®, and Oncotype DX™ are used? |
B0003 | Features of the technology | Phase of the technology: When was it developed or introduced in health care? | yes | When FEMTELLE®, MammaPrint®, and Oncotype DX™ were developed or introduced in health care? |
B0004 | Features of the technology | Who will apply this technology? | yes | Who will apply the FEMTELLE®, MammaPrint®, and Oncotype DX™ test? |
B0005 | Features of the technology | What is the place and context for utilising the technology | yes | What is the place and context for utilising FEMTELLE®, MammaPrint®, and Oncotype DX™? |
B0017 | Features of the technology | Is the technology rapidly changing / improving? | yes | Is the technology rapidly changing / improving? |
B0018 | Features of the technology | Are the reference values or cut-off points clearly established? | yes | Are the reference values or cut-off points clearly established? |
B0006 | Features of the technology | Are there any special features relevant to this technology? | no | This AE has been marked as IRRELEVANT. The technology is additive to the standard pathway for the treatment definition. No predecessors are defined. |
B0016 | Features of the technology | Who are the persons this technology will be used on? | no | Not applicable. Moved to CUR (A0001). |
B0007 | Investments and tools required to use the technology | What material investments are needed to use the technology? | yes | What material investments are needed to use FEMTELLE®, MammaPrint®, and Oncotype DX™? |
B0008 | Investments and tools required to use the technology | What kind of special premises are needed to use the technology? | no | This AE has been marked as IRRELEVANT. We have been not able to identify any special premise needed for use the tests. No purpose-built premises within organizations are required. However, the three tests assessed must be performed exclusively by the manufacturer’ labs (MammaPrint®) or by the labs indicated by the manufacturer (FEMTELLE® and Oncotype DX™). |
B0009 | Investments and tools required to use the technology | What equipment and supplies are needed to use the technology? | no | This AE has been integrated in B0007 (see B0007). |
B0010 | Investments and tools required to use the technology | What kind of data and records are needed to monitor the use the technology? | no | We believe that B0010 and B0011 are related to domain G (Organisational aspects). |
B0011 | Investments and tools required to use the technology | What kind of registers is needed to monitor the use the technology? | no | |
B0012 | Training and information needed for utilizing the technology | What kind of qualification, training and quality assurance are needed for the use or maintenance of the technology? | yes | What kind of qualification, training and quality assurance are needed for the use of FEMTELLE®, MammaPrint®, and Oncotype DX™? |
B0014 | Training and information needed for utilizing the technology | What kind of training and information are needed for the patients receiving or using this technology & their families? | yes | What kind of information is needed for the patients receiving FEMTELLE®, MammaPrint®, and Oncotype DX™ and their families? |
B0015 | Training and information needed for utilizing the technology | What information do patients outside the target group and the general public need on the technology? | yes | What information do patients outside the target group and the general public need on the use of FEMTELLE®, MammaPrint®, and Oncotype DX™? |
B0020 | Training and information needed for utilizing the technology | How does training and quality assurance affect the management or effectiveness? | yes | How does training and quality assurance affect the management or effectiveness? |
No systematic reviews were carried out within this domain. Information was retrieved from previously published health technology assessment (HTA) reports, consensus statements, introduction sections of guidelines, reviews and original articles. We used results from the basic search (run for the whole project and described in the Appendix “Common search strategy” {Appendix COL-1}) and performed additional, specific searches on the web to develop particular assessment elements. Technical details were obtained from the relevant manufacturers’ websites. If unavailable, details were sought directly from the manufacturers using a structured survey. More information is available in the Appendix “Survey across manufacturers” {Appendix COL-2}.
– Manufacturers’ websites;
– Company brochures and data sheets;
– Guidelines;
– HTA reports;
– Regulatory authorities’ websites;
– Governmental institutions’ websites;
– Structured survey across manufacturers.
Not applicable.
Not applicable.
The manufacturer’s website and direct questions to the manufacturer were used to develop this assessment element.
FEMTELLE is a test (classified as an in vitro diagnostic device [IVD]) manufactured by American Diagnostica Inc. (Sekisui Diagnostics LLC from April 2012). It is a prognostic test for primary breast cancer that allows a quantitative determination of the two prognostic factors uPA and its inhibitor PAI-1 in tumour tissue by ELISA technology. The test helps to determine the risk of disease recurrence and to predict the likely benefit from chemotherapy in breast cancer patients. The breast cancer tumour tissue is surgically removed. The specimen is transported fresh (unfixed) to the pathologist who proceeds with the removal of a representative piece of tumour tissue (> 50 mg). The uPA and PAI-1 are extracted and the FEMTELLE test performed by ELISA {2}. If the patient samples need to be shipped to another clinical centre or diagnostic laboratory (Institute of Pathology, laboratories at breast cancer centres or private diagnostic laboratories – decentralised testing) for testing, the frozen samples must be shipped on dry ice. The results are communicated within 3–4 days after receiving the sample. The patient samples have to be kept frozen (-20°C or colder) until test performance. Before shipping of the samples, they can be stored (-20°C or colder) for up to 3 weeks {Appendix COL-2}. More information on FEMTELLE is available in the Appendix “Characteristics of the tests assessed” {TEC-1}.
Importance: Critical
Transferability: Completely
The manufacturer’s website and direct questions to the manufacturer were used to develop this assessment element.
MammaPrint is a qualitative in vitro diagnostic test service that was commercially developed by Agendia BV. MammaPrint is not a commercially available IVD device; it is a testing service provided at the manufacturer’s laboratories. MammaPrint uses the gene expression profile of fresh/fresh frozen or FFPE breast cancer tissue samples to assess a patient’s risk of distant metastasis. The MammaPrint result is indicated for use by physicians as a prognostic marker only, along with all the other clinicopathological factors {Appendix COL-2}. The analysis is based on several sequential processes: isolation of RNA from FFPE tumour tissue sections, DNase treatment of isolated RNA, linear amplification and labelling of DNase-treated RNA, cRNA purification, hybridisation of the cRNA to the MammaPrint microarray, scanning the MammaPrint microarray and data acquisition (feature extraction), calculation and determination of the risk of recurrence in breast cancer patients. The MammaPrint analysis is designed to determine the gene activity of specific genes in a tissue sample compared with a reference standard. The result is an expression profile, or fingerprint, of the sample. The correlation of the sample expression profile with a template (the mean expression profile of 44 tumours with known good clinical outcome) is calculated and the molecular profile of the sample is determined (low risk, high risk) {Appendix COL-2}. The specimen (FFPE tissue taken from a surgical specimen) has to be shipped according to a specific protocol provided by the manufacturer. Once the specimen arrives at the manufacturer’s laboratory, results will be available within 10 working days (by email, fax, hard copy and/or secure intranet account) to the requesting physician {3}. FFPE samples can be sent at room temperature (the manufacturer receives the sample the day after shipment) {Appendix COL-2}. More information on MammaPrint is available in the Appendix “Characteristics of the tests assessed” {TEC-1}.
Importance: Critical
Transferability: Completely
The manufacturer’s website was used to develop this assessment element.
Oncotype DX Breast Cancer Test (Oncotype DX) is multi-gene diagnostic assay that predicts the likelihood of benefit from adjuvant chemotherapy in a subset of breast cancer patients. This is not a commercially available IVD device; it is a testing service provided at the manufacturer’s laboratory {Appendix COL-2}. Oncotype DX quantifies gene expression for 21 genes (16 cancer-related genes and 5 reference genes) in breast cancer tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). First, RNA is extracted from the breast cancer tumour specimen and purified. The RNA is then analysed by real-time RT-PCR. Finally, the recurrence score (RS, corresponding to a point estimate of the 10-year risk of distant recurrence with a 95% CI for an individual patient) is calculated from the gene expression results {4} {5}. To quantify gene expression, RNA is extracted from FFPE tumour tissue and subjected to DNase I treatment. Total RNA content is measured and the absence of DNA contamination is verified. Reverse transcription is performed and is followed by quantitative TaqMan (Roche Molecular Systems, Inc.) RT-PCR reactions in 384-well plates. The expression of each of 16 cancer genes is measured in triplicate and then normalised relative to a set of 5 reference genes {4}. The specimen (tissue block or slides) has to be shipped according to a specific protocol provided by the manufacturer. Once the specimen arrives at the manufacturer’s laboratory, typical processing time for the test to be completed is 7–10 days. The result is sent (by secure intranet account or fax) to the requesting physician {6}. Shipping of the sample is organised via FedEx in priority and takes a maximum of 3 days {Appendix COL-2}. More information on Oncotype DX is available in the Appendix “Characteristics of the tests assessed” {TEC-1}.
Importance: Critical
Transferability: Completely
The manufacturers’ websites as well as the results from the basic search were used to develop this assessment element.
The intended use of the three tests (FEMTELLE, MammaPrint, and Oncotype DX) is prognostic (likelihood of breast cancer recurrence) and the results need to be considered together with all the other clinical and pathological factors.
FEMTELLE assesses the likelihood of breast cancer recurrence in women with newly diagnosed, lymph node-negative (LN-) breast cancer. FEMTELLE quantitatively determines the uPA and PAI-1 levels in tumour tissue extracts, allowing the identification of patients with a high (uPA and/or PAI-1 high) or low (uPA and PAI-1 low) risk of recurrence {7}. The timeframe within which such risk recurrence applies is not clearly stated.
MammaPrint has different indications for Europe and the USA:
Oncotype DX is intended to predict the likelihood of recurrence in women of all ages with newly diagnosed Stage I or II, ER+LN- breast cancer treated with tamoxifen {8}. The test assigns the breast cancer a recurrence score. The test also looks at the expression of hormone receptor genes, both the ER and progesterone receptor (PR), and can provide an indication of how responsive the cancer is likely to be to hormonal therapy {8}.
Importance: Critical
Transferability: Completely
The manufacturers’ websites, the results from the basic search and regulatory authorities’ websites were used to develop this assessment element. Information obtained by free internet searches and snowballing references from relevant documents were integrated.
FEMTELLE received the CE mark in 2004 {10} and currently awaits FDA licensing {11}. FEMTELLE is not registered in the FDA database {12}.
MammaPrint received the CE mark in November 2005. The company voluntarily submitted MammaPrint to the US Food and Drug Administration for approval under proposed new guidelines for such tests: approval was granted in February 2007 {9}. MammaPrint is registered in the FDA database {12}.
Oncotype DX collection kit received the CE mark in 2007 (October) {13}. Oncotype DX has not received FDA approval {14} but the laboratory that performs the Oncotype DX test has been certified by the Clinical Laboratory Improvement Amendments (CLIA) to perform the test for clinical use {15}.
Importance: Critical
Transferability: Completely
The manufacturers’ websites and direct questions to the manufacturer were used to develop this assessment element.
The FEMTELLE uPA/PAI-1 test can be performed at any laboratory that has access to a tissue homogeniser, ELISA reader and cooled centrifuge (16,000 g) {Appendix COL-2}. Detailed information about the FEMTELLE test and technical procedure can be obtained by contacting the manufacturer directly {16}. Alternatively, the sample can be shipped to any laboratory qualified to perform ELISA testing. However, the manufacturer has indicated a list of “recommended laboratories” (based in France and Germany) that have experience in performing the test and that take part in regular quality assessment rounds {Appendix COL-2}. The list of “recommended laboratories” is available from the manufacturer.
The MammaPrint test is performed in the manufacturer’s two laboratories: in Irvine, California (USA) or in Amsterdam, The Netherlands (Europe). The specimen (fresh/fresh frozen or FFPE tissue from a surgical specimen) has to be shipped according to a specific protocol provided by the manufacturer {3}.
The Oncotype DX test is performed in the manufacturer’s laboratories in California (USA) after the specimen (FFPE tissue block or slides) has been shipped according to a specific protocol provided by the manufacturer {6}.
Importance: Critical
Transferability: Completely
The manufacturer’s website and direct questions to manufacturers were used to develop this assessment element.
The three tests (FEMTELLE, MammaPrint, and Oncotype DX) are add-on tests (not replacing any existing tests) to provide additional information in the tertiary care setting (i.e. specialised consultative healthcare facilities). The tissue samples are collected during breast cancer surgery. The information provided by the tests will be used by the multidisciplinary cancer team to supplement the other clinical and pathological information to determine whether or not the patient should receive adjuvant therapy.
Importance: Critical
Transferability: Completely
Free internet searches were used to develop this assessment element.
The technology itself is not characterised by a fast rate of development; the working principles of the tests have been known for a number of years and no breakthroughs are anticipated. However, given the research activities in the field of cancer genetics and genomics, it is likely that new applications of the same technology will be proposed in the future {19}.
Importance: Critical
Transferability: Completely
The manufacturers’ websites as well as the results from the basic search were used to develop this assessment element.
The results of the FEMTELLE uPA/PAI-1 assay are reported as absolute protein concentrations of uPA and PAI-1 in the patient’s tumour tissue. The uPA and PAI-1 values refer to the respective total protein concentrations {16}. The results help to identify those node-negative patients who have a low risk of disease recurrence and those patients who have a high risk of disease recurrence after surgery.
Cut off values are:
Patients with low uPA and low PAI-1 values (below the cut off) are predicted to have a low risk of disease recurrence. The risk value, intended as percentage of recurrence within a timeframe without further adjuvant therapy, is not stated. Patients with high uPA and/or high PAI-1 values (above the cut off) are predicted to have an increased risk of disease recurrence {20}. The risk value, intended as percentage of recurrence within a timeframe without further adjuvant therapy, is not stated.
The results of the MammaPrint test are used for risk-group assignment on the basis of a dichotomised value only (i.e., high or low risk). A tumour is defined as having a low-risk gene signature if the cosine correlation coefficient for the expression of the 70-gene profile in that tumour with the previously established classifier is above 0.4, which is the cut-off point used in the original study by van’t Veer {9} {21}. A “low risk” result means that a patient has a 10% chance that her cancer will recur within 10 years without additional adjuvant treatment, either hormonal therapy or chemotherapy. A “high risk” result means that a patient has a 29% chance that her cancer will recur within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy {9}.
The results of the Oncotype DX are used to calculate the 10-year risk of distant recurrence as a continuous function of the RS. Three risk groups have been defined: low risk (RS ≤17), intermediate risk (18 ≤RS ≤30), and high risk (RS ≥ 31) {9}.
Importance: Critical
Transferability: Completely
A previous result card (RC-TEC8) and direct questions to manufacturers were used to develop the present assessment element.
The three tests assessed either must be performed exclusively by the manufacturer’s laboratories (MammaPrint and Oncotype DX), or, in the case of FEMTELLE, are generally done by the laboratories indicated by the manufacturer, so no material investment, equipment or supplies are needed within the centres other than those required for specimen preparation. The equipment and supplies required for specimen preparation are commonly available in cancer centres and hospitals across the EU. The procedures for sample preparation are already established.
The FEMTELLE test can be also performed in any laboratory equipped with: a tissue homogeniser (e.g. dismembrator) to homogenise the tumour tissue, a cooled laboratory centrifuge (16,000 g), and an ELISA plate reader, and following the indication of the manufacturer. This equipment is available as routine laboratory equipment at many routine diagnostic laboratories {Appendix COL-2}. After a routine inspection of the excised tumour tissue, a representative piece of tissue must be removed by the pathologist from the unfixed tumour tissue. After freezing at -20 °C the tissue can be stored at -20 °C for up to 3 weeks. The frozen samples can be shipped on dry ice to any laboratory that performs the FEMTELLE test.
This assessment element has been integrated with TEC12 “What equipment and supplies are needed to use genetic tests for cancer?” The resulting assessment element is the following “What material investments, equipment, and supplies are needed to use FEMTELLE, MammaPrint, and Oncotype DX?”
Importance: Critical
Transferability: Completely
Direct questions to the manufacturers were used to develop this assessment element.
As the three tests are provided or recommended as testing services (to be performed exclusively by the manufacturer’s laboratories or, in the case of FEMTELLE, by other laboratories as recommended by the manufacturer) no special staff, training or other human resources are needed within the centres to perform the tests. Specimen preparation is the only key issue and needs to be performed by the pathologist, following specific instructions provided by the manufacturer. In particular, FEMTELLE requires fresh/fresh-frozen tumour tissue while MammaPrint can be performed using either fresh/fresh-frozen tumour samples or FFPE samples, and Oncotype DX functions with FFPE samples. For this reason, qualification, training and quality assurance related to the sample preparation strongly depend on the specific local context and on familiarity with the various sample preparation techniques.
Laboratories that want to establish FEMTELLE testing at their site need specific training. For this purpose the technicians involved receive detailed technical training at selected laboratories. The training is usually planned for 3 days. Participants are trained on the whole technical procedure (tissue homogenisation, protein extraction, ELISA testing, total protein determination and calculation of the results). American Diagnostica usually supports the new attendees {Appendix COL-2}.
For Oncotype DX only the manufacturer (Genomic Health) has established guidelines on how to select slides (to ensure that the slide contains sufficient tumour material and that the diagnosis is correct). No further training is needed for a local pathologist. At Genomic Health, all slides are reviewed by board-certified pathologists to ensure the correct diagnosis and if necessary they perform micro-dissection to select material for analysis {Appendix COL-2}.
Importance: Critical
Transferability: Completely
Other domains results (ORG, SOC, ETH, LEG) were used to develop the present assessment element.
The three tests (FEMTELLE, MammaPrint, and Oncotype DX) are being used in women who have already been diagnosed as having breast cancer to determine their risk of recurrence and to determine whether they can avoid potentially unnecessary additional adjuvant therapy or receive potentially beneficial treatment. Clinicians should advise patients on the availability of tests within their own territory. As stated in RC-ORG3, different studies using patient interviews and questionnaires have shown that, given the level of knowledge on prognostic tests for cancer recurrence, there is room for improvement in the patient information {17}. Healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing, and should discuss with patients whether the test results are likely to change their decision about therapy {18}. It may also be worthwhile to consider informed patient consent, since the decision to test usually rests with clinicians (see RC-ORG7). See also SOC domain (RC-SOC5) and LEG domain (RC-LEG1) for more details about information activities for patients.
Importance: Critical
Transferability: Partially
A previous results card (RC-TEC14) was used to develop the present assessment element.
No additional information is required for patients or individuals outside the target group concerning indications/contraindications, the procedure, and role of test in the diagnostic/therapeutic pathway. In the case of the test results, confidentiality is a major concern; no other people apart from the patient need to be informed about them.
Importance: Critical
Transferability: Completely
Other domain results (ORG) were used to develop the present assessment element.
Training in sample collection and preparation is very important to avoid sample failure and to achieve an appropriate balance so that there are enough tumour cells but not too much stromal tissue; this may affect the effectiveness of the tests as well as the management of the patient because if the specimens are of poor quality the biopsy and the test may need to be repeated (see RC-ORG2 for more details).
Importance: Critical
Transferability: Completely
The purpose of this domain is to describe and review the technical characteristics of the assessed prognostic tests (FEMTELLE, MammaPrint, and Oncotype DX). As information available from published literature or manufacturers’ websites was often generic, collaboration with manufacturers has been crucial. A structured survey across the manufacturers was necessary to obtain clarification about information that was not available. This phase was a burden on the whole assessment process and made the technology description time-consuming. Central medical devices databases, including data on IVD tests, managed at the European level could be useful to overcome this problem.
Table 1: Characteristics of the prognostic tests assessed {9} {Appendix COL-2}.
FEMTELLE |
MammaPrint |
Oncotype DX | |
Manufacturer |
American Diagnostica GmbH |
Agendia BV |
Genomic Health, Inc. |
Tumour sample |
Unfixed fresh/fresh frozen |
Fresh/fresh frozen tumour sample or FFPE tissue |
FFPE tissue |
Assay technique |
ELISA |
Two colour microarray |
Real time RT-PCR |
Target population |
Newly diagnosed breast cancer patients; Especially node-negative patients classified as an intermediate risk (G2 differentiation) benefit from the test results. |
i) Stage I, ER+ or ER-, < 61 years ii) Stage II, ER+ or ER-, LN-, < 61 years |
i) Stage I, ER+ patients who will be treated with tamoxifen ii) Stage II, ER+, LN0 negative patients who will be treated with tamoxifen |
Indicators assessed |
uPA and PAI-1 |
70 genes |
16 genes |
Indications |
Women with newly diagnosed, lymph node negative (LN0) breast cancer |
In Europe: - women of all ages, LN- and LN+ (up to 3 nodes positive) with a tumour size of ≤5.0 cm or less; In the USA: - women ≤61 years with primary invasive ER+, or ER-negative (ER-) LN0 breast cancer. |
Women of all ages with newly diagnosed Stage I or II, ER-positive (ER+) lymph node negative (LN0) breast cancer treated with tamoxifen |
Key: FFPE = Formalin-Fixed Paraffin-Embedded tissue; ELISA = Enzyme-linked immunosorbent assay; RT-PCR = Reverse transcriptase-polymerase chain reaction; ER = oestrogen receptor; yo = years old; LN0 = Lymph nodes uninvolved; uPA = Urokinase-type plasminogen activator; PAI-1 = Plasminogen activator Inhibitor.
Authors: Iris Pasternack, Emilio Chiarolla, Narine Sahakyan, Leonor Varela
The three tests under evaluation share general safety concerns of surgical pathology practice such as sample contamination, delays in transfer, incorrect labelling and other features which may affect the reliability of the result and thus patient safety. Formalin fixation is required for Oncotype DX® and optional for MammaPrint®, and this implies occupational and environment precautions. There is insufficient evidence of possible anxiety or other psychosocial harms to patients caused by the tests.
The safety of the prognostic tests for breast cancer, uPA/PAI-1 [FEMTELLE®], Oncotype DX® and MammaPrint®, covers the possible harms of the testing procedure itself, and the psychological effects and possible over- or under-treatment due to false positive or false negative test results, or incidental findings. Personnel and the environment may be affected by potentially harmful constituents and properties of the test itself or products consumed during the testing procedure.
Tissue samples for the three tests are taken during the surgery from the breast tissue removed, or sometimes from the diagnostic core biopsy. As the tests do not require a separate invasive tissue sampling procedure in addition to routine management, we did not consider the safety of biopsies and tissue sampling as part of this health technology assessment (HTA).
The objective of the three tests is not only to provide information on the prognosis of breast cancer but most importantly to guide the physician in treatment selection. Since the tests are part of the diagnostic and treatment pathway, we assumed that they are considered as necessary or unavoidable by patients, which means that they are likely to be considered more acceptable than genetic tests for predicting disease susceptibility.
Samples are analysed and test results determined in manufacturers’ laboratories or in laboratories recommended by the manufacturers. We do not intend to cover the occupational and environmental issues in those laboratories but to focus only on the safety of the hospitals’ surgical and pathological processes.
A modified collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description (modified from collection scope)Very likely we need to include evidence for eg psychological harms to gene tests for other cancers or even gene tests in general |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
C0001 | Patient safety | What kind of harms can use of the technology cause to the patient and what is the incidence, severity and duration of harms? | yes | What are the incidence, severity and duration of direct harms to the patient related to the testing and sampling with uPA/PAI-1, Oncotype DX, or MammaPrint®? What are the incidence, severity and duration of psychological harms to the patient related to the testing and with uPA/PAI-1, Oncotype DX, or MammaPrint®? |
C0002 | Patient safety | What is the dose relatedness of the harms to patients? | no | There is no dose relatedness |
C0003 | Patient safety | What is the timing of onset of harms to patients: immediate, early or late? | no | No obvious changes expected. |
C0004 | Patient safety | Is the incidence of the harms to patients likely to change over time? | no | Psychological consequencies could in principle change over time when awareness increases and processes evolve. The same could be with possible direct harms and accuracy related harms. |
C0005 | Patient safety | Are there susceptible patient groups that are more likely to be harmed through use of the technology? | no | No obvious risk groups for harms. |
C0006 | Patient safety | What are the consequences of false positive, false negative and incidental findings brought about using the technology to the patients from the viewpoint of patient safety? | no | The aim was to look at the prognostic value of the tests and not their effectiveness in the test-treatment intervention. |
C0007 | Patient safety | What are the special features in using (applying/interpreting/maintaining) the technology that may increase the risk of patient safety? | no | Unspecific question. |
C0008 | Patient safety | What is the safety of the technology in comparison to alternative technologies used for the same purpose? | no | These three index tests represent well enough all genetic tests for breast cancer. We don't assume there is fundamnetally different tests that have different safety profile. |
C0020 | Occupational safety | What kind of occupational harms may exist through using the technology? | yes | What kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint®? |
C0040 | Environmental safety | What kind of environmental risks may use of the technology cause? | yes | What kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint®? |
C0062 | Safety risk management | How can one reduce safety risks for patients (including technology-, user-, and patient-dependent aspects)? | yes | How can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint® (including technology-, user-, and patient-dependent aspects)? |
C0063 | Safety risk management | How can one reduce safety risks for professionals (including technology-, user-, and patient-dependent aspects)? | yes | How can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint® (including technology-, user-, and patient-dependent aspects)? |
C0060 | Safety risk management | How does the safety profile of the technology vary between different generations, versions or products? | no | The technologies are in their early developmental phase. |
C0061 | Safety risk management | Is there evidence that harms increase or decrease in different organizational settings? | no | However, there could be differences between specialized breast cancer care centers versus regular oncology hospitals |
C0064 | Safety risk management | How can one reduce safety risks for environment (including technology-, user-, and patient-dependent aspects)? | no | Largely same as occupational safety procedures. Will be handeled in C0063. |
Domain frame
In questions dealing with psychological harm we considered studies related to all similar testing situations in all cancers. In questions dealing with occupational harms related to formalin fixation we considered studies and guidance related to formalin fixation of histological samples in general.
Information sources
Out of the 616 references in the basic search we included 45 articles for full text reading by reading the title and abstract. We included reviews and studies which looked at change in management with the idea that they might provide information on safe patient selection and on the consequences of false positive/negative findings. We excluded all studies that were purely on prognostic value. After full text reading 12 articles from the basic search were included {SAF-1}.
Additional searches were made for occupational and environmental hazards and risk management. Their sources, search strategies and yields are described in the result cards of SAF1, SAF7, SAF8, SAF11 and SAF12.
Quality assessment tools or criteria
No established criteria were used.
Analysis and synthesis
Results are reported descriptively, with added qualitative synthesis. Study card templates proposed by the Core Model were used to collect data from some studies {SAF-2}.
In addition to the basic search, a search was done in PubMed by IP on 15 March 2012 using search string
A questionnaire was sent to the manufacturers asking
As there is no separate sampling needed for the three tests in this HTA, we did not evaluate the harms related to invasive sampling (surgery or core biopsy). Instead we looked at some general safety concerns of surgical tissue sample diagnostics, such as sample contamination, delays in transfer, incorrect labelling, and other features which may affect the reliability of the result and thus patient safety.
T = any surgical tissue analysis
I = NA
C = NA
O = errors and quality issues that affect safety
The tissue sample is cut up and prepared in the surgical theatre, moved to the further preparations gross room or the pathological laboratory, and finally sent to the manufacturer’s own laboratory or those recommended by the manufacturers for analysis. Several factors, both process dependent and operator dependent, contribute to error in this chain. The reported frequency of diagnostic errors in oncologic pathology depends on definitions and detection methods, and ranges from 1% to 15%. The large majority of diagnostic errors do not result in severe harm, although mild to moderate harm in the form of additional testing or diagnostic delays occurs in up to 50% of errors (1).
Pathology laboratories traditionally have considered two types of error: errors of accuracy and errors of precision of the test itself (2). Accuracy is the closeness of a measure to its true value, and precision is the degree to which repeated measures show the same results. But, there are additional process- and operator-dependent related errors that may affect patient safety, such as identification errors, specimen defects or contamination, and delays. In a study where surgical pathology amendment reports were analysed in a university hospital in the USA it was noticed that amendments (changes, corrections) were made to approximately five reports out of 1000. About one fifth of them were due to misidentifications (e.g. attribution of specimens to the wrong patient), one out of ten were due to specimen defects (e.g. lost or inadequate size of specimen), a quarter were due to misinterpretation (e.g. false negative), and almost half were due to reporting defects (e.g. dates, diagnostic codes) (3).
Misidentification
In summary, approximately 1/1000 patients and 2–4/1000 surgical pathology specimens end up being misidentified or having incorrect labels in the report.
Studies: Anecdotal evidence indicated that identification errors are frequent (4). Identification errors were studied in a prospective study including 136 laboratories from several countries (5). Of the 427 255 cases reviewed, 1811 had some type of mislabelling (0.4%). The entire case was mislabelled in 1.1/1000 (490) cases, 1/1000 specimens were mislabelled (796 specimens of 358 cases), 1.7/1000 blocks were mislabelled (2172 blocks in 461 cases) and 1/1000 slides were mislabelled (2509 slides in 502 cases). Misidentification of cases and specimens occurred most often at collection or at accessioning (i.e. when specimens are received, sorted, and entered in the laboratory). In 1751 out of the 1811 mislabelled cases (97%) the mislabelling was corrected without any additional consequences. In 59 cases (3%) a correction report was issued, and in 24 cases (1%) patient care was affected some way. Another retrospective study examined quality control records for an 18-month period and identified mislabelled surgical specimens. Out of 29 500 specimens 2.5/1000 were mislabelled (6). A prospective cohort study with 21 300 surgical specimens noted that 4.3/1000 specimens were incorrectly labelled. Reasons were, in order of frequency: not labelled at all, empty container, laterality incorrect, incorrect tissue site, incorrect patient, no patient name, and no tissue site (7). The majority of routine practices for identification and labelling probably underestimate the frequency of occurrence of errors, and many errors probably go undetected (4). Errors detected before patient harm or inconvenience has occurred are often called near misses.
Contamination
Significant and worrisome levels of contamination of non-primate genome assemblies with human DNA sequences have been noted (8).
Importance: Important
Transferability: Completely
Information has been published on psychological harms related to prognostic genetic tests that estimate the predisposition of healthy individuals to become cancer patients. But, as the three tests in this HTA are part of the cancer management pathway, and are diagnostic aids for physicians to select the best treatment, and the time lag from testing to treatment (adjuvant chemotherapy) is short, it is less likely that these tests have similarly significant psychological consequences for patients. We looked for evidence of psychological outcomes from the effectiveness studies of this report, and identified further studies from the basic search.
In the USA, 78 women who were tested with Oncotype DX and treated for early-stage breast cancer in one clinic between 2004and 2009 were sent a questionnaire assessing their knowledge of breast cancer their experiences of testing (9). Approximately 26% (17 of 65) of women agreed or strongly agreed that getting the Oncotype DX test result made them worried and anxious. Greater endorsement of test-related distress was associated with higher actual recurrence risk based on the test, as the majority of women who experienced test related distress had intermediate or high recurrence risks based on their test results (low = 18%, 6 of 33; intermediate = 30%, 7 of 23; high = 44%, 4 of 9). Stronger feelings of distress were also related to having chemotherapy, rather than radiation, and having more frequent worries about breast cancer recurrence.
The emotions of patients receiving MammaPrint were examined in the Netherlands (10). Patients who received a concordant high-risk result from both tests, i.e. clinical and gene tests, and patients who received a discordant low-risk result in clinical tests and a high-risk result from the gene test showed significantly more negative emotions than patients who received concordant low risk results from both tests or discordant high-risk results from clinical tests and a low-risk result from the gene test.
Importance: Important
Transferability: Partially
A search was done in PubMed by IP on 21 February 2012. Search strategy
The search yielded 35 articles {Appendix SAF-3}. The National Toxicology Program Final Report on Carcinogens 2010 was taken as the basis for carcinogenicity information. As there are sufficient EU sources for safety epidemiology and safety management, all guidelines prepared for non-European contexts were excluded.
Information was also retrieved from web pages of manufacturers, from the European Agency for Safety and Health at Work (EU-OSHA), the draft NICE report 2012, the European Commission Joint Research Centre’s European Chemical Substances Information System (ESIS), and the WHO International Programme on Chemical Safety (IPCS). As there is no free database for Material Safety Data Sheets (MSDS), the best way to find the data sheets is to Google for MSDS and formaldehyde.
T = all surgical tissue sample preparation methods using formalin
I = NA
C = NA
O = occupational risks
Preparation of the tissues samples for each of the three tests under review is different. Before sending the test kit to the manufacturers’ laboratories (or recommended laboratory) preparation of samples for Oncotype DX requires formalin fixation (11). In MammaPrint this is optional; as of January 2012, the manufacturer accepts formalin-fixed paraffin-embedded samples (12). In uPA/PAI-1 formalin fixation is not used.
Risks of formalin fixation
The concentrated water solution (37–40%) of formaldehyde (CAS registry number 50-00-0) is known as formalin (its German trade name). In laboratory practice, 10% and 4% formaldehyde water solutions are used. Formaldehyde evaporates easily from the formalin surface. Formaldehyde (HCHO, methanal) is a colourless gas, which has a short half-life in air due to its decomposition in light. Due to its high solubility in water formaldehyde is fast absorbed in the mucus of the upper respiratory tract, predominantly in the nasal cavity and sinuses, where it can damage the cilia (13). It does not reach the pharynx under non-extreme exposure. Formaldehyde exposure can occur locally, at the place of the initial contact (respiratory or digestive tract, skin etc) and generally, as a result of absorption (14).
Formaldehyde concentrations that have been associated with various toxic effects in humans show wide inter-individual variability and are route dependent. Symptoms are rare at concentrations below 0.5 ppm; however, upper airway and eye irritation, changes in odour threshold, and neurophysiological effects (e.g., insomnia, memory loss, mood alterations, nausea, fatigue) have been reported at concentrations ≤ 0.1 ppm. The odour threshold is 0.8–1 ppm. The most commonly reported effects include eye, nose, throat, and skin irritation. Other effects include allergic contact dermatitis, histopathological abnormalities (e.g., hyperplasia, squamous metaplasia, and mild dysplasia) of the nasal mucosa, occupational asthma, reduced lung function, altered immune response, and haemotoxicity (15).
Formalin has been used for decades and the amounts used in hospitals and laboratories are substantial. Concerns about carcinogenicity and other health hazards have changed its use in past years. Pre-filled containers are used for small biopsies that need to be opened only for a short time, just to remove the specimen, exhaust devices have been developed and formaldehyde exposure is monitored. It has been noted that hospital workers underestimate their levels of exposure to formaldehyde (16).
Carcinogenicity of formaldehyde
The International Agency for Research on Cancer (IARC) concluded in 2006 that there is sufficient evidence of the carcinogenicity of formaldehyde in humans, and placed formaldehyde in Group I—known carcinogens, along with asbestos and benzene (15). This was reinforced in the eleventh Report of Carcinogens based on limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in laboratory animals (13).
A large number of epidemiological studies have been conducted to evaluate the relationship between formaldehyde exposure and carcinogenicity in humans. There are cohort studies and nested case-control studies of health professionals, including physicians, pathologists and laboratory nurses. They generally report mortality or incidence of cancer for ever-exposed workers in analyses using standardised mortality ratios or proportionate mortality ratios. Some of the studies attempted indirect measures of exposure, such as length of professional membership as a proxy for exposure duration.
Cancer risk in healthcare workers exposed to formaldehyde (13):
Other medical problems related to formaldehyde exposure
Eye irritation, tears and sensation of odour are common in most individuals. There can be an adverse reaction of hypersensitivity, even at low concentrations. It has been suggested that long- term inhalation of formaldehyde may trigger classic immunoglobulin E-mediated nasal allergy in atopic individuals (17). Clinical data has revealed dermatitis and skin sensitisation among histotechnologists after chronic exposure to formalin (18). A group of 15 histology technicians had subclinical statistically significant differences in nasal resistance. EU directives list sensitising substances. Respiratory sensitizers are required to be labelled with their R-phrases. Formaldehyde has an R-phrase R43 which means that it may cause sensitisation by skin contact. Significantly elevated odds of work-related asthma have been observed for exposure to formalin/formaldehyde in hospitals (19). A study of 34 workers in an anatomy laboratory revealed decreased pulmonary function (FVC and FEV3) at formaldehyde exposures in the range 0.07– 2.94 ppm. Another study with 280 non-smoker histotechnologists with formaldehyde exposure showed small differences in the reduction of vital capacity during 4 years compared with non-exposed controls (20).
In 1997 the Industrial Health Foundation experts’ panel identified the occupational exposure limit for formaldehyde that would prevent irritation. The panel concluded that there was sufficient evidence to show that persons with asthma do not respond differently from healthy individuals following exposure to concentrations of up to 3.0 ppm. The panel could not identify a group of people who were hypersensitive, nor was there evidence that anyone could be sensitised (develop an allergy) following inhalation exposure to formaldehyde. Although cancer risk did not receive exhaustive evaluation, the panel agreed with other scientific groups who have concluded that the cancer risk of formaldehyde is negligible at airborne concentrations that do not produce chronic irritation (21). More details about the occupational exposure limits are presented in {SAF11}.
Higher rates of spontaneous abortion and low birth weight have been reported among children of women occupationally exposed to formaldehyde (15, 22).
A relatively low threshold of response and the disagreeable, irritating pungent suffocating odour of formaldehyde prevent one from breathing intolerable amounts of gas. Although in rare massive acute exposures victims have suffered pulmonary oedema and even death, such a situation is unlikely in the surgical theatre or pathological laboratory due to the relatively limited amount of formalin that is used.
There is a discrepancy between epidemiological statistical data and clinical observations. Neither otolaryngology nor other manuals mention formaldehyde as a possible aetiological or contributing factor to cancer. Nevertheless, regulatory agencies assume that formaldehyde is a potential occupational carcinogen that requires appropriate regulations
Importance: Important
Transferability: Partially
The search results for {SAF7} were used as the basis for this section. IP performed additional searches in PubMed and Google (10 March 2012) using the search terms, environment, ground water, endocrine disruptor, developmental toxin, reproductive toxin and cholinesterase inhibitor, combined with formaldehyde. No pertinent results were identified.
Further information was searched from EU Chemical agencies web page and the REACH (Registration, Evaluation, Authorisation and Restriction of Chemical Substances) web page. Starting in the late nineties new horizontal chemicals legislation was developed, and in 2007, REACH came into force. REACH’s primary aim is “to ensure a high level of protection of human health and the environment”. In the coming decade, REACH will place the burden of proof on industry, which must collect or generate the data necessary to ensure the safe use of chemicals. This data will be publicly available through the central database held at the European Chemicals Agency and will help to close the current information gap on chemicals. REACH also provides rules for phasing out and substitution of the most dangerous chemicals.
Since little was found in the above-mentioned sources, IP screened several MSDS for information on the ecotoxicity of formaldehyde.
T = Any procedure using formaldehyde
I = NA
C = NA
O = Environmental hazards
Formaldehyde 10%:
Source: http://www.sciencelab.com/msds.php?msdsId=9925911
Formaldehyde 4 %:
Source: http://www.bio-techsolutions.ltd.uk/PDF/BufForm.pdf
Regarding toxicity to the aquatic environment, the following guidance is given on the disposal of formaldehyde waste. Place formaldehyde waste in a chemically compatible container with a sealed lid and label clearly. Complete a hazardous waste tag and call EH&S (486 – 3613). All biological materials preserved in formaldehyde must also be disposed of in this manner, not in medical waste containers. Drain disposal of dilute aqueous solutions containing formaldehyde is permitted to the limit of 100 g of solute per laboratory per day (for example, 1 litre of 10%formalin, or 10 litres of 1% formalin). This limit applies only as long as no other hazardous chemical is present in the solution.
Source: http://www.ehs.uconn.edu/Word%20Docs/Formaldehyde%20Hazards%20and%20Precautions.pdf
Importance: Optional
Transferability: Completely
A search was done in PubMed by IP on 15 March 2012 using search string
See {Appendix SAF-4}
T = all surgical pathology activities
I = interventions which improve quality and safety
C = NR
O = patient safety
Clinical practitioners play an essential role in error reduction through several avenues such as effective test ordering, providing accurate and pertinent clinical information, procuring high quality specimens, providing timely follow-up on test results, effectively communicating on potentially discrepant diagnoses, and advocating second opinions on the pathology diagnosis in specific situations (1).
An important component of improving patient safety is reducing medical errors. A step towards reducing the errors is their identification. Mislabelling occurred significantly less in study laboratories with continuous individual-case (one by one) accessioning and in laboratories with formal, documented quality checks at accessioning (5). Systematic monitoring and subsequent evaluation of various aspects of hospital and laboratory practices is suggested (See TEC and/or ORG domain for quality assurance).
Importance: Important
Transferability: Partially
A search was done by IP on 21 February 2012 in PubMed. Search strategy
The search yielded 35 articles {Appendix SAF-3}. The National Toxicology Program Final Report on Carcinogens 2010 was taken as the basis for carcinogenicity information. As there are sufficient EU sources for safety epidemiology and safety management, all guidelines prepared for the non-European context were excluded.
Information was also retrieved from web pages of manufacturers, the EU-OSHA, the draft NICE report 2012, the European Commission Joint Research Centre’s European Chemical Substances Information System (ESIS), and the WHO IPCS. As there is no free database for MSDS, the best way to find the data sheets is to Google MSDS and formaldehyde.
T = Any tissue sample requiring formalin fixation
I = Staff in surgical theatres and pathological laboratories
C = Procedures by which formalin is eliminated or substituted
O = Cancers, respiratory symptoms
The concentrations of formaldehyde and its metabolite in blood or urine have proven to be inefficient measures of exposure (13). Occupational exposure limits (OELs) are the major control instruments for workers’ exposure assessment and management. There are two types of OELs: atmospheric and biological, and two main legal levels: constraining (binding) and indicative. More information about national exposure limits and monitoring regulation, as well as possible statutory health surveillance can be found through the national Focal Points of the European Agency for Safety and Health at Work, which are official government-nominated representatives of EU-OSHA (http://osha.europa.eu/en/oshnetwork/focal-points/index_html).
Minimum requirements for the protection of workers from risks to their safety and health arising, or likely to arise, from the effects of chemical agents that are present at the workplace or as a result of any work activity involving chemical agents are presented in Directive 98/24/EC—risks related to chemical agents at work (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31998L0024:EN:NOT)
EU regulations* define the preventive measures at work places:
see details in OSHA Factsheet http://osha.europa.eu/en/publications/factsheets/39
Checklist for laboratory accidents http://osha.europa.eu/en/publications/e-facts/efact20
Eliminating exposure:
Several attempts have been made to find a substitute for formalin in hospitals and laboratories but all alternatives have failed (23). Another approach has been to change the work flow so that no formalin is needed in the surgical theatre and the samples are transported to the pathological laboratory for formalin fixation. This would reduce exposure to formaldehyde in the surgical theatre where advanced preventive and exposure limiting solutions, such as hoovers, are missing. A system using cooling and pressure-vacuum sealing of the fresh tissue sample in the surgical theatre before moving it to the pathology laboratory for formalin fixation has been used in a hospital in Turin. According to one before–after study, the quality of tissue conservation improved and the odds of having respiratory symptoms in surgical staff who used formalin fixation in the theatre was 12 times as large as that among staff who use the vacuum sealing method (24, 25).
Preventing exposure:
Several countries have their own standards for limiting exposure to formalin and monitoring procedures. The Industrial Health Foundation experts’ panel identified in 1997 an OEL that would prevent irritation. The panel concluded that for most people, eye irritation that is clearly due to formaldehyde does not occur below at least 1.0 ppm. Information from controlled studies involving volunteers indicated that moderate to severe eye, nose, and throat irritation does not occur for most people until airborne concentrations exceed 2.0–3.0 ppm. The data indicated that below 1.0 ppm, if irritation occurs in some people, the effects rapidly subside due to "accommodation." Based on the weight of evidence from published studies, the panel found that those exposed to 0.3 ppm for 4–6 h in chamber studies generally reported eye irritation at a rate no different than that observed when people were exposed to clean air. It was noted that at a concentration of 0.5 ppm (8-h time-weighted average [TWA]) eye irritation was not observed in the majority of workers (about 80%) (21).
Formalin spills are not that rare and they require attention. Material safety data sheets present protocols for avoiding spills. They should be stated in the laboratory’s standard operating procedures. The amount of formaldehyde gas that evaporates depends on the surface area, not the volume spilled, so the aim should be to minimise the surface area of the spill. Cleaning should therefore start immediately. A dike made of wet paper can be used to prevent the surface area of the formalin from increasing. A spill kit should be reserved, with disposable gowns, gloves, and safety glasses. Goggles and a wet mask should be worn while cleaning up. The wet mask should be changed often while it gets saturated with formalin. Ventilation should be increased and water taps left running to increase the humidity in the room. For irritation of the throat, milk or alkaline drinks are optimal for immediate drinking and gargling. Eye washing for some minutes with cold water after formalin splashing is obligatory and every histology laboratory must have an eyewash fountain.
Checklist for laboratory accidents http://osha.europa.eu/en/publications/e-facts/efact20
Importance: Important
Transferability: Partially
Because of a lack of methodological expertise we had to leave out issue SAF5 “Does implementing of uPA/PAI-1, Oncotype DX or MammaPrint® reduce undertreatment and overtreatment compared to management pathway without it?”, the original issue of which is “What are the consequences of false positive, false negative and incidental findings brought about using the technology to the patients from the viewpoint of patient safety?”. We had planned to produce a qualitative estimate on this, based on the predictive values of each of the tests to identify good prognosis and the evidence on changes in physicians’ treatment decisions, but this appeared to be too complex a task for the present team in the available time frame. As a consequence, the information in this domain is dominated by the risk of laboratory errors and occupational safety issues.
APPENDIX SAF-1. Selecting studies for safety domain
Going through possibly relevant articles, updated 3.2.2012/ip
2011 Ademuyiwa. About change in management. We should receive this information from eff-domain. |Exclude
2011 Albanell. About change in management. We should receive this information from eff-domain. Exclude.
2011 Bedard, Can some patients avoid…: non-systematic but recent review on topic, not directly relevant to us but worthwhile looking. Exclude
2011 Bedard. Review discussing the unnecessary chemotherapies. Useful for C0006
2011 Oratz: change-in management survey. We should receive this information from eff-domain. Exclude
2011 O´Toole: objective in HER2 test, looks also at Oncotype and mammaprint but compares them to other tests, not clinical risk assessment. Exclude
2011 Richman: on test knowledge, mentions concerns but very briefly. Not relevant for us. Exclude
2011 Vanerlaan Cost model, includes AEs on page 457. Include
2010 Bighin; editorial on tumor characteristics. Exclude
2010 Brauchli: a letter commenting Lo 2010,2010 Kelly: case series using Oncotype, examining prognosis. Exclude
2010 Klang: abstract about Oncotype and amount of therapies. Exclude
2010 Lo. using test result in management decision reduced anxiety. Use in C0001
2010 Ontario HTA: about OncotypeDX, not directly relevant for our questions. Exclude
2010 Retel, Cost effectiveness of…: simulation model studying survival and qol, Exclude
2010 Tzeng: 25% of women reported test related distress. Use in C0001
2009 Albain review on test utility, we should get this info from eff-domain. Exclude
2009 Berg: editorial of EGAPP guideline. Exclude
2009 Brewer: about understanding and interpretation, not anxiety etc. Exclude
2009 Brewer examines how women use the test info for decision making. Exclude
2009 EGAPP. Guideline. Include
2009 Henry: change in management. We should receive this information from eff-domain. Exclude
2009 Holzik: abstract about gene test results in the diagnostic phase. Exclude
2009 Lau: abstract on prognosis in time, not relevant. Exclude
2009 Retel, Constructive HTA examines psychological impact. Include C0001
2009 Teutsch: describes the methods of EGAPP guideline. Interesting methods issues. Exclude
2008 Asad about change in management. Exclude
2008 Duffy a review collecting info also of toxicity. Include
2008 Haas: inflammation of the biopsy channel causing things. Include at least C0001
2008 Koscielny. Methodological discussion which we can use when estimating the reliability of the figures,
2008 Leyland-Jones. Gives guidelines for sampling. This can be used to identify search terms for possible occupational harms
2008 Loi: predicting tamoxiphene response. Exclude
2008 Marchionni: Systematic review (AHRQ), not directly relevant to us. Exclude
2008 Mayordomo: abstract of MammaPrint used in core needle biopsies. Exclude
2008 Ross: properties of several tests. Not relevant to us. Exclude
2008 Wittner: mamma print predicting distant metsatsis in post menopausal. Exclude
2007 Ach: Reproducibility of the tests. Exclude
2007 ANZHSN; HTA which estimates the number of unnecessary chemotherapies. Include. Useful for C0006
2007 Bueno de Mesquita examines test that are not in our review. Exclude
2007 Kaklamani: Descriptive review. Exclude
2007 Lillie. About understanding. Exclude.
2007 O Neill about how women perceive the tests, concern mentioned only. Exclude
2007 Oratz: Change in management. Exclude
2006 Paik revieweing tets. Exclude
2000 LeGoff: neural networks. Exclude
APPENDIX SAF-2 Study cards for safety domain
Article |
Full reference |
Layfield LJ, Anderson GM. Specimen labeling errors in surgical pathology: an 18-month experience. Am J Clin Pathol. 2010 Sep;134(3):466-70. | |||
DOI |
PMID:20716804 | ||||
Articles that belong to the same study | |||||
EUnetHTA project details |
Name of the person who reviewed the article |
Iris Pasternack | |||
Date of review |
15 March 2012 | ||||
EUnetHTA project name |
3 gene tests for breast cancer, result cards SAF1 | ||||
EUnetHTA project ID | |||||
Study type |
Study objective |
To quantify the mislabelled cases, specimens, blocks, and slides and to identify the sources of error. | |||
Study method |
Retrospective review of quality control records for an 18 month period. | ||||
Place of study |
Country (area): USA | ||||
Technology and comparison |
Intervention: |
How and where were participants selected (including setting of care)[free text] | |||
Intervention | |||||
How was the intervention conducted and interpreted? e.g. technical details, presentation, who delivered the intervention, frequency and duration of sessions |
Quality assurance records documenting all labelling errors were reviewed for an 18 month period | ||||
Co-intervention description | |||||
Drop-offs and withdrawals (number, reason) | |||||
Previous interventions/tests | |||||
Description of patients and target condition |
Patient characteristics |
Intervention group Control group | |||
Number of institution |
1 | ||||
Country |
US | ||||
Sex | |||||
confounder 1 [Changeable title] | |||||
confounder 2...[add rows if needed] | |||||
Disease/condition |
Intervention group Control group | |||
Duration | ||||
Severity | ||||
Excluded conditions | ||||
...... [add rows if needed] | ||||
Endpoints |
Endpoint measures (all) | |||
Patient relevant endpoint measures | ||||
Internal validity |
Select: +, -, ? or NR “Not relevant or of minor relevance in this study” Add free text to explain | |||
Selection |
Was the sequence generation adequate? |
NR | ||
Was allocation concealment adequate? |
NR | |||
Was a consecutive or random sample of patients enrolled? (applies to non randomised studies) |
NR | |||
Did the study avoid inappropriate exclusions? |
+ | |||
Were the baseline characteristics similar? (applies to non randomised studies) |
NR | |||
Could the selection of patients have introduced bias? |
NO | |||
Conduct |
Were participants and personnel blinded? |
NR | ||
Were the co-interventions identical? |
NR | |||
Was the number of withdrawals or uncompleted measurements appropriately low? |
NR | |||
Could the conduct of the intervention have introduced bias? |
NO | |||
Interpretation |
Were outcome assessors blinded? |
NR | ||
Could the interpretation of the intervention have introduced bias? |
NO | |||
Analysis and reporting |
Was data analysed appropriately? |
+ | ||
Was incomplete outcome data addressed? |
NR | |||
Was the study free from selective reporting? |
+ | |||
Other |
Was the study funding independent from manufacturer? |
+ | ||
Free of other bias? Which? |
+ | |||
External validity | ||||
Relevant patient group |
+ | |||
Relevant intervention |
+ | |||
Relevant comparator |
NR | |||
Relevant endpoint measures |
+ | |||
Results |
29 479 cases accessioned, with 109354 blocks and 248 013 slides. 75 labelling errors were identified (0.25% of cases, 0.068% of blocks and 0.03 % of slides) |
Article |
Full reference |
Nakhleh RE, Idowu MO, Souers RJ, Meier FA, Bekeris LG. Mislabeling of cases, specimens, blocks, and slides: a College of American Pathologists study of 136 institutions. Arch Pathol Lab Med. 2011 Aug;135(8):969-74. | ||
DOI |
PMID:21809987 | |||
Articles that belong to the same study | ||||
EUnetHTA project details |
Name of the person who reviewed the article |
Iris Pasternack | ||
Date of review |
15 March 2012 | |||
EUnetHTA project name |
3 gene tests for breast cancer, result cards SAF1 and SAF11 | |||
EUnetHTA project ID | ||||
Study type |
Study objective |
To quantify the mislabelled cases, specimens, blocks, and slides, and to identify the sources of error and the ways the in which errors were detected | ||
Study method |
Prospective multicentre study. Review of cases until 8 weeks elapsed or 30 error incidents were identified. Mislabelling rates per 1000 were calculated and corrected by regression analysis. Associations between the rates and the demographic and practice variables were investigated using regression analysis for continuous independent variables after independency testing. Variables with significant associations were taken into multivariate regression model. | |||
Place of study |
Country (area): USA (127 of the participating 136 institutions), Saudi Arabia (6), Canada (2), Lebanon (1) Years: autumn 2009 | |||
Technology and comparison |
Intervention: |
How and where were participants selected (including setting of care)[free text] Subscription-based quality assurance study | ||
Intervention | ||||
How was the intervention conducted and interpreted? E.g. technical details, presentation, who delivered the intervention, frequency and duration of sessions |
Subscribers prospectively reviewed surgical pathology cases until 8 weeks had elapsed or 30 error incidents were identified related to mislabelling cases, specimens, blocks or slides. The participants counted the total numbers of cases, specimens, blocks and slides reviewed. They also recorded the instances of mislabelling and consequences. | |||
Co-intervention description | ||||
Drop-offs and withdrawals (number, reason) | ||||
Previous interventions/tests | ||||
Description of patients and target condition |
Patient characteristics |
Intervention group Control group | ||
Number of institutions |
136 laboratories | |||
Country |
United States (127 of the participating 136 institutions), Saudi Arabia (6), Canada (2), Lebanon (1) | |||
Sex | ||||
confounder 1 [Changeable title] | ||||
confounder 2...[add rows if needed] |
Disease/condition |
Intervention group Control group | |||
Duration | ||||
Severity | ||||
Excluded conditions | ||||
......[add rows if needed] | ||||
Endpoints |
Endpoint measures (all) | |||
Patient relevant endpoint measures | ||||
Internal validity |
Select: +, -, ? or NR “Not relevant or of minor relevance in this study” Add free text to explain | |||
Selection |
Was the sequence generation adequate? |
NR | ||
Was allocation concealment adequate? |
NR | |||
Was a consecutive or random sample of patients enrolled? (applies to non randomised studies) |
NR | |||
Did the study avoid inappropriate exclusions? |
+ | |||
Were the baseline characteristics similar? (applies to non randomised studies) |
NR | |||
Could the selection of patients have introduced bias? |
NO | |||
Conduct |
Were participants and personnel blinded? |
NR | ||
Were the co-interventions identical? |
NR | |||
Was the number of withdrawals or incomplete measurements appropriately low? |
NR | |||
Could the conduct of the intervention have introduced bias? |
NO | |||
Interpretation |
Were outcome assessors blinded? |
NR | ||
Could the interpretation of the intervention have introduced bias? |
NO | |||
Analysis and reporting |
Was data analysed appropriately? |
+ | ||
Was incomplete outcome data addressed? |
NR | |||
Was the study free from selective reporting? |
+ | |||
Other |
Was the study funding independent of the manufacturer? |
+ | ||
Free of other bias? Which? |
+ | |||
External validity | ||||
Relevant patient group |
+ | |||
Relevant intervention |
+ | |||
Relevant comparator |
NR | |||
Relevant endpoint measures |
+ | |||
Results |
There were 427 255 reviewed cases. Of them 1811 cases had some type of mislabelling (0.4%). The entire case was mislabelled in 1.1/1000 (490). Specimens were mislabelled 1/1000 (796 specimens of 358 cases). Blocks were mislabelled in 1.7/1000 (2172 blocks in 461 cases). Slides were mislabelled in 1/1000 (2509 slides in 502 cases). Misidentification of cases and specimens occurred most often at collection or at accessioning (i.e. when specimens are received, sorted, and entered in the laboratory). In 1751 of the 1811 mislabelled cases (97%) the mislabelling was corrected without any additional consequences. In 59 cases (3%) a correction report was issued, and in 24 cases (1%) patient care was affected some way. Mislabelling occurred significantly less in laboratories with continuous individual-case (one by one) accessioning and in laboratories with formal, documented quality checks at accessioning. |
Article |
Full reference |
Berton F, Novi CD. Occupational hazards of hospital personnel: assessment of a safe alternative to formaldehyde. J Occup Health. 2012 Mar 5;54(1):74-8. Epub 2011 Dec 16. | |||
DOI |
PMID 22186296 | ||||
Articles that belong to the same study |
Di Novi C, Minniti D, Barbaro S, Zampirolo MG, Cimino A, Bussolati G. Vacuum-based preservation of surgical specimens: an environmentally-safe step towards a formalin-free hospital. Sci Total Environ. 2010 Jul 15;408(16):3092-5. Epub 2010 May 4. PMID:20444497 | ||||
EUnetHTA project details |
Name of the person who reviewed the article |
Iris Pasternack | |||
Date of review |
10 March 2012 | ||||
EUnetHTA project name |
3 gene tests in the management of breast cancer | ||||
EUnetHTA project ID | |||||
Study type |
Study objective |
To assess the effect of substituting formalin with under-vacuum sealing in the respiratory symptoms of staff working in a surgical theatre handling tissue samples. | |||
Study method |
Prospective study. Multivariate analysis | ||||
Place of study |
Country (area): Italy, Turin Years: Data collected December 2008-April 2009 | ||||
Technology and comparison |
Intervention: |
How and where were patients selected (including setting of care)[free text] Random sample of personnel of surgical theatre and pathology laboratory was educated to use the new vacuum sealing. | |||
Intervention Comparison | |||||
How was the intervention conducted and interpreted? E.g. technical details, presentation, who delivered the intervention, frequency and duration of sessions |
Tissue specimens are sealed into plastic bags immediately after removal from human bodies; the bags are labelled with identification data and kept in refrigerator at 4ºC inside the premises of the surgical theatre until they are transferred to pathology. The tissue is routinely processed first in the pathology lab. |
? | |||
Co-intervention description |
It was unclear whether the same person participated in several operations a day, some of which used the pressure sealing and some of which did not. | ||||
Drop-offs and withdrawals (number, reason) |
171 interviewed, final sample includes 156 individuals. 15 drop-offs, i.e. 9%. Reason missing values. | ||||
Previous interventions/tests | |||||
Description of patients and target condition |
Patient characteristics |
Intervention group Control group Difference | |||
Number of patients |
70 |
86 | |||
Age, mean/years |
40.3 |
40.0 |
not given | ||
Sex: Women |
72.9% |
75.6% |
not given | ||
existing respiratory conditions, symptoms |
30.0% |
29.1% |
not given | ||
living in metropolitan area |
78.6% |
80.2% |
not given | ||
level of experience in tissue sample preparation/years (measured of 115 only!) |
18.4 |
18.7 |
not given | ||
Occupation/physicians |
27.1% |
25.6% |
not given | ||
Occupation/ laboratory technicians |
38.6% |
37.2% |
not given | ||
Education/ tertiary degree or more |
54.3% |
47.7% |
not given | ||
Personal perception of difficulties in handling the tissue sampling procedure |
10.0% |
23.3% |
not given, authors say this is the only relevantly different | ||
Disease/condition NA (healthy personnel) |
Intervention group Control group | |||
Duration | ||||
Severity | ||||
Excluded conditions | ||||
......[add rows if needed] | ||||
Endpoints |
Endpoint measures (all) |
Respiratory symptoms: cough, chest pain, shortness of breath and wheezing | ||
Patient relevant endpoint measures |
Respiratory symptoms: cough, chest pain, shortness of breath and wheezing | |||
Internal validity |
Select: +, -, ? or NR “Not relevant or of minor relevance in this study” Add free text to explain | |||
Selection |
Was the sequence generation adequate? |
? | ||
Was allocation concealment adequate? |
NR | |||
Was a consecutive or random sample of patients enrolled? (applies to non randomised studies) |
+ | |||
Did the study avoid inappropriate exclusions? |
? | |||
Were the baseline characteristics similar? (applies to non randomised studies) |
– | |||
Could the selection of patients have introduced bias? |
NO | |||
Conduct |
Were participants and personnel blinded? |
NR | ||
Were the co-interventions identical? |
NR | |||
Was the number of withdrawals or uncompleted measurements appropriately low? |
+ It was 9%, and after controlling for the missing data some analyses were performed with the whole population, n = 156. | |||
Could the conduct of the intervention have introduced bias? |
YES NO ? | |||
Interpretation |
Were outcome assessors blinded? |
– | ||
Could the interpretation of the intervention have introduced bias? |
YES It was not explicitly stated that the individuals who worked with the new sealing method did that all the time. If they occasionally did formalin preparations this could blur the results. | |||
Analysis and reporting |
Was data analysed appropriately? |
? Mantel Haenszel test is used as a repeated test of independence in situations. There were quite a lot of possible confounders in relation to the small sample size. | ||
Was incomplete outcome data addressed? |
+ Multiple independence testing | |||
Was the study free from selective reporting? |
+ | |||
Other |
Was the study funding independent from manufacturer? |
? | ||
Free of other bias? Which? |
NR | |||
External validity | ||||
Relevant patient group |
+ | |||
Relevant intervention |
? | |||
Relevant comparator |
? | |||
Relevant endpoint measures |
+ | |||
Results |
4.3% of the individuals using the pressure sealing system experienced respiratory symptoms. The same figure was 34.9% for formalin users (confidence interval [CI] not given). There were however some differences in the groups’ baseline characteristics: mainly in the level of the perceived difference of using the method. The overall odds ratio for having respiratory symptoms if using formalin was about 12 | |||
Results
APPENDIX SAF-3. Search for SAF7 and SAF12
21 March 2012 search by Iris Pasternack in PubMed
Search strategy
Appendix SAF-4. Search for SAF1 and SAF11
15 March 2012 Iris Pasternack
Search strategy
Authors: Authors: Mirjana Huic, Narine Sahakyan, Gurleen Jhuti, Anna Panasiuk, Heike Raatz, Petra Schnell-Inderst, Katarzyna Sejbuk, Eva Turk, Marjetka Jelenc
Aim: The primary aim of this assessment was to determine whether, compared with current practice, using the three prognostic tests (uPA/PAI-1, MammaPrint® and Oncotype DX®) to guide the use of adjuvant chemotherapy effectively improves long-term clinical outcomes, safety (adverse events due to adjuvant chemotherapy) and quality of life in women with early-stage breast cancer. The secondary aims were to assess changes both in clinical decisions about the choice of treatment with adjuvant chemotherapy and in patient satisfaction.
Methods: As currently only three applications of the HTA (health technology assessment) Core Model exist (medical and surgical interventions, diagnostic technologies, and screening technologies), the Core Model for Diagnostic technologies was used. A number of HTA Core assessment elements questions for diagnostic technologies are not suited for prognostic technologies and prognostic or predictive accuracy was not assessed. A systematic review was done according to Cochrane methodology. Only a qualitative synthesis was planned.
Results: Overall, 4539 references were available for screening, with 15 observational studies included in the qualitative synthesis. There are no randomised controlled trials (RCTs) or prospective cohort studies that determined whether using these three prognostic tests to help guide the use of adjuvant chemotherapy effectively improves long-term clinical outcomes compared with current practice. A number of ongoing RCTs will not give direct evidence on these important clinical outcomes. Oncotype DX influenced the physicians’ adjuvant treatment recommendation in 19–51% of patients. Using MammaPrint would have resulted in altered treatment advice in up to 40% of patients.
Quality of life remained stable according to the Functional Assessment of Cancer Therapy 12 months after the Oncotype DX test recurrence score (RS). So-called state or situational anxiety (STAI) mean scores decreased significantly over time. More than 90% of patients continued to feel satisfied that they had used the RS assay and were satisfied with their treatment decision 12 months after the RS assay. Only five patients, who were not satisfied, noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and a negative impact on self image. Most women (95%) reported that they would have the Oncotype DX test again if they had to decide today, and would recommend the test to other women.
Further high quality evidence on uPA/PAI-1, Oncotype DX and MammaPrint tests from RCTs is needed to guide the use of adjuvant chemotherapy in women with early invasive breast cancer. There is a clear need for communication, at an early stage, between the manufacturers and the European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and the HTA bodies on so-called “early scientific advice” for designing RCTs.
The Clinical Effectiveness Domain describes the spectrum and extent of beneficial effects on health and quality of life expected through the use of the technology {1}.
There are still no gold standard tools or guidelines to assist decision-making relating to adjuvant chemotherapy in women with early-stage breast cancer. This may result either in unnecessary use of chemotherapy with short- or long-term serious adverse drug reactions or in avoidable death if chemotherapy was withheld.
The primary aim of our assessment was to determine whether use of the three prognostic tests (uPA/PAI-1, MammaPrint® and Oncotype DX®) to guide the use of adjuvant chemotherapy improves long-term clinical outcomes, safety (adverse events due to adjuvant chemotherapy) and quality of life in women with early-stage breast cancer compared with current practice. The secondary aims were to evaluate the impact of prognostic tests on clinical decision making and patients’ satisfaction.
Currently there are only three applications of the HTA Core Model: medical and surgical interventions, diagnostic technologies, and screening technologies. The Core Model for diagnostic technologies was selected as the most appropriate for assessing the clinical effectiveness of the three prognostic tests. However, there are fundamental differences in the assessment of diagnostic and prognostic tests. Some HTA Core assessment element questions for diagnostic technologies are thus not suited for prognostic technologies {2}. The methodology for designing and assessing genetic risk prediction models is still developing, and methods specific to conducting a systematic review of a prognostic test are not well established {3}.
A prognostic factor or prognostic marker is any patient or tumour characteristic that is predictive of the patient’s outcome. Outcomes are usually measured in terms of overall survival and/or disease-free survival. A prognostic index is a quantitative set of values based on the results of a prognostic model. A prognostic model is a statistical combination of at least two separate prognostic variables used to predict a patient outcome.
A predictive factor or predictive marker is defined as any patient or tumour characteristic that is predictive of the patient’s response to a specified treatment. Response is usually measured in terms of overall survival and/or disease-free survival. A predictive model is a statistical combination of at least two predictive factors used to predict the response to a specified treatment {4}.
A prognostic test is used to estimate a patient’s likelihood of developing a disease or experiencing a medical event over time. The “reference test” is the observed probability of developing the event being predicted within prognostic groups, and is defined by the predicted probabilities that are estimated using the prognostic test. The predictive accuracy of a prognostic test is evaluated as the difference between the observed and predicted outcome probabilities within prognostic groups {2}.
A separate category of prognostic test is a test that predicts responsiveness to treatment (success or adverse effects). Predictive genetic tests are characterised by a delayed time between testing and observing clinically important outcomes. Many prognostic tests, unlike diagnostic tests, are based on multivariable regression models {2}.
The only reliable evidence on whether a prognostic test does more good than harm are well conducted RCTs (randomised controlled trials; gold standard methodology for research into the effectiveness of an intervention, so-called “direct evidence”) with a study population representative of those eligible for the prognostic test. The control group should receive usual care. A problem in evaluating predictive genetic tests is that direct evidence for the impact of the test results on health outcomes is often lacking.
As stated for diagnostic technologies, inferences regarding the effectiveness of prognostic technologies are often based on so-called “linked evidence” from studies on accuracy, change in management and treatment effectiveness, because test treatment RCTs are rare. If the clinical endpoints (patient-relevant endpoints) are not available then surrogate endpoints may be used to indicate or predict clinically important outcomes {1}. To be valid, it must have been shown that the effect on the surrogate correlates sufficiently with the effect on the outcome of interest {5}.
The authors of a recent systematic review of RCTs on positron emission tomography (PET) stated that, in addition to diagnostic and prognostic accuracy studies, RCTs on PET should be conducted to prove its benefit in terms of patient-relevant outcomes. Despite the fact that 12 RCTs have already been published on PET, and 5 will be published per year in the future, the authors stressed that more high quality RCTs on PET are needed to prove its benefit for patients. They also pointed out that funding is usually difficult because RCTs are not yet mandatory for the approval of non-drug interventions {6}.
The majority of previous HTAs and systematic reviews of clinical effectiveness of prognostic genetic tests have used frameworks for the evaluation of genetic tests developed by the United States Preventive Services Task Force, the CDC (US Centers for Disease Control and Prevention), and EGAPP (Evaluation of Genomic Applications in Practice and Prevention). These examine: (1) analytical validity (technical accuracy and reliability), (2) clinical validity (ability to detect or predict an outcome, disorder, or phenotype), and (3) clinical utility (whether use of the test to direct clinical management improves patient outcomes) (Box 1). A fourth criterion has also been added: (4) ethical, legal, and social implications {2, 7}.
Box 1. Definitions of analytic validity, clinical validity and clinical utility {2, 7}
Analytic validity |
the ability of the test to accurately and reliably measure the expression of mRNA or proteins by breast cancer tumour cells |
Clinical validity |
the degree to which the test could accurately predict the risk of an outcome and discriminate patients with different outcomes |
Clinical utility |
the utility of the test in relation to harm, evidence of improvement in clinical outcomes and healthcare costs, impact on clinical decision making |
There is no consensus on the meaning/definition of clinical utility and multiple perspectives have been adopted. Direct evidence of clinical utility of a gene expression profile can only be provided in the context of a randomised clinical trial where benefit can be measured in terms of an improvement of clinical outcomes such as overall survival, disease-free survival, chemotherapy toxicity or quality of life {8-11}. Well-designed clinical trials should be used to assess the clinical utility of markers, multiple markers or a comprehensive set of markers, a unit or classifier. Four clinical trial designs for assessing the clinical utility of a predictive marker have been described: (1) Marker by treatment interaction design, separate tests; (2) Marker by treatment interaction design, test of interaction; (3) Marker-based strategy design and (4) Modified marker-based strategy design {12}.
A modified collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
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Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
More information | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
D0010 | Change-in management | How does the technology modify the need for hospitalization? | yes | Does the test-treatment chain of uPA/PAI, Mammaprint, or Oncotype for adjuvant therapy reduce or increase the number of women (diagnosed with early stage, invasive breast cancer) requiring hospitalization or hospitalization due side-effects compared to treatment on the basis of the standard practice? |
D0023 | Change-in management | How does the technology modify the need for other technologies and use of resources? | yes | Do uPA/PAI, Mammaprint, or Oncotype compared to the standard practice in women diagnosed with early stage invasive breast cancer increase or decrease the probability of adjuvant therapy performed? |
D0021 | Change-in management | Does the use of the technology lead to a change in the physicians' management decisions? | yes | Did the results in uPA/PAI, Mammaprint, or Oncotype tests in women diagnosed with early stage invasive breast cancer lead to changes in the treatment choice with adjuvant therapy and/or further imaging compared to the standard practice? |
D0020 | Change-in management | Does the use of the technology lead to improved detection of the disease? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D0022 | Change-in management | Does the use of technology detect other health conditions which have impact on the treatment decisions concerning the target condition? | no | Our tests are prognostic tests, not diagnostic tests. |
D0012 | Function / HRQL (Health-related quality of life) | What is the effect of the technology on health-related quality of life? | yes | What is the effect of adjuvant therapy on the basis of uPA/PAI, Mammaprint, or Oncotype test results on health related quality of life compared to treatment on the basis of the standard practice? |
D0016 | Function / HRQL (Health-related quality of life) | How does the use of technology affect activities of daily living? | yes | Does adjuvant therapy on the basis of uPA/PAI, Mammaprint, or Oncotype test results compared to treatment on the basis of the standard practice affect their activities of daily living? |
D0017 | Patient satisfaction | Was the use of technology worth it? | yes | Do women diagnosed with early stage, invasive breast cancer feel that the guidance of their adjuvant therapy on the basis of uPA/PAI, Mammaprint, or Oncotype test results was worth it? |
D0018 | Patient satisfaction | Would the patient be willing to use the technology again? | yes | Would the patient be willing to use the technology (uPA/PAI or Mammaprint or Oncotype test) again? |
D0030 | Patient satisfaction | Does the knowledge of the test result improve the patient's quality of life? | yes | Does the knowledge of the tests results (uPA/PAI, Mammaprint, or Oncotype) improve the patient quality of life in women diagnosed with early stage invasive breast cancer compared to standard practice? |
D0025 | Test-treatment chain | What is the effect of the test-treatment intervention on mortality? | yes | What is the effect of adjuvant therapy on the basis of uPA/PAI, Mammaprint, or Oncotype test compared to treatment on the basis of the standard practice in women diagnosed with early stage invasive breast cancer on overall survival and disease specific survival (for example: disease-free-, progression free-, recurrence-free-survival)? |
D0032 | Test-treatment chain | How does the test-treatment intervention modify the magnitude and frequency of morbidity? | yes | How does the treatment with adjuvant therapy on the basis of the test results of uPA/PAI, Mammaprint, or Oncotype compared to treatment on the basis of the standard practice in women diagnosed with early stage invasive breast cancer modify the magnitude and frequency of morbidity? |
D0024 | Test-treatment chain | Is there an effective treatment for the condition the technology is detecting? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D0026 | Morbidity | How does the technology modify the effectiveness of subsequent interventions? | yes | Does adjuvant therapy on the basis of genetic testing results (uPA/PAI, Mammaprint or Oncotype) compared to treatment on the basis of the standard practice in women diagnosed with early stage invasive breast cancer improve patient morbidity? |
D0004 | Mortality | What is the mortality related to the technology studied? | no | As the tissue is usually being taken in a routine surgical procedure we could assume that it doesn’t add to the mortality of the surgery. |
D0027 | Test accuracy | What are the negative consequences of further testing and delayed treatment in patients with false negative test result? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D0028 | Test accuracy | What are the negative consequences of further testing and treatments in patients with false positive test result? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D0029 | Test accuracy | What are the overall benefits and harms in health outcomes considering the amount of false positive and false negative test results. | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1001 | Test accuracy | What is the accuracy of the test against reference standard? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1002 | Test accuracy | How does the technology compare to other optional diagnostic technologies in terms of accuracy measures? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1003 | Test accuracy | What is the reference standard and how likely does it classify the target condition correctly? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1004 | Test accuracy | What are the requirements for accuracy in the context the technology will be used? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1005 | Test accuracy | What is the optimal threshold value in this context? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1006 | Test accuracy | Does the technology have the potential to reliably rule in or rule out the target condition? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1007 | Test accuracy | How does test accuracy vary in different settings? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1008 | Test accuracy | What is known about the intra- and inter-observer variation in test interpretation? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D1019 | Test accuracy | Is there evidence that the replacing technology is more specific or safer than the old one? | no | Our tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies. |
D0031 | Safety | What is the mortality and morbidity related to the diagnostic technology? | no | Our tests are prognostic tests, not diagnostic tests. This question belongs to safety domain and seems not to be relevant to genetic test. |
Domain frame
Deviations from the project scope: More information:
The tests being investigated are prognostic tests, not diagnostic tests.
Because currently only three applications of the HTA Core Model exist (medical and surgical interventions, diagnostic technologies, and screening technologies), the Core Model for Diagnostic technologies was used to assess the clinical effectiveness of the three prognostic tests.
There are fundamental differences between diagnostic and prognostic tests. A number of the HTA Core assessment element questions for diagnostic technologies are not suited to prognostic technologies. Prognostic/predictive accuracy was not assessed in this HTA Core Model.
Information sources
A systematic literature review was performed according to the Cochrane methodology {13}. This was carried out on standard medical and HTA databases.
Literature search and selection of literature
Using PICO (D), the overall research question for this domain is as follows.
Population: Women with early invasive breast cancer.
Intervention: Use of at least one of the following prognostic tests: uPA/PAI-1, MammaPrint or Oncotype DX.
Comparison: standard/or current practice. As currently there is no standard universally accepted practice, different practices may be involved, such as testing with St Gallen consensus recommendations, National Comprehensive Cancer Network guidelines (NCCN), Adjuvant! Online, or Nottingham Prognostic Index (NPI).
Outcomes: morbidity and survival, safety (adverse events due to adjuvant chemotherapy), quality of life, the impact of prognostic tests on clinical decision making and patients’ satisfaction.
Design: studies comparing the effects of treatment with and without the use of the index test, but excluding studies limited to the prognostic/predictive accuracy of the test. An ideal testing plan for tests to direct treatment would be assessment in randomised conditions as the first level of evidence (followed by prospective cohort studies if RCTs are not available) of each test compared with standard first and then, if found dominant, compared with treatment, direct (head to head) comparison of the effects of each of the dominant tests compared with the others.
Due to the nature of the disease stage, tests and treatment (which is envisaged to be chemotherapy), prospective study designs are preferred to retrospective designs.
As a consequence the inclusion criteria were studies that:
Exclusion criteria were studies that:
Literature search
The systematic literature search was performed according to the search strategy described in Appendix COL-1, in October 2011, in the following databases: Ovid MEDLINE(R) <1948 to September Week 4 2011>; Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <October 07, 2011>; Embase <1980 to 2011 Week 40>; Cochrane Issue 4 of 4, October 2011; Cinahl (Accessed 12 October 2011); CRD databases: DARE, NHS EED, HTA (Accessed 13 October 2011).
In addition, the following clinical trials registries were assessed (13 October 2011), for registered ongoing clinical trials or observational studies: ClincalTrials.gov, ISRCTN, metaRegister of Controlled Trials (mRCT) and International Clinical Trials Registry Platform (ICTRP). The last database update was on 19 December 2011.
Selection of literature
Relevant references, after duplicates were removed, were screened and assessed for eligibility independently by two reviewers. The reference lists of relevant systematic review and health technology assessment reports were also checked for other relevant studies.
Differences in selection results were discussed in order to achieve consensus; a third reviewer was involved where there was uncertainty.
Following removal of duplicates, 4539 references were available for screening. Finally, only 15 studies were included to answer domain assessment element questions (Appendix 1). The PRISMA flowchart outlining the study selection process is presented in Figure 1.
Figure 1. Selection process according to the PRISMA flowchart {14}
Quality of evidence
There were no RCTs or prospective cohort studies that assessed whether use of the prognostic tests (uPA/PAI-1, MammaPrint or Oncotype DX) to guide the use of adjuvant chemotherapy improves long-term clinical outcomes. For this reason, neither the internal validity (risk of bias) of the studies nor quality of the body of evidence (assessed by two researchers independently) could be assessed. This assessment was performed using a few studies, although they did not satisfy the inclusion criteria, to raise important ethical and legal questions on the current use of these three prognostic tests, which are part of the medical devices technology group.
Differences in reviewer findings were discussed in order to achieve consensus. A third reviewer was involved in cases of uncertainty.
The Cochrane Collaborations tools were used to assess risk of bias {15, 16}.
The GRADE working group approach was used to assess the quality of the evidence {17}. This approach specifies four levels of quality:
Data extraction was done independently by two researchers. Data on study characteristics (study design, registration number, country and centre, study period, ethics committee approval, sponsor, study methodology); patient characteristics (age, gender, tumour size, histological grade, lymph node status, oestrogen and progesterone receptor status, human epidermal growth factor receptor (HER2), menopausal status); outcomes; intervention (test characteristics—threshold values for categorisation of risk recurrence); comparator; flow of patients; results on primary and secondary outcomes; and conflict of interest data were all extracted. Any differences in extraction results were discussed to achieve consensus; a third reviewer was involved where there was uncertainty. Synthesis was limited to a qualitative synthesis of the data.
No studies that addressed this question were identified.
Importance: Critical
Transferability: Completely
Please see the answer provided for assessment element question EFF6 (D0021): Did the results in uPA/PAI, MammaPrint®, or Oncotype DX tests in women diagnosed with early stage invasive breast cancer lead to changes in the treatment choice with adjuvant therapy and/or further imaging compared to standard practice?
Importance: Important
Transferability: Completely
uPA/PAI-1 test
No studies were identified that addressed this question for uPA/PAI-1 tests.
Oncotype DX test
Eleven observational studies were found for Oncotype DX that addressed the part of the question relating to the treatment choice with adjuvant therapy. Two of these had a prospective design (Table 1 in Appendix 5). Only one study measured changes in the decisions made by patients {22}.
No studies were identified for Oncotype DX that addressed the part of the question relating to changes in further imaging.
Overall, Oncotype DX influenced the physicians’ adjuvant treatment recommendations in 19%–51% of patients.
Lo et al. 2010 {22} conducted a prospective observational study in which patients and physicians served as their own controls, with observations made before and after the RS assay {22}. 67 (75%) patients, and 16 (out of 17) medical oncologists completed the 12-month follow up questionnaire. Physicians changed their treatment recommendation and actual treatment in 28 patients (31.5%) after RS assay results compared with their decision using standard clinicopathological prognostic factors (41 physicians [46%] also used Adjuvant! Online). The greatest change was from a pre-test recommendation of chemotherapy plus hormonal therapy (CHT) to a post-test recommendation of hormonal therapy (HT), which occurred in 20 cases (22.5%). RS assay results increased the physicians’ confidence in their treatment recommendation in 68 cases (76%), 14 (88%) believed that RS assay results influenced their treatment recommendation and all the physicians would use the RS assay again.
According to this study, 24 (27%) patients changed their treatment decision on the basis of the results of the RS assay. The greatest change was from CHT to HT with 9 (10.1%) patients changing their treatment decision from CHT to HT.
Henry et al. 2009 {25} presented the results of a prospective single centre, small sample size USA study in lymph-node negative patients on changes between the initial recommendation for or against chemotherapy and the actual administration of chemotherapy based on RS assay, compared with clinicopathological data and Adjuvant! Online {25}. RS results changed the panel’s recommendation in 7 cases (24%). Prior to RS testing, the expert panel recommended chemotherapy in 12 patients (41%) and hormonal therapy only (no chemotherapy) in 17 (59%) patients. Five of 12 initial recommendations in favour of chemotherapy were changed to against and two of the 17 initial recommendations against chemotherapy were changed to favouring chemotherapy when the test results were known. RS results altered the plan for chemotherapy in 9 patients (31%); 7 patients (54%) initially recommended for chemotherapy did not receive it, and 2 (13%) received chemotherapy following initial recommendations against it.
Seven of the studies found (Oratz et al. 2007, Asad et al. 2008, Ademuyiwa et al. 2011, Partin et al. 2011, Rayhanabad et al. 2009, Joh et al. 2011 and Kamal et al. 2011 {26–32}) were retrospective chart reviews and cross-sectional studies on medical oncologists in the USA. These studies investigated the effect on changes in the decision to use chemotherapy of using the Oncotype DX test compared with standard clinicopathological factors, clinical guidelines, or prognostic tools such as Adjuvant! Online and the Nottingham Prognostic Index {26–32}. All but one {31} used test results in lymph node-negative patients while Joh et al. {31} used results in both node-negative and -positive early breast cancer patients.
In the Oratz et al. 2007 {26} study, the oncologists changed the adjuvant treatment recommendation in 14 (20%) patients when they knew the RS assay results, compared with their recommendation based on commonly used prognostic factors alone. Of 68 patients, 17 (25%) received a different adjuvant treatment (HT vs. chemotherapy [CT]) from that recommended without knowledge of the RS assay results. For three patients who eventually received CT, the original recommendation was HT. Two of these three patients had a high RS.
Asad et al. 2008 {27} assessed the affect of the RS assay results on the reccomendation about chemotherapy administration compared with a presumed treatment recommendation based on the 2007 NCCN guideline. RS influenced the recommendation concerning chemotherapy in 37 (44%) patients; 4 patients with tumours <1.0 cm in size were advised to have chemotherapy, and 33 patients with tumours ≥1.0 cm in size were advised to undergo hormone treatment only.
Ademuyiwa et al. 2011 {28} analysed the impact of Oncotype DX testing on physicians’ recommendations about adjuvant chemotherapy and on the receipt of chemotherapy, compared with clinicopathological characteristics, Adjuvant! Online and the Nottingham Prognostic Index. Knowledge of RS assay results led to a change in management for 38% of women. Of the 188 patients who did not receive chemotherapy, 71 had a recommendation favouring chemotherapy from an oncologist who was blinded to the RS score. Of the 88 patients who received chemotherapy, 34 did not have a chemotherapy recommendation when the oncologist did not know the RS assay result.
Partin et al. 2011 {29} analysed the change in the decision to administer chemotherapy compared with a presumed treatment recommendation based on the 2007 NCCN guideline, St. Gallen Consensus Recommendations 2007, and Adjuvant! Online. Knowledge of RS assay results led to a change in management for 27% to 74% of women, depending on the guidelines used for comparison. According NCCN guidelines, seven patients who were deemed low risk should have received HT but five of them received CHT. 162 patients who were deemed high risk by NCCN should have received chemotherapy but 124 (77%) received HT. According to the St. Gallen recommendations, 32 patients who were deemed low risk should have received HT but 5 received chemotherapy. According to Adjuvant! Online, 92 patients were deemed low risk and should have received HT, but 20 of them received chemotherapy (22%). Of 16 patients who were deemed high risk by Adjuvant! Online, chemotherapy was used in 44%.
Rayhanabad et al. 2009 {30} assessed the change in physician management, based on RS assay results, compared with using traditional NCCN guidelines; 15 of 58 women (26%) had a change in their breast cancer management based on the gene assay results (P<0.05).
Joh et al. 2011 {31} analysed the impact of Oncotype DX compared with clinicopathological data on chemotherapy recommendations. Including Oncotype DX RS data led to a change in the treatment recommendation in 24.9% of cases.
Kamal et al. 2011 {32} similarly analysed the impact of Oncotype DX compared with clinicopathological data on chemotherapy recommendations. In this study the Oncotype DX results led to a change in the treatment recommendation in 19% of cases. Based on clinical data without the Oncotype DX results, five oncologists recommended chemotherapy in 16%–23% of the 31 cases and one oncologist recommended chemotherapy in 52% of cases. When given the Oncotype DX results, the same five oncologists recommended chemotherapy in 10%–19% of the 31 cases, and the other oncologist recommended chemotherapy in 58% of cases.
Geffen et al. 2011 {33} conducted an observational study on medical oncologists in Israel, looking at their treatment recommendations for node-negative and node-positive patients, after Oncotype DX test results compared with using clinicopathological features and Adjuvant! Online alone {33}. In 34 patients (25.2%, 95% confidence interval (CI) 17.9% to 32.5%), the recommendation for chemotherapy was changed after obtaining the assay result. Most changes (70.6%) were from chemotherapy to no chemotherapy. For 24 (17.8%) patients (95% CI 11.3% to 24.2%), the treatment recommendation was changed after receiving the Oncotype DX test results to hormonal therapy; while only 10 (7.4%) patients (95% CI 2.9% to 11.8%) had a treatment recommendation changed to chemotherapy (P<0.0001). 16 (11.9%) patients, chose not to accept the recommendations after the Oncotype DX test results, with 2 (1.5%) requesting chemotherapy after being recommended hormonal therapy alone and 14 (10.4%) patients refusing recommended chemotherapy.
Oratz et al. 2011 {34} performed a cross-sectional web-based survey on physicians in the USA investigating their treatment recommendations, for lymph node-positive patients, after receiving the Oncotype DX test results, compared with using clinicopathological data alone {34}. Out of 1017 invited oncologists, 232 accessed the survey but only 160 (16%) completed it. Of these 160 medical oncologists, 70 (51%) changed their recommendations after receiving the Oncotype DX test results. In 33%, the recommended treatment intensity decreased from chemotherapy plus hormonal therapy to hormonal therapy alone. In 9%, the treatment intensity increased from hormonal therapy alone to chemotherapy plus hormonal therapy and in 8%, the treatment recommendation changed in a way that did not fit the definition of either increased or decreased intensity.
Two observational studies of Oncotype DX are currently ongoing, one in France {35} and one in Canada {36} (Table 2 in Appendix 5).
The French study http://prsinfo.clinicaltrial.gov/ct2/show/record/NCT01446185?id=NCT01446185&rank=1 {35} aims to independently evaluate the adoption of this test for decision making in France, in the context of the local treatment guidelines and practices, and to provide data that are meaningful to the French health system and medical community.
The Canadian study, http://prsinfo.clinicaltrial.gov/ct2/show/NCT01423890?id=NCT01423890&rank=1 {36} is a prospective population-based cohort that aims to evaluate the adoption of this test for decision making in Ontario; one thousand eligible consenting women will have their tumour tissue specimen sent to Genomic Health where the Oncotype DX assay will be performed. The estimated completion date is December 2012.
MammaPrint test
Two studies (one with a prospective design) were found that assessed whether the results of the MammaPrint tests in women diagnosed with early stage invasive breast cancer lead to changes in the choice of treatment with adjuvant therapy compared with standard practice (Table 3 in Appendix 5).
No studies were found that addressed whether the results in MammaPrint tests in women diagnosed with early stage invasive breast cancer lead to changes in additional imaging compared with standard practice.
Using MammaPrint would have resulted in altered treatment advice in 13% to 40% of patients. There are currently no ongoing studies in clinical trials registers.
Bueno-de-Mosquita et al. 2007 {37} conducted a prospective community-based observational study in the Netherlands to analyse the effect of the prognosis signature on the use of adjuvant systemic treatment. They studied both changes in the adjuvant therapy advice given (recommendation) and changes in the actual adjuvant therapy received, compared with using the Dutch CBO (Centraal BegeleidingsOrgaan - Institute for Healthcare Improvement) guidelines alone, in 427 lymph node-negative patients{37}. Adjuvant systemic treatment were advised in 56 (13%) additional patients (when the prognosis signature was used in combination with the Dutch CBO guidelines for adjuvant systemic treatment advice compared with using the Dutch CBO guidelines alone); chemotherapy in six (1%) additional patients, endocrine treatment in 40 (9%) additional patients, and both in ten (2%) additional patients. These increases were mainly because 12% (50) more patients received endocrine treatment (54 [13%] had endocrine treatment added, and four [1%] had endocrine treatment withheld).
Chemotherapy was added in 35 (8%) patients and withheld in 19 (4%) patients (net 16 (4%) patients had more chemotherapy). 83 (19%) patients received another adjuvant systemic treatment (combined Dutch CBO guidelines, prognosis signature findings, and patient’s preference compared with treatment advice based only on the Dutch CBO guidelines).
Gevensleben et al. 2010 {38} performed a retrospective chart review and a cross-sectional study in Germany to investigate the change in treatment advice using MammaPrint test results, compared with the St. Gallen criteria and Adjuvant! Online, in 140 lymph node-negative and -positive, early invasive, breast cancer patients {38}. Using the MammaPrint test would have resulted in altered treatment advice in 40% of patients. In 59 out of 62 patients with a poor prognosis signature identified by MammaPrint, the clinical treatment was recorded. Of these 59 patients, 19 (32%) did not receive any adjuvant systemic treatment other than endocrine therapy and were potentially under treated. Of 77 patients who were classified as having a good prognosis by MammaPrint, and for whom treatment was known, 35 (45%) received chemotherapy and were potentially over treated.
Importance: Important
Transferability: Completely
Only one observational study that assessed patient quality of life was identified {22}. This reported the impact of using the Oncotype DX test on quality of life, in parallel with its impact on patient satisfaction (Table 1, Appendix 3).
Lo et al. 2010 conducted a prospective observational study in which patients and physicians served as their own controls; observations were made before and after the RS assay {22}. A total of 67 (75%) patients and 16 (out of 17) medical oncologists completed the 12-month follow-up questionnaire. Outcomes considered relevant to this question were: change in patient quality of life; change in patient satisfaction with the choice of treatment; change in patient anxiety; and change in patient decisional conflict. Patient quality of life was assessed using the Functional Assessment of Cancer Therapy, FACT-B, FACT-G survey. This was administered before and 12 months after the RS assay. To assess the impact of using the RS assay on the patient’s perceived risk of recurrence and satisfaction with the adjuvant therapy decision, differences in the results of questionnaires administered before ordering the RS assay, after the RS results, and at 12-month follow- up were compared. Changes in patient satisfaction were assessed by comparing the results of the questionnaire administered immediately after the RS results, with that administered 12 months after the start of study. Changes in decisional conflict were assessed by comparing results of the Decisional Conflict Scale (DCS) administered before and immediately after the RS assay results. Changes in patient anxiety were assessed by comparing the results of the State—Trait Anxiety Inventory (STAI) administered: before, immediately after and 12 months after the RS assay results.
The results indicated that patient quality of life remained stable when assessed using the Functional Assessment of Cancer Therapy (FACT-B: pre-RS mean 112.2 (SD = 17.4), 12 months post-RS 114.3 (SD = 18.6) P = 0.55; and FACT-G: pre-RS mean 88.7 (SD = 12.3): 12 months post-RS 87.6 (SD = 14.9); P = 0.49) {22}. State or situational anxiety (STAI) mean scores significantly decreased over time; from 39.6 (SD = 14.5) to 36 (SD = 12.6) and 34 (SD = 11.5); P = 0.007, as did decisional conflict (statistically significant decrease immediately post-RS; from mean DCS 1.99 (SD = 0.62) to 1.69 (SD = 0.50); p < 0.001).
Patient satisfaction immediately after the RS assay was as follows: 78 (95%) were glad they took the RS assay test; 77 (87%) understood how the assay works; 79 (89%) felt that the results were easy to understand; and 74 (83%) indicated that the results of the RS assay influenced their decision making. At 12-months after the RS assay (67 (75%) completed the 12-month questionnaire), 62 (92.5%) continued to feel satisfied that they had used the RS assay; 64 (95.5%) were satisfied with their treatment decision; and 54 (80.6%) continued to believe that the results influenced their treatment decision. Those patients (n = 5) not satisfied noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain and mood alteration, and a negative impact on self image.
Importance: Critical
Transferability: Completely
No studies that addressed this question were identified.
Importance: Optional
Transferability: Partially
This question could only be answered indirectly for the Oncotype DX test.
Please see the answers and evidence tables in assessment element questions: EFF3 (D0012): What is the effect of adjuvant therapy on the basis of uPA/PAI-1, MammaPrint®, or Oncotype DX test results on health-related quality of life compared to treatment on the basis of standard practice?; and EFF14 (D0018): Would the patient be willing to use the technology again?
According to the results from Lo et al. 2010 {22}, patient satisfaction immediately post-RS assay was as follows: 78 (95%) were glad they took the RS assay test; 77 (87%) understand how the assay works; 79 (89%) felt that the results were easy to understand; 74 (83%) indicated that the results of the RS assay influenced their decision making. At 12-months post-RS assay (67 (75%) completed the 12-month questionnaire) 62 (92.5%) continued to feel satisfied that they had used the RS assay; 64 (95.5%) were satisfied with their treatment decision and 54 (80.6%) continued to believe that the results influenced their treatment decision.
Those patients (n = 5) not satisfied noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and negative impact on self image.
According to results from Tzeng et al. 2010 and Richman et al. 2011 {23,24} most women (96%, 74/77) reported that they would have the test again if they had to decide today, and 95%, 73/77 would recommend the test to other women. In Richman et al. 2011 {24} most outcome data are duplicates of the data reported in Tzeng et al. 2010 {23}.
Importance: Important
Transferability: Partially
Two published articles on Oncotype DX test addressed the question “Would the patient be willing to use the technology again?”
A multicentre cross-sectional study was performed in the Netherlands using a questionnaire, and supplemented by retrospective medical chart review; in Richman et al. 2011{24} most outcome data are duplicates of those reported in Tzeng et al. 2010 {23}. Of 104 invited women (mainly lymph node-negative), 78 completed the survey and 77 were analysed. Most women (96%, 74/77) reported that they would have the test again if they had to decide today, and 95%, 73/77 would recommend the test to other women (Table 1 in Appendix 4).
Importance: Critical
Transferability: Partially
This question could only be answered for the Oncotype DX test, indirectly, through results from the Tzeng et al. 2010 and Richman et al. 2011 articles {23,24}. In Richman et al. 2011 {24}, most outcome data are duplicates of those reported in Tzeng et al. 2010 {23}.
Please see the answer and evidence table provided in assessment element question: EFF14 (D0018): Would the patient be willing to use the technology again?
According to results from Tzeng et al. 2010 and Richman et al. 2011 {23, 24}, 95% of women (73/77) agreed that the Oncotype DX test gave them a better understanding of the chances of success with their treatment options. A few women had concerns about the test: 8% (6/77) reported that they had the test only because other family members wanted them to; 5% (4/77) reported that having the test had a negative effect on their family; and 3% (2/76) agreed that this information about one’s cancer is better left unknown.
According to Richman et al. 2011 {24}, approximately 26% (17/65) of women agreed or strongly agreed that receiving the Oncotype DX test result made them worried and anxious. Greater test-related distress was associated with higher recurrence risk based on the test, as the majority of women who experienced test-related distress had intermediate or high recurrence risks based on their test results (low = 18% (6/33); intermediate = 30% (7/23); high = 44% (4/9)). Stronger feelings of distress were also related to receiving chemotherapy, not receiving radiation, and having more frequent worries about breast cancer recurrence.
Importance: Important
Transferability: Partially
No RCTs or prospective cohort studies on uPA/PAI-1, MammaPrint and Oncotype DX tests were found that assessed whether using these three prognostic tests (each test compared with standard/current practice or direct (head to head) comparison) to guide the use of adjuvant chemotherapy effectively improves long term clinical outcomes such as overall survival and disease-specific survival (for example: disease-free, progression-free, or recurrence-free survival)?
A few studies were found that did not satisfy the inclusion criteria and are discussed in the Domain discussion section.
In clinical trials registries the following trials were found: one ongoing RCT, the NNBC3-Europe trial, on the uPA/PAI-1 test; two RCTs, the TAILORx Trial and the WSG Plan B trial on Oncotype DX test; and one RCT, the MINDACT trial, on the MammaPrint test (Tables 1–3 in Appendix 2).
The aim of the NNBC3-Europe trialhttp://prsinfo.clinicaltrial.gov/ct2/show/record/NCT01222052?id=NCT01222052&rank=1 {18} is to compare the biological risk assessment using the uPA/PAI-1 test with a clinicopathological algorithm in patients with newly diagnosed node-negative breast cancer and to investigate whether high-risk node-negative patients should receive adjuvant chemotherapy with or without taxanes. The type of risk assessment used will be decided by each centre. Patients found to be at low risk will be observed. High-risk patients were randomised to one of the two adjuvant chemotherapies. The estimated completion date is February 2019.
The TAILORx (Trial Assigning Individualized Options for Treatment) trial http://prsinfo.clinicaltrial.gov/ct2/show/NCT00310180?id=NCT00310180&rank=1 {19} is a prospective clinical trial in which all patients undergo an Oncotype DX assay; if the RS is <11 patients will receive hormonal therapy alone. If the RS is >25, patients will receive chemotherapy plus hormonal therapy. If the RS is between 11 and 25, patients will be randomised to receive chemotherapy plus hormonal therapy (the standard treatment arm) versus hormonal therapy alone (the experimental treatment arm). The choice of the hormonal therapy and chemotherapy regimens will be at the discretion of the treating physicians and must be consistent with one of several standard options. The RS ranges differ from those originally described as low <18, intermediate (18–30) and high risk >30 for the assay. The estimated primary outcome completion date is April 2014.
The WSG Plan B trial is a randomised comparison of adjuvant docetaxel/cyclophosphamide with sequential adjuvant EC/docetaxel chemotherapy in patients with HER2/Neu-negative early breast cancer, http://prsinfo.clinicaltrial.gov/ct2/show/NCT01049425?id=NCT01049425&rank=1 {20} Classification of patients will be by Oncotype DX test results (in addition, optional uPA/PAI-1 may be done). Low-risk patients, with RS≤11 will receive hormone therapy alone. High-risk (including intermediate) patients, RS>11, will be randomised to two chemotherapy arms: epirubicin/cyclophosphamide followed by docetaxel or docetaxel/cyclophosphamide. The estimated primary outcome completion date is October 2016.
The MINDACT (Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial http://prsinfo.clinicaltrial.gov/ct2/show/NCT00433589?id=NCT00433589&rank=1 {21} is the first prospective, randomised study comparing the 70-gene signature with the common clinicopathological criteria in selecting patients for adjuvant chemotherapy in breast cancer with 0 to 3 positive nodes. All eligible women undergo a MammaPrint assessment and a traditional clinicopathological risk assessment, performed using a modified version of Ajuvant! Online.
Women with both clinical and genomic high risks are offered adjuvant chemotherapy; women with both clinical and genomic low risks do not receive chemotherapy; women with discordant risk are randomised for the decision of adjuvant chemotherapy based on clinical or genomic risk. All patients are candidates for adjuvant chemotherapy and are offered a non-mandatory second randomisation between an anthracycline-based regimen and docetaxel/capecitabine therapy. All ER-positive women may be offered a non-mandatory endocrine therapy randomisation between 7 years of letrozole and 2 years of tamoxifen following 5 years of letrozole. The estimated primary outcome completion date is March 2019.
Importance: Critical
Transferability: Completely
No RCTs or prospective cohort studies on uPA/PAI-1, MammaPrint and Oncotype DX tests were found that addressed how does treatment with adjuvant therapy on the basis of the test results of uPA/PAI-1, MammaPrint and Oncotype DX compared with treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer modify the magnitude and frequency of morbidity.
Please see the answer provided in the Assessment element question: EFF9 (D0025): What is the effect of adjuvant therapy on the basis of uPA/PAI-1, MammaPrint, or Oncotype DX test compared to treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer on overall survival and disease specific survival (for example: disease-free-, progression free-, recurrence-free-survival)?
Importance: Critical
Transferability: Completely
No RCTs or prospective cohort studies on uPA/PAI-1, MammaPrint and Oncotype DX tests were found that addressed how treatment with adjuvant therapy on the basis of the test results of uPA/PAI-1, MammaPrint and Oncotype DX tests compared with treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer improves patient morbidity.
Please see the answer provided in the Assessment element question:
EFF9 (D0025): What is the effect of adjuvant therapy on the basis of uPA/PAI-1, MammaPrint or Oncotype DX test compared to treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer on overall survival and disease specific survival (for example: disease-free-, progression free-, recurrence-free-survival)?
Importance: Critical
Transferability: Completely
The primary aim of our assessment was to determine whether, compared with current practice, using these three prognostic tests (uPA/PAI-1, MammaPrint and Oncotype DX) to help guide the use of adjuvant chemotherapy effectively improves long-term clinical outcomes, safety (adverse events due to adjuvant chemotherapy) and quality of life in women with early-stage breast cancer.
The secondary aims were to assess changes both in clinical decisions made about choice of treatment with adjuvant chemotherapy and in patient satisfaction.
There are no RCTs or prospective cohort studies that determined whether using these three prognostic tests to help guide the use of adjuvant chemotherapy effectively improves long-term clinical outcomes compared with current practice. A few studies were found that did not satisfy the inclusion criteria (Appendix 6). All but one {39} of these studies had a retrospective design {40–46}; they assessed the predictive accuracy of the test (“does the test accurately predict patients who will benefit most from chemotherapy?”), or the studies did not have a standard/current care comparator. These studies were assessed internally, and it was concluded that all were of very low level of quality according to the GRADE working group approach {17}. The very low quality of the studies raises important ethical and legal questions on the current use of these three tests, which are part of the medical devices technology group. We also found evidence of duplicate publications, author non-cooperation with our requests for more data, and inadequate trial registration in public, non-profit clinical trials registries.
A number of ongoing RCTs will also not produce direct evidence on these important clinical outcomes. Clearly, the manufacturers should communicate at an early stage with the EMA, FDA and HTA bodies to obtain so-called “early scientific advice” for designing RCTs {47}.
The majority of previous HTAs and Systematic Reviews of clinical effectiveness on the two prognostic genetic tests (Oncotype DX and MammaPrint) came to the same conclusion on these important clinical questions {8–11}.
Smart et al. 2010 {9} updated the Marchionni et al. 2008 {8} systematic review and concluded, similarly to the original review, that there were no studies that provided direct high quality evidence that Oncotype DX and MammaPrint lead to any improvement in outcome or that they are able to predict the response to chemotherapy. The most likely source of evidence on clinical utility will be the two ongoing RCTs: MINDACT and the TAILOR X trial.
The Ontario 2010 report {48} on Oncotype DX concluded that low quality evidence exists on its prognostic value in women who are being treated with adjuvant tamoxifen or anastrazole, and have newly diagnosed early breast cancer (stage I–II) that is oestrogen receptor-positive and/or progesterone receptor-positive and lymph node-negative. The same is true for lymph node-positive patients.
Very low quality evidence showed that Oncotype DX could predict which women will benefit from adjuvant CMF/MF chemotherapy in those being treated with adjuvant tamoxifen, in lymph node- negative as well as lymph node-positive early breast cancer patients.
The Blue Cross 2010 report {49} concluded that the use of the Oncotype DX test for selecting adjuvant chemotherapy in patients with lymph node-positive breast cancer is not recommended.
The systematic review by Ward et al. 2011 {10} reported that very limited evidence exists on the clinical utility of Oncotype DX and MammaPrint, so additional robust evidence is needed.
Very recently a NICE report {11} concluded that MammaPrint and Oncotype DX are not recommended in guiding the use of adjuvant chemotherapy in women aged 75 years or under with oestrogen receptor -positive, lymph node-negative and human epidermal growth factor receptor 2 (HER2) negative early breast cancer. The committee could not recommend these tests because of uncertainty in the evidence on clinical effectiveness leading to uncertainty about cost effectiveness.
According to the St. Gallen Consensus Document 2011 {50}, only the multiparameter gene assay Oncotype DX (Genomic Health Inc., Redwood City, CA, USA) was considered by a majority (84%) as potentially useful for decision making on adjuvant chemotherapy in cases where other factors (grade, HER2 etc.) do not help. On the other hand, the alternative test, the multigene array MammaPrint (Agendia, Amsterdam, The Netherlands), was not accepted (69% against). The option of using uPA/PAI-1 as a potential help in decision making was also not accepted (23% in favour, 50% against) {50}.
According to the assessment and report of the Dutch Health Insurance Board College voor zorgverzekeringen’ (CVZ) regarding the gene expression test, MammaPrint {51} the clinical utility of using MammaPrint has not yet been demonstrated. The current MINDACT trial, a prospective, randomised, multicentre study that compares use of MammaPrint with standard clinical risk estimates will have to demonstrate whether its use really does lead to health benefits. CVZ concluded that using the medical test MammaPrint, based on the results of the literature search relating to its clinical utility, does not comply with the criterion “established medical science and medical practice”.
All included studies in this domain that address the other assessment element questions were observational studies. Oncotype DX influenced a change in the physician’s adjuvant treatment recommendation in 19%–51% of patients. Using MammaPrint would have resulted in altered treatment advice in up to 40% of patients.
It should be noted that if a study finds that such changes in management are frequent, this does not imply that these changes in therapy are beneficial for the patients.
Only limited evidence was found on Quality of life, which remained stable according to Functional Assessment of Cancer Therapy 12 months after the Oncotype DX RS test. So-called State or situational anxiety (STAI) mean scores significantly decreased over time. More than 90% of patients continued to feel satisfied that they had used the RS assay and were satisfied with their treatment decision at 12 months after the RS assay. Five patients who were not satisfied noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and negative impact on self image.
Most women (95%) reported that they would have the Oncotype DX test again if they had to decide today, and would recommend the test to other women {22}.
Unsuitable evidence was found on the question of whether knowledge of the test results (uPA/PAI-1, MammaPrint, or Oncotype DX) improves the patient’s quality of life compared with standard practice (once again only on the Oncotype DX test). The majority of women agreed that the Oncotype DX test gave them a better understanding of the chances of success of their treatment options; only a few women had concerns about the test or agreed that this information about one’s cancer is better left unknown {23,24}. Approximately one quarter of women agreed or strongly agreed that receiving the Oncotype DX test result made them worried and anxious {24}.
In the Constructive Technology Assessment {52}, as part of the clinical RASTER study on the MammaPrint test, a questionnaire was sent to part of the patient population (only 77 were analysed, out of 427 patients in the RASTER study in which prognostic signatures were assessed, out of 812 accrued patients), and showed that the satisfaction about receiving the 70-gene signature per risk group was 76%. It should be noted that the distribution of the risk groups was different from that of the total RASTER population (more concordant low-risk patients) {52}.
The assessment has several limitations. The major limitation was that we assessed prognostic tests within the framework of a Core HTA Model for diagnostic technologies. Due to the different assessment element questions we were not able to assess analytical and clinical validity, only clinical utility. Prognostic/predictive accuracy was not assessed in this HTA Core Model. Despite these limitations our conclusion on uncertainty in the evidence of clinical effectiveness was the same as in other systematic reviews and HTA reports {8–11, 48, 49, 51}.
Clinical utility is based on a study defined as providing direct evidence of improvement in clinical outcomes. The use of the prognostic test in decision making is compared with not using the test, with health outcomes as an endpoint, generally in an RCT; so the primary intervention is the use of the prognostic test (with additional therapeutic decision making directed by the results) and the clinical outcomes are, for example, patient morbidity, mortality and/or quality of life. The analytical and clinical validity are of course of utmost importance for the assessment of clinical utility (or effectiveness).
There is a clear need to develop a new Core HTA Model for prognostic technologies, and probably for genetic tests separately. As pointed out in the published literature, in order to assess their reliability and generalisability for use, prognostic models need to have been validated and measures of model performance reported. Previously published studies and reviews of prognostic factors results highlight serious concerns about the quality of prognostic studies. Many published prognostic models have been developed using poor methods and many are poorly reported, both of which compromise the reliability and clinical relevance of the models, and of prognostic indices and risk groups derived from them. It is of concern that health professionals may direct patient treatment on the basis of poorly developed and reported prognostic studies. Good reporting is also critical for the interpretability and clinical applicability of prognostic studies. Reporting of key information is currently poor, resulting in reporting bias, which has a negative influence on the further development of systematic reviews and evidence-based medicine. Study publication and outcome reporting biases are two major obstacles to evidence-based practice because they overestimate the effect of experimental treatments, can cause harm, and are unethical {53–56}.
Genetic tests are considered to be part of the group of medical devices technologies. Different regulations, according to marketing authorisation, even on innovative high-risk medical devices (class III) are recognised in the USA and the EU, putting the EU patients at higher risk of developing serious adverse events as a result of decision making based on these results {57}. As remarked in the report, HTA agencies are repeatedly confronted with a relative lack of clinical data when assessing the value of innovative high-risk devices when they enter the market in Europe (innovative high-risk devices in Europe include innovative class III devices and innovative implantable devices). In the USA innovative high-risk devices (class III) typically undergo a pre-market approval (PMA) process. In Europe, the pre-market clinical evaluation is defined as the assessment and analysis of clinical data pertaining to a medical device to verify the clinical safety and performance of the device when used as intended by the manufacturer. Clinical safety is the absence of unacceptable clinical risks, when using the device according to the manufacturer’s instructions for use. Clinical performance is the ability of a medical device to achieve its intended purpose as claimed by the manufacturer. In the USA, under the PMA process, each manufacturer must independently demonstrate “reasonable assurance of the safety and effectiveness” of the device for its intended use.
High quality evidence on the clinical effectiveness (clinical utility) of uPA/PAI-1, MammaPrint and Oncotype DX tests is lacking. The majority of included observational studies have retrospective or cross-sectional study designs, and small sample sizes with heterogeneity of patient cohorts. Although current ongoing RCTs were found some of these will not give direct evidence on important clinical outcomes. There is a clear need for early manufacturers’ communication with EMA, FDA and HTA bodies on so-called “early scientific advice” for designing RCTs. Further high quality evidence on uPA/PAI-1, MammaPrint and Oncotype DX tests from RCTs is needed to guide the use of adjuvant chemotherapy in women with early invasive breast cancer.
Appendix EFF-1 List of included studies in the systematic review of Clinical Effectiveness domain
Oncotype DX test |
Ademuyiwa FO et al. The effects of oncotype DX recurrence scores on chemotherapy utilization in a multi-institutional breast cancer cohort. Breast Cancer Res Treat. 2011;126:797-802. |
Asad J et al. Does oncotype DX recurrence score affect the management of patients with early-stage breast cancer? The American Journal of Surgery.2008; 196:527–9. |
Geffen et. al. The impact of the 21-gene recurrence score assay on decision making about adjuvant chemotherapy in early-stage estrogen-receptor-positive breast cancer in an oncology practice with a unified treatment policy. Annals of Oncology. 2011;22: 2381–6. |
Henry LR et al. The influence of a gene expression profile on breast cancer decision. Journal of Surgical Oncology. 2009;99:319-23. |
Joh JE et al. The Effect of Oncotype DX Recurrence Score on Treatment Recommendations for Patients with Estrogen Receptor–Positive Early Stage Breast Cancer and Correlation with Estimation of Recurrence Risk by Breast Cancer Specialists. The Oncologist. 2011;16:1520-26. |
Kamal AH et al. Breast Medical Oncologists’ Use of Standard Prognostic Factors to Predict a 21-Gene Recurrence Score. The Oncologist. 2011;16:1359-66. |
Lo SS et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28:1671-6. Epub 2010 Jan 11. |
Oratz et.al. Physician Survey of the Effect of the 21-Gene Recurrence Score Assay Results on Treatment Recommendations for Patients With Lymph Node–Positive, Estrogen Receptor–Positive Breast Cancer. Journal Of Oncology Practice. 2011;7:94-9. |
Oratz R et al. Impact of a Commercial Reference Laboratory Test Recurrence Score on Decision Making in Early-Stage Breast Cancer. JOP. 2007;3:182-6. |
Partin JF et al. Impact of the 21-gene recurrence score assay compared with standard clinicopathologic guidelines in adjuvant therapy selection for node-negative, estrogen receptor-positive breast cancer. Annals of Surgical Oncology. 2011;18: 3399-3406. |
Rayhanabad JA et al. Changing paradigms in breast cancer management: introducing molecular genetics into the treatment algorithm. The American Surgeon. 2009;74:887-90. |
Richman AR et al. Knowledge of genomic testing among early-stage breast cancer patients. Psycho-Oncology. 2011;20:28-35. |
Tzeng JP et al. Women’s Experiences With Genomic Testing for Breast Cancer Recurrence Risk Cancer. 2010;116:1992-2000. |
MammaPrint test |
Bueno-de-Mesquita JM et al. Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol. 2007;8:1079–87. |
Gevensleben et al. Comparison of MammaPrint and TargetPrint results with clinical parameters in German patients with early stage breast cancer; International Journal of Molecular Medicine. 2010; 26:837-43. |
Appendix EFF-2 Ongoing RCTs in clinical trials registries on the uPA/PAI-1, Oncotype DX and MammaPrint tests
Table 1. Clinical trials registries—ongoing RCTs on the uPA/PAI-1 test (FEMTELLE, ELISA tests, American Diagnostica Inc.)
Official Study title | |
Randomized Multicenter Study Comparing 6xFEC With 3xFEC-3xDoc in High-risk Node-negative Patients With Operable Breast Cancer: Comparison of Efficacy and Evaluation of Clinico-pathological and Biochemical Markers as Risk Selection Criteria NNBC3-Europe trial | |
Study characteristics | |
Study design |
Partially RCT |
Study Registration number |
NCT01222052 |
Country of recruitment |
Germany and France |
Sponsor |
Martin-Luther-Universität Halle-Wittenberg |
Collaborators |
Not reported |
Study methodology |
Risk assessment tool; classification of patients by uPA /PAI-1 results or clinicopathological results (each centre was allowed to select the method of risk assessment for all of their patients, according to the results they selected in one of two groups) Low vs High (by either clinicopathological results or uPA /PAI-1 test results) Low risk (by prognostic test: uPA ≤3 ng/mg and PAI-1 ≤14 ng/mg or clinicopathological results ) - observation only High risk (by prognostic test, uPA /PAI-1 or clinicopathological results; patients will be stratified by HER2 receptor and then randomly assigned) RANDOMISATION (patients will be randomly assigned to one of two chemotherapy arms - chemo th FEC (anthracycline-containing chemotherapy; 5-fluorouracil/epirubicin/cyclophosphamide) vs. - chemo th FEC-docetaxel (anthracycline and taxane-containing chemotherapy; 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel) |
Study start |
January 2001 |
Estimated completion date |
February 2019 |
Patient characteristics | |
Age of patients |
18–65 |
Gender | |
Tumour size |
0.5–5.0 cm |
Histological grade |
T1–T2 |
Lymph-node status |
Negative |
Oestrogen receptor status | |
HER 2 |
Positive and negative |
Progesterone receptor status | |
Menopausal status |
Pre- and postmenopausal |
Estimated Enrolment |
4149 (from literature) |
Intervention | |
Test |
uPA/PAI-1 (FEMTELLE, ELISA tests - American Diagnostica Inc.): Low and High risk |
Comparator | |
Clinicopathological algorithm | |
Outcomes | |
Primary |
Disease-free survival (DFS) |
Secondary |
Overall survival (OS); compliance; toxicity of chemotherapy in each patient group; The proportion of low risk versus high risk patients; DFS; OS |
Table 2. Clinical trials registries—ongoing RCTs on the Oncotype DX test
Official Study title | ||
Program for the Assessment of Clinical Cancer Tests (PACCT-1): Trial Assigning Individualized Options for Treatment: The TAILORx Trial |
Randomised Comparison of Adjuvant Docetaxel/Cyclophosphamide With Sequential Adjuvant EC/Docetaxel Chemotherapy in Patients With HER2/Neu Negative Early Breast Cancer, WSG Plan B trial | |
Study characteristics | ||
Study design |
Partially RCT |
Partially RCT |
Registration number |
NCT00310180 |
NCT01049425 |
Country of recruitment |
United States, Australia, Canada, Peru |
Germany |
Sponsor |
Eastern Cooperative Oncology Group |
West German Study Group |
Collaborators |
National Cancer Institute (NCI); Southwest Oncology Group; Cancer and Leukemia Group B; American College of Surgeons; North Central Cancer Treatment Group; NCIC Clinical Trials Group; National Surgical Adjuvant Breast and Bowel Project (NSABP) |
Sanofi-Aventis, Amgen |
Study methodology |
Risk assessment tool; classification of patient by genetic test results Oncotype DX alone Low vs. intermediate vs. high ) (by Oncotype DX test results) Low risk, RS<11 - hormone th alone Intermediate risk, RS 11-25 RANDOMISATION (the patient will be randomly assigned to two arms) -hormone therapy alone -hormone therapy + chemotherapy High risk RS >25 - hormone therapy + chemotherapy |
Risk assessment tool; classification of patient by genetic test results Oncotype DX (in addition optional uPA/PAI-1 may be done) Low vs. High (including Intermediate) (by Oncotype DX test results) Low risk RS≤11 - hormone therapy alone High risk (including intermediate) RS>11 RANDOMISATION (the patient will be randomly assigned to two chemotherapy arms) - chemotherapy; epirubicin/cyclophosphamide followed by docetaxel vs. - chemotherapy: docetaxel/ cyclophosphamide |
Study start |
Not reported |
January 2009 |
Estimated Primary outcome completion date |
April 2014 |
October 2016 |
Estimated completion date |
Not reported |
Not reported |
Patient characteristics | ||
Age of patients |
17–75 |
18–75 |
Gender |
Female |
Female |
Tumour size |
1.1–5.0 cm | |
Histological grade |
Not reported |
T1–T4 |
Lymph-node status |
Negative |
Positive and negative |
Oestrogen receptor status |
Positive |
Positive |
HER 2 |
Negative |
Negative |
Progesterone receptor status |
Positive |
Positive |
Menopausal status |
Pre- and postmenopausal |
Pre- and postmenopausal |
Estimated Enrolment |
11248 |
2448 |
Intervention | ||
Test |
The Oncotype DX 21-gene Recurrence Score (RS) (Oncotype DX, Genomic Health, Redwood City, CA): Low, Intermediate, High |
The Oncotype DX 21-gene Recurrence Score (RS) (Oncotype DX, Genomic Health, Redwood City, CA): Low, Intermediate, High |
Comparator | ||
None. Risk assessment according Oncotype DX |
None. Risk assessment according Oncotype DX (in addition optional uPA/PAI-1 may be done) | |
Outcomes | ||
Primary |
Disease-free survival; distant recurrence-free interval; recurrence-free interval ; overall survival; comparison of FACT-Cog perceived cognitive impairment scores between participants at 3 months |
Disease-free survival in two chemotherapy arms (patients treated with either 6 cycles of docetaxel / cyclophosphamide chemotherapy vs 4 cycles of EC followed by 4 cycles of docetaxel as adjuvant treatment (time frame: 5 years) |
Secondary |
Comparison of FACT-Cog scores between arms B and C at 3, 12, 18, 24, and 36 months; Differences in FACT-Cog change scores from randomisation to 3, 6, 12, 18, 24, and 36 months; Differences between arms B and C on other patient-reported outcomes measures; Differences between participants receiving hormonal treatment alone (arm B vs arm A) on patient-reported outcomes measures; Differences between participants receiving chemotherapy followed by hormonal treatment (arm C vs arm D) on patient-reported outcomes measures |
Not reported |
Table 3. Clinical trials registries-ongoing RCTs on the MammaPrint test
Official Study title | |
MINDACT (Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy): A Prospective, Randomized Study Comparing the 70-gene Signature With the Common Clinical-Pathological Criteria in Selecting Patients for Adjuvant Chemotherapy in Breast Cancer With 0 to 3 Positive Nodes | |
Study characteristics | |
Study design |
Partially RCT |
Study Registration number |
NCT00433589 |
Country of recruitment |
Netherlands |
Sponsor |
European Organization for Research and Treatment of Cancer - EORTC |
Collaborators |
Not reported |
Study methodology |
Risk assessment tool; classification of patient by both genetic test (MammaPrint) results and clinicopathological results Low vs. High risk (with both clinicopathological and genetic test [MammaPrint] results) Clinicopathological and MammaPrint Low risk - hormone therapy alone: tamoxifen vs letrozole Clinicopathological and MammaPrint High risk - chemotherapy: antracycline based vs docetaxel + capecitabine Discordant risk between genetic test risk assessment and clinicopathological risk assessment (Clinicopathological High and MammaPrint Low or Clinicopathological Low and MammaPrint High) RANDOMISATION (the patient will be randomly assigned for assessment either by clinicopathological risk results or by MammaPrint risk results to decide on the use of chemotherapy or not) - Low risk hormone therapy: sequential tamoxifen-letrozole vs letrozole - High risk chemotherapy: antracycline based vs docetaxel + capecitabine |
Study start |
December 2006 |
Estimated primary outcome completion date |
March 2019 |
Estimated completion date | |
Patient characteristics | |
Age of patients |
18 years and older |
Gender |
Female |
Tumour size | |
Histological grade |
T1-T3 |
Lymph-node status |
Positive and negative |
Oestrogen receptor status |
Positive |
HER 2 | |
Progesterone receptor status |
Positive |
Menopausal status |
Pre- and postmenopausal |
Estimated Enrolment |
6600 |
Intervention | |
Test |
MammaPrint (the 70-gene prognosis signature, Amsterdam, Netherlands): low and high risk |
Comparator | |
Clinicopathological algorithm using Adjuvant! Online | |
Outcomes | |
Primary |
Distant metastasis-free survival at 5 years; disease-free survival (DFS) |
Secondary |
Proportion of patients treated with chemotherapy based on clinical prognosis compared with 70-gene signature prognosis; overall survival at 5 years; DFS at 5 years; safety (early and late) |
Appendix EFF-3 Evidence table on Oncotype DX test on the research question: changes in health related quality of life
Table 1. Oncotype DX (21-gene recurrence score (RS) assay, Genomic Health, Redwood City, CA) on research question: changes in health related quality of life (22)
Author, year, reference number: | |
Lo SS et al. J Clin Oncol. Apr 1;28(10):1671-6. Epub 2010 Jan 11. | |
Study title | |
Prospective multicentre study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection | |
Study characteristics | |
Study design |
Observational study— prospective, pre-post design (patients and physicians served as their own controls at two time-points, pre- and post-RS assay) |
Study Registration number |
Not reported |
Country |
USA |
Centre |
Multicentre (one community and three academic practices) |
Ethics Committee Approval |
Yes |
Sponsor |
Unrestricted clinical trials grant from Genomic Health Inc. |
Study period (study start, study end) |
December 2005–August 2006 (pre-, and immediately post RS assay, and follow up at 12 months) |
Patient characteristics | |
Age of patients mean with SD (range) |
55 (35–77) |
Tumour size (diameter) |
1.7 cm (0.6–3.5) |
Histological grade (1-good, 2-intermediate, 3-poor) |
1–2 |
Lymph-node status (negative, positive) |
Negative |
Oestrogen receptor status (negative, positive) |
Positive |
HER 2 (positive, negative) |
Both |
Progesterone receptor status (negative, positive) |
Not reported |
Menopausal status |
Both |
Intervention | |
Test |
Oncotype DX (21-gene recurrence score (RS) assay, Genomic Health, Redwood City, CA); High-Intermediate-Low |
Threshold values for categorisation of high/intermediate/low risk and number of patients |
Low <18 n = 38 (42.7%) Intermediate 18–30 n = 42 (47.2%) High >31 n = 9 (10.1%) |
Central analysis/centre specific of test |
Not reported |
Comparator | |
Standard clinicopathological prognostic factors (41 physicians (46%) also use Adjuvant!Online) | |
Outcomes | |
Change in patient satisfaction with choice of treatment; Change in patient anxiety; Change in patient decisional conflict; Change in patient quality of life | |
Flow of patients | |
No of patients enrolled |
N = 93 |
Number of analysed patients |
N = 89 (96%) N = 67 (75%) after 12 months |
Results | |
Change in patient quality of life |
FACT-B: pre-RS mean 112.2 (SD = 17.4): 12 months post-RS 114.3 (SD = 18.6); P = 0.55 FACT-G: pre-RS mean 88.7 (SD = 12.3): 12 months post-RS 87.6 (SD = 14.9); P = 0.49 |
Change in patient satisfaction |
Immediately post-RS assay: 78 (95%) were glad they took the RS assay test. 77 (87%) understand how the assay work. 79 (89%) felt that the results were easy to understand. 74 (83%) indicated that the results of the RS assay influenced their decision making. 12-month post-RS assay: 67 (75%) completed the 12-month questionnaire. 62 (92.5%) continued to feel satisfied that they had used the RS assay. 64 (95.5%) were satisfied with their treatment decision. 54 (80.6%) continued to believe that the results influenced their treatment decision. Those patients (n = 5) not satisfied noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and negative impact on self image. |
Change in patient anxiety |
State or situational anxiety (STAI) mean scores significantly decreased over time; 39.6 (SD = 14.5): 36 (SD = 12.6): 34 (SD = 11.5); P = 0.007 Trait anxiety or the dispositional tendency to be anxious mean did not significantly decreased over time; 32.2 (SD = 14.5): 31.7 (SD = 13.3): 33.2 (SD = 11.0), P = 0.27 |
Change in patient decisional conflict |
Statistically significant decreased immediately post-RS; mean DSC 1.99 (SD = 0.62): 1.69 (SD = 0.50); P<0.001 |
Author disclosure (Conflict of interest) | |
Genomic Health (Research funding: Consultant or Advisory Role: Honoraria ) |
Appendix EFF-4 Evidence table on Oncotype DX test on patient satisfaction questions
Table 1. Oncotype DX (21-gene recurrence score (RS) assay, Genomic Health, Redwood City, CA) (23,24)
Author, year, reference number: | ||||||
Richman AR et al. Psycho-Oncology. 2011;20:28-35. |
Tzeng JP et al. Cancer. 2010;116:1992-2000. | |||||
Study title | ||||||
Knowledge of genomic testing among early-stage breast cancer patients |
Women’s experiences with genomic testing for breast cancer recurrence risk | |||||
Study characteristics | ||||||
Study design |
Observational study: cross-sectional study (questionnaire), supplemented by medical chart review |
Observational study: cross-sectional study (questionnaire), supplemented by medical chart review | ||||
Study registration number |
Not reported |
Not reported | ||||
Country |
USA and Netherlands |
USA | ||||
Centre |
Multicentre |
Multicentre | ||||
Ethics committee approval |
Yes |
Yes | ||||
Sponsor |
Grant MSRG-06-259-01-CPPB from the American Cancer Society |
Grant MSRG-06-259-01-CPPB from the American Cancer Society | ||||
Study period (study start, study end) |
December 2008 and June 2009 |
December 2008 and May 2009 | ||||
Study period (study start, study end) |
December 2008 and June 2009 |
December 2008 and May 2009 | ||||
Patient characteristics | ||||||
Age of patients |
58 (38-83) |
58 (38-83) | ||||
Tumour size (diameter) |
Not reported |
Not reported | ||||
Histological grade (1-good, 2-intermediate, 3-poor) |
1-2 |
1-2 | ||||
Lymph-node status |
Majority node negative (66/68, 97%) |
Majority node negative (66/68, 97%) | ||||
Oestrogen receptor status |
Positive |
Positive | ||||
HER 2 |
Not reported |
Not reported | ||||
Progesterone receptor status |
Positive |
Positive | ||||
Menopausal status |
Both |
Both | ||||
Intervention | ||||||
Test |
Oncotype DX (21-gene recurrence score (RS) assay, Genomic Health, Redwood City, CA); High-Intermediate-Low |
Oncotype DX (21-gene recurrence score (RS) assay, Genomic Health, Redwood City, CA); High-Intermediate-Low | ||||
Threshold values for categorisation of high/intermediate/low risk and number of patients |
Low (≤11%) n = 34/68 (50%) Intermediate (12–21%) n = 25/68 (37%) High (>21%) n = 9/68 (13%) |
Low (≤11%) n = 34/68 (50%) Intermediate (12–21%) n = 25/68 (37%) High (>21%) n = 9/68 (13%) | ||||
Central analysis/centre specific of test |
Not reported |
Not reported | ||||
Comparator | ||||||
None |
None | |||||
Outcomes | ||||||
Primary and Secondary |
Knowledge of genomic testing (identify correlates of knowledge, including patient characteristics, experiences with breast cancer treatment, and experiences with genomic testing, whether different ways of presenting test results was associated with higher knowledge); Role in treatment decision; how patients received test results; patients perceived consequences of genomic recurrence risk testing |
Patient numeracy and literacy; breast cancer worres; how patients learnt about the test; how patients received the test results; patients attitudes towards Oncotype DX testing; participants recalled recurrence risk; perceived recurrence risk; patient treatment decision. | ||||
Flow of patients | ||||||
No of patients enrolled |
N = 104 invited women |
N = 104 invited women N = 78 completed the survey | ||||
Number of analysed patients |
N = 78 completed the survey N = 68 (87%) gave authorisation to review medical charts |
N = 77 analysed | ||||
Results | ||||||
Change in patient satisfaction |
Most women (96%, 74/77) reported that they would have the test again if they had to decide today. 95%, 73/77 would recommend the test to other women. 95%, 73/77 agreed that having the test gave them a better understanding of their treatment option’s chances of success. Few women had concerns about the test: 8% (6/77) of women reported that they had the test only because other family members wanted them to; 5% (4/77) reported that having the test had a negative effect on their family; only 3% (2/76) agreed that this information about one’s cancer is better left unknown. |
Most women reported that they would have the test again if they had to decide today (96%). 95% would recommend the test to other women in the same situation. Almost all women (95%) agreed that having the test gave them a better understanding of their treatment option’s chances of success. Few women agreed that they had the test only because other family members wanted them to (8%); the test had a negative effect on their family (5%); that information about one’s cancer is better left unknown (3%, 2 of 76). About 25% of women recalled experiencing test-related distress. Approximately 26% (17 of 65) of women agreed or strongly agreed that receiving the test result made them worried and anxious. Greater endorsement of test-related distress was associated with higher actual recurrence risk based on the test, as the majority of women who experienced test-related distress had intermediate or high recurrence risks based on their test results (low=18%, 6 of 33; intermediate =30%, 7 of 23; high=44%, 4 of 9). Stronger feelings of distress were also related to receiving chemotherapy, not receiving radiation, and having more frequent worries about breast cancer recurrence. Approximately 3/4 said they trusted the test results (77%, 57 of 74); believed they were accurate (71%, 53 of 75); found the test useful because it could determine with certainty whether their cancer had a high chance of coming back (76%, 57 of 75). | ||||
Author disclosure (Conflict of interest) | ||||||
No conflict of interest |
Not reported | |||||
Appendix 5 Evidence table on uPA/PAI-1, Oncotype DX, MammaPrint test on research question: Changes in the treatment choice with adjuvant therapy
Appendix 6 Excluded studies from the Systematic review of Clinical Effectiveness Domain (assessed only predictive accuracy or studies without standard/current care comparator) on assessment element question: ”Whether use of the three prognostic tests (uPA/PAI-1, OncotypeDX and MammaPrint to guide adjuvant chemotherapy effectively improves long term clinical outcomes, like overall survival and disease free survival”, with quality assessment according the GRADE
Authors: Isaura Vieira, Mirella Corio, Maria Rosaria Perrini, Matteo Ruggeri
Based on the literature reviewed, the introduction of prognostic tests into the clinical pathway of women with early invasive breast cancer could bring a positive impact on the management, treatment costs and quality of life due to more appropriate treatment following better prognostic testing. In other words, the introduction of these tests may avoid unnecessary use of expensive chemotherapy with its associated adverse effects for women who derive little or no benefit from it and may reduce the mortality rate in high-risk women who would have benefitted from chemotherapy {13}.
We do not yet have enough information to reach conclusions about the cost-effectiveness ratios. Further generation of effectiveness data may make the estimation of such ratios possible in the future.
The results of prognostic tests for breast cancer recurrence (PTBCRs) can influence further therapeutic decisions about the use of adjuvant chemotherapy to treat women diagnosed with early stage invasive breast cancer. However these tests are more costly than current practice (St Gallen consensus recommendations, National Comprehensive Cancer Network guidelines (NCCN), Adjuvant! Online, and Nottingham Prognostic Index (NPI)). The aim of the costs and economic evaluation domain is to determine whether the use of the PTBCRs (uPA/PAI-1[FEMTELLE®], MammaPrint®, Oncotype DX®) is a cost-effective option, taking into consideration both the clinical outcomes (for example, patient morbidity, mortality and/or quality of life) and the costs/resources used.
The costs and economic evaluation domain consists of five topics: cost-effectiveness, resource utilisation, unit costs, indirect costs and outcomes/consequences.
According to the findings of the clinical effectiveness domain {EFF domain}, there was insufficient good quality evidence to determine whether using these PTBCRs to guide the use of adjuvant chemotherapy effectively improves long term clinical outcomes. The EFF domain found a few studies of very low quality that assessed the predictive ability of the tests. In the absence of an accurate estimate of the clinical value of the tests, it was not possible to estimate cost effectiveness and only a rough description has been provided of how an economic evaluation would be prepared if clinical effectiveness data were to become available.
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
E0001 | Resource utilization | What types of resources are used when delivering the assessed technology and its comparators (resource use identification)? | yes | What types of resources are used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® and what types of resources are used when delivering standard clinical practice? |
E0002 | Resource utilization | What amounts of resources are used when delivering the assessed technology and its comparators (resource use measurement)? | yes | What quantity of resources is used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® and what quantity of resources are used when delivering standard clinical practice? |
E0003 | Unit costs | What are the unit costs of the resources used when delivering the assessed technology and its comparators? | yes | What are the unit costs of the resources used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® and what are the unit costs of the resources used when delivering standard clinical practice? |
E0004 | Indirect Costs | What is the impact of the technology on indirect costs? | yes | What is the impact of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® on indirect costs? |
E0005 | Outcomes | What are the incremental effects of the technology relative to its comparator(s)? | yes | What are the incremental effects of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® relative to standard clinical practice? |
E0006 | Cost-effectiveness | What is the incremental cost-effectiveness ratio? | yes | What is the incremental cost-effectiveness ratio of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® compared to standard clinical practice? |
Domain frame
The project scope is applied in this domain and we have added the time frame and perspective to the economic analysis:
Target population |
Women with early invasive breast cancer |
Intervention |
Use of at least one of the following prognostic tests: uPA/PAI-1 (FEMTELLE), MammaPrint or Oncotype DX |
Comparators |
Standard care without any of the three index tests (uPA/PAI‐1 [FEMTELLE], MammaPrint, Oncotype DX). As currently there is no standard universally accepted practice, different practices may be involved such as testing with St Gallen consensus recommendations, NCCN guidelines , Adjuvant! Online, or the NPI |
Outcomes |
Quality-adjusted life years (QALY) (morbidity and mortality or survival, safety [adverse events according adjuvant chemotherapy], quality of life, clinical decision making on treatment choice with adjuvant chemotherapy, patient satisfaction, overall benefit and harms in health outcomes) |
Time frame |
Until the end of life |
Perspective |
Consequences and costs are assessed from the societal perspective |
Information sources
The information sources and search strategy were contained in the one adopted for the Core HTA {Appendix COL-1}. Of the 616 articles identified, 61 studies were identified for use in this domain by one reviewer who used the following search terms alone included in the title and abstract of each article: “resource”, “cost”, “impact” and “effectiveness”. The 61 studies identified were divided among four reviewers for a second review based on the abstract and using the following inclusion criteria:
18 of the 61 papers were selected, divided among the four reviewers and the data were extracted by each reviewer.
The authors of the studies presented in conferences or meetings and that were only available in abstract or poster format were contacted to request information about the status of the study. All authors successfully contacted responded that their studies had not been published and that there had been no further developments.
A specific search of the National Institute for Health and Clinical Excellence (NICE) website was also performed to identify guidance concerning the treatment of early invasive breast cancer.
uPA/PAI-1 (FEMTELLE)
The search did not identify any economic studies.
MammaPrint
The search identified three economic studies. Chen et al. {6} compared MammaPrint with Adjuvant! Online. Eng-Wong et al. {10} used Oncotype DX and Adjuvant! Online. Retel et al. {5} compared MammaPrint with St Gallen consensus recommendations and Adjuvant! Online.
Oncotype DX
The search identified nine economic studies. Bacchi et al. {9} compared Oncotype DX with standard care (data collected from a survey of doctors). Eng-Wong et al. {10} used MammaPrint and Adjuvant! Online. Vanderlaan et al. {7} and Hornberger et al. {8} used NCCN as comparator. Tsoi et al. {4} used Adjuvant! Online as comparator. Kondo et al. {2,3} compared Oncotype DX with NCCN and St Gallen consensus. Klang et al. {1} and Kelly et al. {11} did not identify the comparator used in their studies.
Quality assessment tools or criteria
Quality assessment criteria were not applied to the studies that were identified for review. The quality assessment of economic studies could be done using Drummond's criteria {12} although we have decided not to use it here as there were few studies and all the information available was required.
Analysis and synthesis
Data from the different studies were not synthesised as this was not necessary for this domain. The studies were compared, however, to identify any differences in study methodology.
Studies extracted from the basic literature search were analysed. Data from eight studies {1; 2; 3; 4; 5; 7; 8; 9} were found to be relevant to this question. The ORG and TEC domains also provided information relevant to this question.
None
Taking into account the outcomes described in the scope, the resources to be included in the analysis extend beyond those used in the diagnostic process.
Depending on the patient’s risk of recurrence, early invasive breast cancer may be treated, after primary surgery, with adjuvant chemotherapy to prevent or delay distant recurrence {1; 2}. The introduction of prognostic tests that assess the likelihood of breast cancer recurrence {TEC domain} could change the probability of using adjuvant chemotherapy to treat invasive breast cancer. Thus the use of prognostic tests will change the costs associated with treatment and the downstream costs of dealing with any cancer recurrences. It is important to include all the resources used and their costs. The resources used were identified from four main studies {2; 3; 4; 5}.
According to Chen et al. {6} after patients are divided according to risk profiles, they can be assigned to different treatment scenarios: chemotherapy plus endocrine therapy for oestrogen (ER)-positive, high-risk patients; chemotherapy alone for ER-negative, high-risk patients; endocrine therapy alone for ER-positive, low-risk patients; and no adjuvant therapy for ER-negative, low-risk patients. Anti-HER2 (human epidermal growth factor receptor 2) agents (e.g trastuzumab) can be added to chemotherapy depending on the risk classification and HER2 status {3}.
Table 1. Resources identified
Resources |
Source |
Delivery of prognostic tests | |
Test |
TEC domain |
Trained resources to collect the tissue samples (nurse and pathologist) |
TEC and ORG domain |
Adjuvant therapy | |
Endocrine therapy |
{2; 3} |
Chemotherapy including supportive medications such as antiemetics |
{2; 3;7} |
Anti-HER2 Agents |
{2; 3} |
Day care costs |
{5} |
Treatment for adjuvant chemotherapy toxicity | |
Major resources (includes unplanned hospitalisation) |
{2; 3} |
Treatment for distant recurrence | |
Endocrine therapy and chemotherapy including supportive medications such as antiemetics |
{2; 3;7} |
Anti-HER2 Agents |
{2; 3} |
Monitoring | |
Laboratory test per cycle of chemotherapy |
{4} |
Follow up of recurrence-free patient |
{4} |
Follow up of patient with distant recurrence |
{4} |
Tamoxifen therapy over 5 years |
{4} |
Medical care for the end of life |
{4} |
Since few studies have a well-described coverage of the costs included in the model, further information about the resources used in the treatment decisions and treatment of women diagnosed with early invasive breast cancer would be needed to provide an appropriate economic evaluation.
Importance: Critical
Transferability: Completely
Selected studies extracted from the basic literature search were analysed. Eight studies {1; 2; 3; 4; 5; 7; 8; 9} were found to be relevant to this question.
The quantity of resources used, excluding the resources associated with the delivery of the prognostic tests, will be highly dependent on the distribution of patients over the risk profiles and on the distribution of the duration in each of the different health states. Thus the amount of resources used, after the risk of recurrence profile distribution (using the prognostic tests or standard of care), will need to be modelled separately for each of the treatment scenarios and patient health states.
A number of the studies selected and analysed describe the quantity of resources used in their models {2; 3; 4; 5}. These estimates of resource utilisation were based on different sources of information including treatment guidelines, observational studies, and retrospective studies leading to different estimates of overall resource utilisation in different studies.
This variability, based on the inconsistency of the data, could be reduced with further high quality evidence from randomised controlled trials (RCTs) as discussed in the EFF domain.
Due to the limitations referred to in the domain introduction, the objective here is to prepare a rough description of the structure of an economic evaluation. It was not considered appropriate to present the unit costs for each resource identified.
Importance: Critical
Transferability: Partially
The studies selected and extracted from the basic literature search were analysed. Eight studies {1; 2; 3; 4; 5; 7; 8; 9} were found to be relevant to this question because they had a chapter dedicated to costs.
The majority of the studies that were found to be relevant did not present the unit costs by resource but instead provided only the total cost of the identified resource. Additionally, costs can vary from region to region and are not transferable to national HTA production.
Due to the limitations referred to in the domain introduction, the objective here is to prepare a rough description of the structure of an economic evaluation. It was not considered appropriate to present the unit costs for each resource identified.
Importance: Critical
Transferability: Not
Selected studies extracted from the basic literature search were analysed. Only two economic studies {1; 7} were found to be relevant to this question.
The study perspective selected in the scope—societal perspective—requires consideration of the inclusion of indirect costs in the model.
It is known that both chemotherapy treatment, mainly its adverse effects, and cancer recurrence can generate productivity loss in active women. Only two of the studies referred to indirect costs and they did not consider the inclusion of productivity losses due to the perspective adopted (payer’s perspective) {1; 7}.
The use of prognostic tests is expected to have a positive impact on indirect costs if, from its utilisation, there is a resulting decrease in the utilisation of chemotherapy and a decrease in cancer recurrence. There is not enough high quality evidence to assess this impact.
Further evidence development is needed to address this question.
Importance: Optional
Transferability: Not
Analysis of selected studies extracted from the basic literature search.
According to the EFF domain, there is insufficient high quality evidence to assess the effectiveness of the intervention. Without this information, it is not possible to calculate the incremental effects.
More information on this topic can be found in result cards RC-EFF9, RC-EFF10, RC-EFF11, RC-EFF13.
Further development of high quality evidence from RCTs on effectiveness is needed as discussed in the EFF domain.
Importance: Critical
Transferability: Completely
An analysis of the selected studies extracted from the basic literature search was performed. Seven economic studies {1;2;3;4;5;6;9} were found to be relevant to this question.
The societal perspective was adopted. A decision analytic model followed by a Markov model was designed to evaluate the cost-effectiveness/cost-utility of prognostic tests compared with standard care as defined in the scope. The model was based on information included in the literature {1;2;3;4;5;6;9} and from the TEC domain.
The model addresses the evolution of early invasive breast cancer in women and compares the costs and outcomes in terms of QALYs (expected Quality Adjusted Life Years) for a patient’s lifetime. A simplified presentation of the decision model is shown in Figures 1 and 2.
The two initial branches of the decision tree represent a choice between the use of a prognostic test (uPA/PAI-1([FEMTELLE], Oncotype DX or MammaPrint) and the use of standard care (St Gallen consensus recommendations, NCCN, Adjuvant! Online or NPI) to stratify the women with early invasive breast cancer as at high or low risk of having distant recurrence. The probability distribution should be drawn from the literature, preferably from RCTs. The selection of treatment will also depend on ER status.
After this stratification there are four different treatment scenarios: chemotherapy plus endocrine therapy for patients who are ER-positive and at high-risk of recurrence; chemotherapy alone for ER-negative, high-risk patients; endocrine therapy alone for ER-positive, low-risk patients; and no adjuvant therapy for ER-negative, low-risk patients. Anti-HER2 agents can be added to chemotherapy depending on the risk classification and HER2 status {3}. Branches that include chemotherapy lead to subtree 1 via a chance node that considers the existence of toxicity associated with chemotherapy.
The Markov model shows the clinical after adjuvant therapy with 3 stages modelled. The structure of the Markov model is the same for all the “M” nodes but the transition probabilities and state utilities differ depending on each branch.
Figure 1 – Decision tree analysis
Figure 2 – Markov model
The objective here is only to present a rough description of the model. The necessary cost and outcome data were not collected and the model was not constructed or run. The quantity of resources used should be drawn from the literature, namely RCTs. The unit costs should be collected from national or regional data sources. The outcomes should also be drawn from the literature, namely RCTs.
It is necessary to investigate the impact of uncertainty in the model input parameter values. The most important values to explore on sensitivity analyses are the values of the probabilities used, mainly the ones related to the definition of high and low risk of recurrence. Also, the cost of adjuvant chemotherapy because these costs vary depending on the type of regimen used {8} and the utility values are important parameters to examine with sensitivity analysis.
Due to the lack of quality evidence to identify the effectiveness of the interventions {EFF domain} it was not possible to identify the cost-effectiveness ratio.
A rough description of an appropriate economic evaluation was created in case clinical effectiveness data becomes available in the future.
It is important to keep in mind that cost-effectiveness ratios are usually not directly transferable between countries because the values, in particular the cost values, included in the model may vary by nation or region. However, the model structure presented here could be used by changing the input data to reflect the situation locally.
Importance: Critical
Transferability: Partially
Due to the lack of high quality evidence to identify the effectiveness of the tests compared with standard care {EFF domain}, it was not possible to compute the cost-effectiveness ratios or to provide the information requested in the result cards. The main objective has been to present a rough description of what could be used when new evidence becomes available.
As described in the section on domain methodology, quality criteria were not applied to the studies identified for review. The impact of the information obtained from the literature used is unknown. In future evaluation efforts, it is important to assess the quality of economic studies using, for example, the Drummond’s criteria {12}. It has been noted that the economic studies provided differing results. It is not possible to conclude whether these differences result from differences in study quality, or from the variations in prices in different countries, or from the different perspectives used in the studies.
Further research will be needed in order to generate more evidence and to increase the certainty of almost all of the domain assessment elements.
APPENDIX ECO-1. Study cards for costs and economic evaluation domain
Author |
Tsoi DT, Inoue M, Kelly CM, Verma S, Pritchard KI. | |||||
Year |
2010 | |||||
Study title |
Cost-effectiveness analysis of recurrence score-guided treatment using a 21-gene assay in early breast cancer. | |||||
Study objective |
to compare the cost-effectiveness of treatment guided either by 21-gene assay or by Adjuvant! Online program | |||||
Study design |
Markov model | |||||
Study methodology |
Is in the article | |||||
Population (target) |
50-year-old woman with lymph node-negative HR-positive breast cancer | |||||
Intervention (genetic test for cancer) |
recurrence score (RS)-guided treatment using 21-gene assay | |||||
Comparator |
Adjuvant! Online program | |||||
Clinical outcomes (source) |
Literature | |||||
Types of resources used (source of information) - for tests - for standard practice |
healthcare payer's perspective with results reported in 2008 Canadian dollars ($). | |||||
Quantity of resources used (source of information) - for tests - for standard practice |
Event rates, costs, and utilities were derived from the literature | |||||
Unit costs of resources used (source of information) - for tests - for standard practice |
Canadian dollars | |||||
Types of costs (source of information): - Direct costs (to distinguish between for tests and for standard practice) - Indirect costs (to distinguish between for tests and for standard practice) |
Direct costs | |||||
Are chemotherapy regimens identified? (treatment decided based on tests results) |
Women classified to be at high risk all received chemotherapy followed by tamoxifen and those classified to be at low risk received tamoxifen only. | |||||
Modelling structure of economic analysis (CEA, CUA, etc) |
Cost effectiveness analysis | |||||
Effectiveness measure (LY, QALY,…) |
QALY | |||||
Cost/effectiveness ratio (ICER) |
For a 50-year-old woman, RS-guided treatment was associated with an incremental lifetime cost of $4,102 and a gain in 0.065 QALY, with an ICER of $63,064 per QALY compared with AOL-guided treatment. | |||||
Description of adverse events considered (stratified by treatment arm or stated) |
Yes, stratified | |||||
Author conclusions |
The 21-gene assay appears cost-effective from a Canadian healthcare perspective. | |||||
Author disclosure (conflict of interest) |
no | |||||
Author |
Retel VP, Joore MA, Knauer M, Linn SC, Hauptmann M, Harten WH | |||||
Year |
2010 | |||||
Study title |
Cost-effectiveness of the 70-gene signature versus St. Gallen guidelines and Adjuvant Online for early breast cancer. | |||||
Study objective |
To assess the cost effectiveness of the 70-gene signature (MammaPrint) prognostic test to guide adjuvant treatment decisions in patients with node-negative breast cancer. | |||||
Study design |
Markov model to simulate the 20-year costs and outcomes (survival and quality-of-life adjusted survival (QALYs)) | |||||
Study methodology |
Is in the article | |||||
Population (target) |
a hypothetical cohort of node-negative, oestrogen receptor positive breast cancer patients. | |||||
Intervention (genetic test for cancer) |
70-gene signature | |||||
Comparator |
St. Gallens guidelines and Adjuvant Online Software | |||||
Clinical outcomes (source) |
Sensitivity and specificity | |||||
Types of resources used (source of information) - for tests - for standard practice |
pooled analysis consisting of 305 tumour samples from 3 previously reported validation studies concerning the 70-gene signature | |||||
Quantity of resources used (source of information) - for tests - for standard practice |
Literature | |||||
Unit costs of resources used (source of information) - for tests - for standard practice |
Health Care Insurance Board. Pharmacotherapeutic Compass (in Dutch), 2006 | |||||
Types of costs (source of information): - Direct costs (to distinguish between for tests and for standard practice) - Indirect costs (to distinguish between for tests and for standard practice) |
Direct costs, literarue | |||||
Are chemotherapy regimens identified? (treatment decided based on tests results) |
Yes | |||||
Modelling structure of economic analysis (CEA, CUA, etc) |
Markov model, Cost effectiveness analysis | |||||
Effectiveness measure (LY, QALY,…) |
QALY | |||||
Cost/effectiveness ratio (ICER) |
the 70-gene signature has the highest probability of being cost-effective for a willingness to pay for a QALY higher than €12.000. | |||||
Description of adverse events considered (stratified by treatment arm or stated) |
NA | |||||
Author conclusions |
the 70-gene signature improves quality-adjusted survival and has the highest probability of being cost-effective. | |||||
Author disclosure (conflict of interest) |
NA | |||||
Author |
Er Chen, MPP; Kuo Bianchini Tong, MS; and Jennifer L. Malin, MD, PhD | ||
Year |
2010 | ||
Study title |
Cost-effectiveness of 70-gene MammaPrint signature in node-negative breast cancer | ||
Study objective |
Evaluate the cost-effectiveness of 70-gene MammaPrint signature vs Adjuvant! Online software in patients 60 years or younger with early-stage breast cancer. | ||
Study design |
Cost-effectiveness and cost-utility analyses from a US payer perspective | ||
Study methodology |
Is in the article / Is not in the article | ||
Population (target) |
Patients 60 years or younger with ER-independent, T1 or T2, lymph node-negative tumours. | ||
Intervention (genetic test for cancer) |
70-Gene MammaPrint Signature (Agendia Inc, Huntington Beach, CA) | ||
Comparator |
Adjuvant! Online software | ||
Clinical outcomes (source) |
risk classification and 10-year overall survival (Buyse M, Loi S, van’t Veer L, et al; TR ANSBIG Consortium. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006; 98(17):1183-1192) | ||
Types of resources used (source of information) - for tests - for standard practice |
cost of risk classification, adjuvant endocrine therapy, adjuvant chemotherapy, administration, treatment-related toxic effects, and breast cancer surveillance, treating local recurrence or distant recurrence, terminal care for cancer-related death, terminal care for patients without cancer (literature) | ||
Quantity of resources used (source of information) - for tests - for standard practice |
Not identified | ||
Unit costs of resources used (source of information) - for tests - for standard practice |
Not identified (literature) | ||
Types of costs (source of information): - Direct costs (to distinguish between for tests and for standard practice) - Indirect costs (to distinguish between for tests and for standard practice) |
Direct costs | ||
Are chemotherapy regimens identified? (treatment decided based on tests results) |
No | ||
Modelling structure of economic analysis (CEA, CUA, etc) |
Cost-effectiveness and cost-utility | ||
Effectiveness measure (LY, QALY,…) |
LY and QALY | ||
Cost/effectiveness ratio (ICER) |
$10,000 per LY or QALY | ||
Description of adverse events considered (stratified by treatment arm or stated) |
chemotherapy-related serious adverse events | ||
Author conclusions |
The model results suggest that treatment guided by 70-gene signature may be associated with an increase in the mean life expectancy and a slight increase in cost. The ICER of approximately $10,000 per LY or QALY for the base case is well within the range of value generally considered cost-effective for a diagnostic or therapeutic intervention and is substantially lower than ICERs reported in the literature for other oncology therapies. Our study findings suggest that the use of this test is highly cost-effective among ER-positive patients but is less so among ER-negative patients. In addition, the clinical and economic trade-offs of using the test in postmenopausal women need further evaluation. | ||
Author disclosure (conflict of interest) |
Author Affiliations: From Quorum Consulting, Inc (EC, KBT), San Francisco, CA; and the Department of Medicine (JLM), University of California at Los Angeles, Los Angeles, CA. Funding Source: Funding for this study was provided through an unrestricted grant from Agendia Inc. Author Disclosures: Ms Chen and Mr Tong report being employees of Quorum Consulting, which received payment from Agendia for the preparation of the manuscript. Dr Malin reports serving as a paid consultant to Quorum and receiving payment for her involvement in the preparation of this manuscript. | ||
Author |
Vanderlaan BF, Broder MS, Chang EY, Oratz R, Bentley TG. | ||
Year |
2011 | ||
Study title |
Cost-effectiveness of 21-gene assay in node-positive, early-stage breast cancer | ||
Study objective |
To assess impact on health outcomes and healthcare expenditures of adopting a 21-gene assay | ||
Study design |
deterministic decision-analytic model | ||
Study methodology |
Is in the article | ||
Population (target) |
women with early-stage, minimally node-positive, oestrogen receptor-positive (N (1-3)/ER) HER2-negative breast cancer | ||
Intervention (genetic test for cancer) |
care determined by the 21-gene assay recurrence score | ||
Comparator |
Usual care/ chemotherapy | ||
Clinical outcomes (source) |
Annual numbers of events were multiplied by quality-adjusted life-years (QALYs) lost | ||
Types of resources used (source of information) - for tests - for standard practice |
costs and quality-of-life outcomes, chemotherapy, adverse events, supportive care, recurrence, and second primary cancers for usual care | ||
Quantity of resources used (source of information) - for tests - for standard practice |
Literature, national statistics, physician surveys, and Medicare Part B prices. | ||
Unit costs of resources used (source of information) - for tests - for standard practice |
managed care payer perspective for the US population.. US dollars | ||
Types of costs (source of information): - Direct costs (to distinguish between for tests and for standard practice) - Indirect costs (to distinguish between for tests and for standard practice) |
Direct costs | ||
Are chemotherapy regimens identified? (treatment decided based on tests results) |
yes | ||
Modelling structure of economic analysis (CEA, CUA, etc) |
Cost effectiveness | ||
Effectiveness measure (LY, QALY,…) |
QALY | ||
Cost/effectiveness ratio (ICER) |
Patients receiving the assay were predicted to gain 0.127 QALY and save $4359 annually from avoiding chemotherapy, adverse events, supportive care, and secondary primary tumours. Although overall results were sensitive only to reduced impact of testing and chemotherapy costs, they were still highly cost-effective (incremental cost-effectiveness ratio <$20,000/QALY). | ||
Description of adverse events considered (stratified by treatment arm or stated) |
Yes, stratified by treatment arm | ||
Author conclusions |
Use of a 21-gene assay in patients with early-stage N (1-3)/ER HER2-negative breast cancer may improve health outcomes and add no incremental cost, thereby providing valuable insight for health plans, the Centers for Medicare and Medicaid Services, and clinicians regarding coverage policies and treatment decisions. | ||
Author disclosure (conflict of interest) |
No | ||
Author |
Carlos Eduardo Bacchi1*, Flavio Prisco2, Filom ena M. Carvalho3, Elida B. Ojopi4, Everardo D. Saad5 | |
Year |
2010 | |
Study title |
Potential economic impact of the 21-gene expression assay on the treatment of breast cancer in Brazil | |
Study objective |
investigate the potential impact of incorporating the 21-gene expression assay into private practice in Brazil, from the perspective of third party payers. | |
Study design |
web-based survey with 30 (of a total of approximately 700) Brazilian medical oncologists, stratified by State according to the proportion of patients with breast cancer and private health insurance and not aware of the study objective The questionnaire consisted of case vignettes presenting different clinical scenarios aiming to investigate the treatment of first choice for patients with axillary-node negative, oestrogen-receptor-positive, early breast cancer, regardless of menopausal status. Responses allowed a quantitative assessment of the care patterns regarding chemotherapy regimen for each of the four tumour sizes. In addition, we assessed interviewees’ preferences regarding the type and dose of antiemetic premedication used in each case, the dose and duration of use of granulocyte colony-stimulating factor (G-CSF) and antibiotics for in-hospital treatment of febrile neutropenia, should it develop. In each subgroup of patients defined by tumour size in the hypothetical cohort with no access to the 21-gene expression assay, the proportion of patients receiving chemotherapy, as well as regimens used in each subgroup, were derived from the survey with medical oncologists. The model assumed that patients with access to the 21-gene expression assay would receive chemotherapy if their recurrence score was intermediate or high, whereas patients with a low score would not receive chemotherapy. The model followed the perspective of private third party payers, and incorporated only the direct medical expenses associated with treatment. | |
Study methodology |
Is in the article | |
Population (target) |
Patients with axillary-node negative, oestrogen-receptor-positive, early breast cancer, regardless of menopausal status | |
Intervention (genetic test for cancer) |
21-gene expression | |
Comparator |
Not identified – standard practice based on the survey | |
Clinical outcomes (source) |
Not identified | |
Types of resources used (source of information) - for tests - for standard practice |
Only identified the resources associated with chemotherapy, based on the survey and the tests | |
Quantity of resources used (source of information) - for tests - for standard practice |
The number of cycles of chemotherapy and type of drugs used were identified, but not quantified. | |
Unit costs of resources used (source of information) - for tests - for standard practice |
Costs were calculated using the manufacturer’s recommended prices | |
Types of costs (source of information): - direct costs (to distinguish between for tests and for standard practice) - indirect costs (to distinguish between for tests and for standard practice) |
Direct medical expenses assessed in the study were costs of chemotherapy, antiemetic premedication, prophylactic or therapeutic G-CSF, and antibiotics for in-hospital treatment of febrile neutropenia and the cost of the test. Other direct medical costs, indirect medical costs, and non-medical costs were not considered in the model. | |
Are chemotherapy regimens identified? (treatment decided based on tests results) |
Yes (yes) Different regimen depending on the tumour size | |
Modelling structure of economic analysis (CEA, CUA, etc) |
Cost analysis | |
Effectiveness measure (LY, QALY,…) |
Not measured | |
Cost/effectiveness ratio (ICER) |
not calculated | |
Description of adverse events considered (stratified by treatment arm or stated) |
incidence of febrile neutropenia associated with the regimens (stratified by treatment arm) | |
Author conclusions |
Results of our study suggest that the 21-gene expression assay would be a cost-saving in Brazil, from the perspective of third-party payers and considering the current price for the test in Brazil. However, results also suggest that testing could actually increase direct medical costs in patients with lymph node negative, oestrogen-receptor-positive T1 tumours, and reduce costs in patients with tumour size >2 cm. The model included the main financial costs associated with adjuvant therapy for breast cancer, but many other direct costs, as well as indirect costs, were not taken into account by the model. In addition, the effectiveness of therapy based on risk prediction by the 21-gene expression assay was not considered in the model. | |
Author disclosure (conflict of interest) |
None | |
Author |
Jennifer Eng-Wong, Claudine Isaacs | |
Year |
2010 | |
Study title |
Prediction of benefit from adjuvant treatment in patients with breast cancer | |
Study objective |
review the clinical tools that are commonly used as well as those under development and the clinical trials in which they are being further evaluated to better determine which tumours will benefit from chemotherapy | |
Study design |
Descriptive analysis to | |
Study methodology |
Is not in the article | |
Population (target) |
Not applicable | |
Intervention (genetic test for cancer) |
Not applicable | |
Comparator |
Adjuvant!, Oncotype DX, and MammaPrint | |
Clinical outcomes (source) |
Not applicable | |
Types of resources used (source of information) - for tests - for standard practice |
Not applicable | |
Quantity of resources used (source of information) - for tests - for standard practice |
Not applicable | |
Unit costs of resources used (source of information) - for tests - for standard practice |
Not applicable | |
Types of costs (source of information): - Direct costs (to distinguish between for tests and for standard practice) - Indirect costs (to distinguish between for tests and for standard practice) |
Not applicable | |
Are chemotherapy regimens identified? (treatment decided based on tests results) |
Not applicable | |
Modelling structure of economic analysis (CEA, CUA, etc) |
Not applicable | |
Effectiveness measure (LY, QUALY,) |
Not applicable | |
Cost/effectiveness ratio (ICER) |
Not applicable | |
Description of adverse events considered (stratified by treatment arm or stated) |
Not applicable | |
Author conclusions |
Significant advances in molecular biology and the foresight to maintain tumour specimens in the clinical trial setting have led to major improvements in selecting appropriate candidates for adjuvant chemotherapy, in particular those with hormone receptor–positive, node-negative cancer. For hormone receptor–negative and more advanced disease, clinicians typically use adjuvant chemotherapy; however, treatment choices are expected to be better informed based on incorporation of molecular profiling analyses into current trials. | |
Author disclosure (conflict of interest) |
Not identified | |
Authors: Dario Sacchini, Roberta Minacori, Pietro Refolo
From the ethical point of view, the foundation of any medical act – including the utilisation of prognostic tests for breast cancer recurrence (PTBCRs) – is the evaluation of (and respect for) the clinical (diagnostic/therapeutic) benefit for patients. At the moment, the available literature shows the following.
These new tests raise the question of the extent to which patients are prepared to participate in informed decision making about their care. Information from these tests about the risk of breast cancer recurrence should play a significant role in women’s breast cancer treatment decisions. But few studies indicate whether patients understand genomic and similar tests and their results adequately to be informed decision makers when using them.
The results of the studies underscore the comparative weight that participants placed on their physicians’ recommendations and the importance of patient education regarding how clinicians incorporate genomic risk of recurrence information into treatment decision-making. Indeed, the value placed on testing by the physician and how this is conveyed will likely be critical to patients’ decision-making processes. Some studies show that health literacy is fundamental to understanding women’s capacity to learn about the new PTBCRs as well as their desire for active participation in medical care: women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Studies show that most patients prefer to be involved in medical decisions that affect their care and that patients who are active participants in their medical decisions are better adjusted psychologically, report being more satisfied with their decisions, and are more likely to adhere to their treatment regimens. These new tests raise important new issues for the clinicians about how to communicate with patients about their recurrence risks.
Acknowledgement by clinicians of the potential problems and subsequent clarification of any misconceptions should prevent or relieve patients’ anxiety and help them to cope with the situation.
Physicians should explain the difference between genomic signatures and genetic testing, the clinical meaning of the result of the test with the standard clinicopathological criteria and the expressions that relate to technical problems of these tests. Improving the quality of the information with which patients are provided about these new methods – by taking more time to explain what they involve, favouring discussions and eliciting feedback from the patients – will enable them to play an active role in the decision-making process about their treatment.
In general, the physician should be a skilful guide for the patient, on the grounds of scientific knowledge and personal experience. Choosing a prognostic test for breast cancer recurrence balancing between risks and benefits pertains to the physician, followed by the patient’s free consent based on adequate information. Particularly, the use of uPA/PAI-1, Oncotype or MammaPrint affect the patient’s autonomy and play an important role in the decision-making process about their treatment.
Finally, distributive justice needs to be faced by health policy makers. In general, the main question for our project is the evaluation of the cost-effectiveness of the tests while assuring that economic and organisational feasibility is maintained. From the point of view of distributive justice, following the specific available literature shows that:
This domain aims to highlight the ethical implications of using the prognostic tests for the prediction of risk of breast cancer recurrence.
We believe that a thorough understanding of the technical and others characteristics of these prognostic profiling tests forms a necessary basis for all further ethical discussions in the field.
Consequently, analytical validity has traditionally been a primary criterion in the ethical evaluation of clinical applications of genetic testing {1}. This is derived from basic consumer rights: a genetic test, like any other product, ought to “conform to contract” and be as described in its labelling. In addition, clinical validity (the interpretation of assay results to classify individuals as those at risk of developing the disease and those who will not) and clinical utility (the outcomes in terms of morbidity or mortality improvement, benefits—risks balance or effectiveness of the treatments) are necessary criteria for the ethical evaluation.
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
F0001 | Principal questions about the ethical aspects of technology | Is the technology a new, innovative mode of care, an add-on to or modification of a standard mode of care or a replacement of a standard? | yes | Are uPA/PAI-1, Oncotype or Mammaprint intended to be an, innovative mode of care, an add-on to or modification of a standard mode of care or a replacement of a standard? |
F0002 | Principal questions about the ethical aspects of technology | Can the technology challenge religious, cultural or moral convictions or beliefs of some groups or change current social arrangements? | yes | Can uPA/PAI-1, Oncotype or Mammaprint challenge religious, cultural or moral convictions or beliefs of some groups or change current social arrangements? |
F0003 | Principal questions about the ethical aspects of technology | What can be the hidden or unintended consequences of the technology and its applications for different stakeholders. | yes | What can be the hidden or unintended consequences of uPA/PAI-1, Oncotype or Mammaprint and its applications for different stakeholders? |
F0005 | Autonomy | Is the technology used for patients/people that are especially vulnerable? | yes | Are uPA/PAI-1, Oncotype or Mammaprint used for patients that are especially vulnerable? |
F0006 | Autonomy | Can the technology entail special challenges/risk that the patient/person needs to be informed of? | yes | Can uPA/PAI-1, Oncotype or Mammaprint entail special challenges/risk that the patient/person needs to be informed of? |
F0007 | Autonomy | Does the implementation challenge or change professional values, ethics or traditional roles? | yes | Does the use of uPA/PAI-1, Oncotype or Mammaprint challenge or change professional values, ethics or traditional roles? |
F0004 | Autonomy | Does the implementation or use of the technology challenge patient autonomy? | no | The implementation of these tests is in tissues, so the patient doesn't need to be present or affect the patient authonomy to perform his/her dailly life |
F0008 | Human Dignity | Does the implementation or use of the technology affect human dignity? | yes | Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human dignity? |
F0009 | Human integrity | Does the implementation or use of the technology affect human integrity? | yes | Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human integrity? |
F0010 | Beneficence/nonmaleficence | What are the benefits and harms for patients, and what is the balance between the benefits and harms when implementing and when not implementing the technology? Who will balance the risks and benefits in practice and how? | yes | What are the benefits and harms for patients, and what is the balance between the benefits and harms when implementing and when not implementing uPA/PAI-1, Oncotype or Mammaprint? Who will balance the risks and benefits in practice and how? |
F0011 | Beneficence/nonmaleficence | Can the technology harm any other stakeholders? What are the potential benefits and harms for other stakeholders, what is the balance between them? Who will balance the risks and benefits in practice and how? | yes | Can uPA/PAI-1, Oncotype or Mammaprint harm any other stakeholders? What are the potential benefits and harms for other stakeholders, compared to standard prognostic or predictive factors, what is the balance between them? Who will balance the risks and benefits in practice and how? |
F0012 | Justice and Equity | What are the consequences of implementing / not implementing the technology on justice in the health care system? Are principles of fairness, justness and solidarity respected? | yes | What are the consequences of implementing / not implementing uPA/PAI-1, Oncotype or Mammaprint on justice in the health care system? Are principles of fairness, justness and solidarity respected? |
F0013 | Justice and Equity | How are technologies presenting with relevantly similar (ethical) problems treated in health care system? | yes | How are technologies presenting with relevantly similar (ethical) problems treated in health care system? |
F0014 | Rights | Does the implementation or use of the technology affect the realisation of basic human rights? | yes | Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect the realisation of basic human rights? |
F0016 | Legislation | Is legislation and regulation to use the technology fair and adequate? | yes | Is legislation and regulation to use Genetic Test fair and adequate? |
F0017 | Questions about effectiveness and accuracy | What are the proper end-points for assessment and how should they be investigated? | yes | What are the proper end-points for assessment and how should they be investigated? |
F0018 | Questions about effectiveness and accuracy | Are the accuracy measures decided and balanced on a transparent and acceptable way? | yes | Are the accuracy measures decided and balanced on a transparent and acceptable way? |
Information sources
The Ethical domain relies on information from the following sources.
Quality assessment tools or criteria
For literature from other domains, we counted on the quality criteria adopted by them (namely, GRADE and PICO methodologies).
About available literature on the ethical impact of the technologies in hand, the adopted first baseline quality criterion was inclusion in the Medline Database. Further quality assessment criteria were not applied.
Analysis and synthesis
Data extraction, analysis and synthesis was done by three researchers, independently. Different extraction results were discussed to achieve a consensus, a third person was involved in cases of uncertainty. So, we present study information and, consequently, qualitative analysis and synthesis.
uPA/PAI-1, Oncotype DX® and MammaPrint® are prognostic tests for the prediction of risk of breast cancer recurrence and, thus, for treatment decision making. They are applied in the decision about chemotherapy in lymph node negative cancers. The effects of the tests on the clinical outcome can be either avoiding unnecessary chemotherapy as well as its side-effects or by employing it where it might not otherwise have been used, thereby reducing recurrence risk.
The presented tests aim to improve the risk stratification based on clinical and pathological factors but are currently experimental although commonly used in clinical practice by academic and community oncologists. So they would be an add-on to standard modes of diagnosis and care based on clinicopathological criteria (such as age, tumour size, type, grade, and histological characteristics, HER2 status, hormone receptor status, menopausal status and lymph node status), but we have found no direct evidence to suggest that, at the moment, these tests are actually an add-on to standard mode of diagnostic/care. The intended use of these three tests, and the data about their performance, are different. First of all, the data available relate mainly Oncotype DX and MammaPrint, while there are few data on uPA/PAI-1. In the absence of a gold standard or reference technology, no estimates are available for analytic false positive or false negative rates {2, 3, 4}.
The performance of all three of these assays as prognostic tests is very similar. Level 1 evidence has been achieved for the Oncotype DX and uPA-PAI-1 assays for their roles as predictive as well as prognostic tests. MammaPrint is the first FDA-approved gene-expression-based assay to be used as a prognostic test for women with node-negative breast cancers. Therefore these tests may be considered as an adjunct to clinical and pathological information and have been incorporated into clinical guidelines in the USA. Direct evidence from randomised clinical trials is lacking and therefore their clinical utility is mainly in risk prognostication while more data are needed to validate their predictive value for selecting the best adjuvant chemotherapy. Despite many gene-expression profiling studies in neo-adjuvant settings, no one has been able to develop a robust predictive marker for a specific chemotherapeutic agent or specific combination regimen. However this does not mean that gene expression profiles cannot be used to provide clinically useful guides for chemotherapy {4}. It is clear that these tests have the potential to change the prognostication and treatment options for patients with breast cancer.
Studies about changes in clinical management using these test (in practice for the Oncotype DX test only) are minimally informative, because they do not specify the information actually given to the patient or how clinicians combine test results with other risk factors to limit or expand therapeutic choices. Changes in adjuvant systemic chemotherapy recommendations have been demonstrated in 21–74% of cases with addition of the 21-gene recurrence score (Oncotype DX test) compared with standard guidelines alone (the NCCN guidelines, or the St.Gallen Consensus Statement or The Adjuvant! Online). In the majority of cases, the change in treatment recommendations included a shift from chemotherapy and hormonal therapy to hormonal therapy alone in patients with low 21-gene recurrence scores, irrespective of their categorisation by traditional guidelines {5,6, 7, 8, 9}. It is not possible to determine, however, whether documented changes in management are due to compliance with the physician recommendations, and weighing of risks and benefits, or reflect the effects of test marketing.
So, at this time, strong claims cannot be made about the clinical value of these assays and their potential superiority over standard clinico-pathological parameters alone {10, 11, 12, 13, 14, 15}.
These trials should provide clinicians with fundamental, probably definitive, information regarding the clinical utility of these tests.
Importance: Critical
Transferability: Completely
Not applicable for specific ethical issues. For social arrangements, see the Social domain of this report.
Importance: Unspecified
Transferability: Unspecified
Two points should be highlighted: firstly, from the justice point of view, there are ethical considerations because moving resources into unproven technologies such as these tests, which have a prognostic function (and the link between the test and both distant recurrence and overall survival are not well understood), may affect the access of other breast cancer patients to chemotherapy. Secondly, there may be opportunity costs for other breast cancer patients in terms of lost opportunities to develop other prognostic tests for this other patient group that might prove to be better. These tests could be diverting research resources and expertise away from other tests and treatments that may prove more useful.
Importance: Unspecified
Transferability: Unspecified
These tests are applied for potentially “fragile” patients, if they are affected by breast cancer and the tests are used to evaluate the possible recurrence of the pathology. For the social impact of the patient’s vulnerability see also the Social domain of the Report.
Importance: Unspecified
Transferability: Unspecified
It is possible that the harms associated with chemotherapy among women who will not have a distant recurrence outweigh the benefits of chemotherapy among women who are destined to have a distant recurrence. These recurrence risk tests may also correctly recategorise women who were determined to be at high risk using existing risk indicators as being at low risk for recurrence. It seems plausible that more women will benefit (i.e., avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefited from chemotherapy), possibly resulting in breast cancer recurrence or death. There are currently insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine what proportion of women with moderate to high risk, based on conventional risk assessments, will have “low enough” recurrence scores in the prognostic tests to affect their decision about chemotherapy.
It has been suggested, in a small retrospective study {16}, that a differential benefit may arise from chemotherapy in the low and moderate risk groups. If this were substantiated by further evidence then the relative benefit for the low and moderate risk groups would be relevant in the ethical analysis.
Moreover, some data on the technical performance of assays were identified for Oncotype DX and MammaPrint tests (not sufficiently for the uPA/PAI-1 test), though estimates of analytic sensitivity and specificity [respectively the capacity that the test will be positive if the genetic variant is present and negative if it is absent {17}] could not be made. Based on the reported rates of testing failures related to sample quality, pre-analytic issues related to sample preparation, transport, and processing should be addressed in routine practice {18}.
In the absence of a gold standard or reference technology, no estimates are available for analytic false positive or false negative rates. Knowledge of the risks of the analytic false positive or false negative rates are fundamental for clinicians’ and patients’ decision making.
So, one big limitation of these new tests is that their biological basis and clinical implications for treatment are just now beginning to be well understood. In this initial stage of the introduction of the tests, which can span many years, patients and clinicians will face difficult decisions about how to integrate potentially discordant information from the standard methods for deriving information about patients and the new genomic tests. Some women may not fully understand and may be reluctant to forgo chemotherapy when genomic tests indicate low recurrence risk but standard criteria suggest high recurrence risk. Research is needed to find out how women understand and use the risk information and investigate tolerance levels for risk in decision making.
This highlights the potential need for clinicians to take added care in explaining the benefits and the risks of genomic testing for breast cancer recurrence risk, especially issues surrounding conflicting test results {19}.
Importance: Critical
Transferability: Completely
The purpose of the tests being evaluated is to replace or supplement prognostic guidelines and tools in current use, such as Adjuvant! Online. These involve cut-off values for risk classification which provide a gateway to further treatment or advice. Cut-off values are based on scientific evidence but their implementation affects the stage at which patients access treatment, as well as the overall number being treated. They therefore involve normative concerns beyond the clinical evidence on which they are based that are rarely explained transparently to patients. Implementing a cut-off value in a new group of patients, or a new cut-off for an existing group, may change the traditional professional approach of clinical staff, for example by causing them to deny treatment to individual patients who do not fall into the right risk category.
These new tests raise the question of the extent to which patients are prepared to participate in informed decision making about their care.
Information about the risk of breast cancer recurrence from these tests should play a significant role in women’s breast cancer treatment decisions. One study using data from existing risk indicators showed that reducing the risk of dying from breast cancer by even 0.5% to 1% would make adjuvant chemotherapy acceptable to patients {20}. Breast cancer patients often do not understand basic information about their prognosis, including their risk of recurrence {21}. Many women even have difficulty in understanding their risk of breast cancer {22} even after risk counselling {23}. There are few studies that indicate whether patients understand genomic tests and their results adequately to be informed decision makers when using them.
In one study assessing interest in genomic tests to determine the risk of recurrence of breast cancer in women previously treated for early-stage breast cancer {24}, most participants indicated that they would have been interested in this genomic testing. The women stated that they preferred an active role in decision making about treatment and would have wanted the results incorporated into treatment planning. In this study a scenario, less likely to happen in practice, such as a physician’s recommendation to have chemotherapy in response to a test result that indicated a low risk of recurrence was also used to elicit participants’ reactions to a situation that presented conflicting information. The results underscore the considerable weight that participants placed on their physicians’ recommendations and the importance of patient education about how clinicians incorporate genomic risk of recurrence information into decision making about treatment. Indeed, the value placed on testing by the physician, and how this is conveyed, will likely be critical to patients’ decision-making processes.
However, among early-stage breast cancer patients who received Oncotype DX, it seems that there is low knowledge about many aspects of genomic recurrence risk testing. Few patients understood that the test shows the likelihood of metastasis assuming additional treatment and does not provide information about the familial risk of breast cancer {25}.
One potential reason for misunderstanding risk is low health literacy. The U.S. Department of Health and Human Services defines health literacy as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions” {26}. Some studies show that health literacy is fundamental to women’s understanding and capacity to learn about the new breast cancer recurrence risk genomic tests as well as their desire for active participation in medical care: women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Health literacy was not related to the amount of additional information women desired. Women with higher health literacy preferred to have a more active role in decisions about the test. Health literacy may affect women’s capacity to learn about the new genomic tests as well as their desire for informed participation in their medical care {27, 28}.
Given the possible misinterpretation of specific (genomic) terminology as well as less specific terminology (e.g. “not done”, “not interpretable”) {29}, it is imperative that more attention should be paid to information issues in this field. Studies show that most patients prefer to be involved in medical decisions that affect their care {30,31} and that patients who are active participants in their medical decisions are better adjusted psychologically; they report being more satisfied with their decisions, and are more likely to adhere to their treatment regimens {32, 33, 34}. These new tests raise important new issues for the clinicians about how to communicate with patients about their recurrence risks.
Acknowledgement by clinicians of the potential problems and subsequent clarification of any misconceptions should prevent or relieve patients’ anxieties and help them to cope with the situation.
Therefore, in addition to giving us insights into their understanding of this new procedure, the participants in a study also provided insights into the ways clinicians may be able to help them. Two specific points in particular that need to be improved in clinical practice emerge. Firstly, healthcare professionals should explain to patients the difference between genomic signatures and genetic testing, and should emphasise that the analysis focuses solely on the tumour genes and has nothing to do with whether or not the disease is hereditary. Secondly, the disclosure of “not done” and “not interpretable” results should be handled with care because of the potentially negative implications of these terms. Physicians should explain that these expressions refer to technical problems that have arisen, and not to the tumour itself. Improving the quality of the information with which patients are provided about these new methods – by taking more time to explain what they involve, favouring discussions and eliciting feedback from the patients – will enable them to play an active role in the decision-making process about their treatment and ensure that those who agree to have gene analysis performed on their tumours are satisfied with the procedure {26}.
These findings have practical implications. When communicating recurrence risk test information to patients, clinicians and others health professionals should pay attention to patient health literacy and numeracy, and perhaps adjust the delivery of and time spent on communication of risk information to patients.
Importance: Important
Transferability: Completely
Not Applicable.
Importance: Unspecified
Transferability: Unspecified
Not applicable.
Importance: Unspecified
Transferability: Unspecified
In this context, clinical utility is the likelihood that using a gene expression profiling test to guide management in patients with diagnosed early-stage breast cancer will significantly improve health-related outcomes. Clinical utility is assessed by investigating the balance of benefits (reduced adverse events due to low-risk women avoiding chemotherapy) and harms (cancer recurrence that might have been prevented) associated with the use of the test, compared with the use of alternative management strategies.
No direct evidence links use of the MammaPrint test to clinical outcomes.
No studies evaluated the capacity of MammaPrint to predict benefit from other treatments (e.g., chemotherapy).
No studies determined whether use of MammaPrint in place of, or in addition to, current clinicopathological approaches (e.g., Adjuvant! Online, St. Gallen) changes management, and/or improves outcomes based on management with clinicopathological markers alone.
Retrospective analysis of one arm of a prospective clinical trial showed that the chemotherapy benefit in ER-positive, node-negative patients, randomised to tamoxifen or to tamoxifen plus chemotherapy, was most convincing in women in the Oncotype DX RS high-risk category (27% reduction in 10-year recurrence rate) {35}.
Many persons would likely have been offered chemotherapy without testing, but test results may influence patient–clinician decision making. This study provided the strongest evidence available addressing the clinical utility of the Oncotype DX test, but the study design was not optimal and prospective confirmation of these findings is needed. Three quarters of Oncotype DX results are in the intermediate and low risk ranges, where estimates of recurrence risk have wide and overlapping confidence intervals, and evidence of benefit provided by chemotherapy is inadequate to make decisions. The TAILORx trial will focus on these result groups, {37} but results will not be known for some time.
No direct evidence was found that links the use of the uPA/PAI-1 test to clinical outcomes.
Direct evidence was not found linking any of the three tests to improved outcomes, but there are studies about the components of clinical utility that might provide indirect evidence for clinical utility. There is encouraging indirect evidence for Oncotype DX, and plausibility for potential use of MammaPrint and, possibly, the uPA/PAI-1 test {36, 37, 38, 39, 2, 4}.
It seems plausible that more women will benefit (i.e., avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefitted from chemotherapy), possibly resulting in breast cancer recurrence or death. There are currently insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine what proportion of women with moderate to high risk based on conventional risk assessments will have a “low enough” score to affect their decision about chemotherapy.
Importance: Critical
Transferability: Completely
Not Applicable. See also the results of RC-ETH11.
Importance: Unspecified
Transferability: Unspecified
Up to now, through the available studies, it is not possible to evaluate the consequences of using these tests on a large scale, within a healthcare system, because the clinical efficacy data are still insufficient and still heterogeneous for these three tests. In addition, the three tests so far have probably had different frequencies of use in the USA and Europe. Moreover, among the economic analyses that have been conducted on these assays, almost all of them involve the Oncotype DX test; only one study examined MammaPrint, and one study compared directly the cost-effectiveness of Oncotype DX and MammaPrint {40, 41, 42, 43, 44, 45, 46, 47, 48}. The use of these gene expression profiling tests for early-stage breast cancer may have significant effects on patient outcomes, medical services use, and costs. These tests may potentially contribute to higher quality, more efficient care and reduce rising healthcare expenditures. A key challenge for patients with breast cancer and their healthcare providers, while making treatment decisions, relates to the decision to use or forego adjuvant chemotherapy. Chemotherapy is expensive for payers and healthcare systems and it can produce significant side-effects (e.g., myelosuppression and permanent ovarian failure), which may have a substantial impact on quality of life. Thus, assessing the outcomes, use, and costs associated with these genomic diagnostic tests is critical for future clinical and health policy decision making as well as for future applications in healthcare systems.
The few available studies suggest that, although both Oncotype DX and MammaPrint are costly and have high incremental cost-effectiveness ratio (ICERs), it is reasonable to presume a willingness to pay for testing strategies that are likely to yield reduced expenditures for payers, health systems, patients, and society in the long term.
Unfortunately, however, these studies are at an early stage, so inconclusive.
From the point of view of justice within the healthcare system, it is not reasonable to deny resources to populations on the basis of unproven new treatments. In particular the uncertain correlation between these tests and both distant recurrence and overall survival, plus their relatively high ICER mean that other more effective treatments may need to be foregone in order for patients to access these tests.
Importance: Important
Transferability: Completely
Not Applicable.
Importance: Unspecified
Transferability: Unspecified
Not Applicable.
Importance: Unspecified
Transferability: Unspecified
We refer to the Legal domain of the present report.
Importance: Unspecified
Transferability: Unspecified
The body of evidence on the three marketed gene expression tests for breast cancer prognosis show that these tests have considerable potential for improving prognostic and therapeutic prediction. It also provides valuable lessons about the complexity of evaluating such tests {1} . Because the role of the genes included in these tests in determining prognosis is not completely understood, it is often unclear which clinical or tumour characteristics are being measured. Intrinsic tumour aggressiveness, ability to metastasise, and responsiveness to treatment (hormonal, radiation, or chemotherapy) — each of which might involve different genes — could determine prognosis.
However, the characteristic to be assessed in a particular study must often be inferred from the treatment, tumour, and clinical characteristics of the study population. Results from populations that are clinically and therapeutically heterogeneous might not be optimal in determining the prognosis or risk for a particular woman. Endpoints also varied. Survival was defined in the studies as disease-free, distant recurrence-free, or overall, measured at 5 or 10 (or more) years. Predictive strength varied considerably depending on which endpoint the test was optimised for.
Finally, performance of the underlying gene signature is not necessarily identical to the marketed test, because many test procedures, including pretest sample preparation and transport, can differ. It is therefore critical to pay close attention to the test description, population, and endpoints for each study to understand which studies are mutually supportive, which are adding qualitatively different information, and to whom they apply {2} . Despite the clinical novelty of these tests, their development must follow the same principles and procedures as those for any multivariate clinical prediction rule. These principles are outlined in detail in the clinical literature {49,50} and have been agreed on in reporting guidelines {51} and articulated with respect to expression-based predictors in various review articles {52, 53} .
Importance: Important
Transferability: Partially
There is limited evidence about the laboratory procedures used for these tests, including information about their reproducibility {54, 55}. Concerns have been expressed about the potential influence of several factors on the performance of these tests, such as intra-tumour molecular heterogeneity, warm/cold ischaemia time, fixation and processing using formalin fixed tumour tissue, and influence of biopsy cavity {2, 3, 4}.
More studies are available that assess the analytic performance of the Oncotype DX and MammaPrint tests, though additional data on some points (e.g. impact of variability on risk classification) are needed. Since all three of the prognostic tests are proprietary (single clinical source), and external proficiency testing is not available at this time, reporting by the laboratories of quality control/ quality assessment protocols and analytic performance data would provide additional information for clinicians and patients {18}.
Importance: Important
Transferability: Completely
uPA/PAI-1, MammaPrint and Oncotype DX are molecular tests for the prediction of risk of breast cancer recurrence and, thus for treatment decision (chemotherapy in lymph node negative cancers). The effects of the tests on the clinical outcome can be either avoiding unnecessary chemotherapy and its side-effects or reducing recurrence risk by employing chemotherapy where it might not otherwise have been used.
These tests are currently experimental and commonly used in clinical practice by academic and community oncologists. So they would be added on to standard modes of diagnosis/care based on clinicopathological criteria such as age, tumour size, type, grade, and histological characteristics, HER2 status, menopausal status, hormone receptor status, and lymph node status. But we found no direct evidence to suggest that these tests are actually ready to be an add-on to standard modes of diagnosis/care.
In the absence of a gold standard or reference technology, no estimates are available for analytic false positive or false negative rates. Some authors have noted the limited evidence about the laboratory procedures used for these tests, including information about their reproducibility {2}, until demonstrated by single laboratories not in multisite.
Direct evidence from randomised clinical trials is lacking and therefore the clinical utility of the tests is mainly in risk prognostication, while more data are needed to validate their predictive value for adjuvant chemotherapy. Despite many gene expression profiling studies in the neo-adjuvant setting, no one has been able to develop a robust predictive marker for a specific chemotherapeutic agent or a specific combination regimen. However this does not mean that gene expression profiles cannot be used to provide clinically useful guides for chemotherapy. It is clear that these tests have the potential to change the prognostication and treatment options for patients with breast cancer. At this time, strong claims cannot be made about the clinical value of these assays and their potential superiority to standard clinicopathological parameters. Many data on these tests are based on retrospective studies of archival material, and thus, they do not provide the level of evidence that could only be gained from prospective, randomised, high-powered clinical trials. The MINDACT and TAILORx clinical trials should provide clinicians with fundamental, probably definitive, information about the clinical utility of these tests.
Authors: Jennifer Butt, Marco Marchetti, Angelica Carletto, Americo Cicchetti, Chiara Filippi
As far as can be judged from the literature and the survey results, introducing these tests into the clinical pathway of women with breast cancer does not have significant organisational impacts. However, the following must be kept in mind:
Research in the Organisational Aspects domain seeks to find out what resources (equipment, running costs, human skills and knowledge, etc) must be mobilised and organised when implementing a new technology. It also looks at the consequences for an organisation and for stakeholders (other than patients and their carers) of introducing the technology. The focus is on how the technology is delivered. Organisational aspects are included in a health technology assessment (HTA) because they may reveal essential challenges and barriers in implementing health technologies.
In this Core HTA the new technologies are prognostic tests for breast cancer recurrence, and the objective is to assess the organisational effects of introducing them compared with the standard care pathway, which does not include such tests.
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
G0001 | Process | What kind of work flow and patient flow processes are needed? | yes | What work flow and patient flow processes are needed to use the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) on women with invasive breast cancer? |
G0003 | Process | What kind of staff, training and other human resources is required? | yes | What kind of staff, training and other human resources are required when the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) are used to support treatment choice? |
G0004 | Process | What kind of co-operation and communication of activities have to be mobilised? | yes | What kind of co-operation and communication of activities have to be mobilised when the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) are introduced in the clinical pathways of women with invasive breast cancer? |
G0002 | Process | What kind of patient and relative involvement in treatment or care has to be mobilized? | no | This is appropriate for the social domain, not the organisational domain |
G0005 | Structure | What consequences the implementation of the new technology will have in respect of decentralisation or centralisation? | yes | What are the advantages and disadvantages of providing the tests centrally or locally? |
G0006 | Structure | What kinds of investments are needed (material or premises)? | yes | What kind of investment is needed (equipment, premises, staffing costs, running costs) in order to introduce use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) for women with invasive breast cancer? |
G0007 | Structure | What is the likely budget impact of the implementation of the technology for the payers (e.g. government)? | no | This question should be included in the ECO domain, not the ORG domain |
G0008 | Management | What management problems and opportunities are attached to the new technology? | yes | What management problems and opportunities are attached to use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)? |
G0009 | Management | Who decides which patients are to undergo a treatment and on what basis? | yes | Who decides which women are eligible for the tests and on what basis (e.g. likelihood of cancer recurrence)? |
G0010 | Culture | How is the new technology accepted? | yes | How are the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) accepted by healthcare professionals and other staff? |
G0011 | Culture | How will the other interest groups of the new technology be taken into account in the planning / implementation of the new technology? | yes | How should stakeholders (excluding patients/carers, their representative organisations and the public) be taken into account in planning the introduction of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)? |
Domain frame
The project scope applies to this domain and in addition all uPA/PAI-1 (urokinase plasminogen activator/plasminogen activator inhibitor 1) tests were included, not just FEMTELLE®. Where FEMTELLE-specific information was available this has been included; otherwise the data are about generic uPA/PAI-1 tests.
Information sources
Organisational aspects are rarely covered in clinical studies or HTA reports. Such information as there is tends to be sparse and anecdotal. We therefore undertook several activities:
1. Literature search and review
The literature search was carried out in two stages:
This review identified 84 articles that were potentially relevant to the Organisational Aspects domain. The full text for 82 of the 84 references was retrieved. Two articles were not available within the resource constraints of this project. Data extraction was divided between the five authors: each of the 82 articles was reviewed by one author for relevant data. Data from 27 articles were used.
2. Survey of clinicians and administrators
To complement the low level of data available in the literature, two electronic surveys covering areas in the Organisational Aspects and the Current Use domains of this HTA were developed. One survey was for clinicians and one for lead administrators. Both surveys consisted mainly of multiple choice questions with the option of selecting more than one answer per question. There were 17 questions in the clinician survey and 10 in the administrator survey. The surveys were developed mainly by NICE, with additional input from members of the two domain teams and Agenas. A link to the surveys, and a request to identify clinicians and administrators to complete it, was sent by Agenas to the national EUnetHTA agency in all 26 EUnetHTA countries on 14 February 2012. The deadline for completing the surveys was 5 March 2012. Due to low response rates the survey was made live again on 3 April with a deadline of 27 April 2012, and individuals from EUnetHTA agencies undertook to identify clinicians and administrators who could respond. Response rates were still low: eight responses were received in total from clinicians: three from the UK, two from Spain, two from Italy and one from Slovenia. Two responses were received in total from administrators (one from Spain and one from Italy). The survey questions and the results are in {COL-3}.
3. Grey literature searches
Grey literature was searched for the ORG3 and ORG9 assessment elements. Details of the searches are covered in those elements and the identified literature is included in the domain references. Grey literature was not searched for any other assessment element.
Quality assessment tools or criteria
We are not aware of quality criteria for articles that consider the organisation of healthcare. Quality assessment criteria were therefore not applied to the studies that were identified for review.
Analysis and synthesis
Data from different studies were not synthesised as this was neither appropriate nor necessary for this domain. A narrative synthesis was undertaken instead.
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search). Three articles were found to be relevant to this question. Information provided by the manufacturers to the HTA was also reviewed.
uPA/PAI-1 and FEMTELLE
For the purposes of this HTA, the uPA/PAI-1 test may be analysed in three ways:
All of the literature refers to the generic uPA/PAI-1 test rather than to the brand FEMTELLE. Unless specified otherwise, the information which follows therefore relates to the generic uPA/PAI-1 test and may not apply to FEMTELLE. It may also not apply consistently to the uPA/PAI-1 test since processes may differ from one laboratory to another.
Obtaining tissue samples
Tissue may be obtained from surgical specimens or from core needle biopsies for Oncotype DX® {1}, MammaPrint® {2} and uPA/PAI-1{3}. It is possible that the uPA/PAI-1 test can only reliably be carried out on tissue from surgery rather than core biopsy tissue {4}. Care must be taken in obtaining the samples in accordance with the manufacturer’s instructions (see RC-TEC13 for more details).
Preserving tissue samples
MammaPrint uses fresh-frozen tissue, tissue preserved in an RNA preservative solution, or formalin- fixed paraffin-embedded (FFPE) tissue. Oncotype DX uses FFPE breast cancer tumour tissue. The uPA/PAI-1 test, including FEMTELLE, requires fresh-frozen tissue. {RC-TEC2, RC-TEC3, RC-TEC4}
If one particular tissue collection and preservation system is normally used in the clinical setting, use of a test that requires a different system will have an impact on work flows.
Impact on clinical communication and cooperation
Use of these tests may require some additional forms of communication and cooperation between hospital units, outpatient services and hospital structures. There is more detail on this in question ORG3 below.
Impact on patient flow
Tissue samples for Oncotype DX and MammaPrint must be sent to a central laboratory for processing. This may have implications for patient flow as the results are received in 10–14 days (Oncotype DX) or 7–10 days (MammaPrint). If the FEMTELLE test is analysed in house according to the manufacturer’s instructions, this takes two days. If it is sent to a designated laboratory for processing the results should be received in 3–4 days {COL-2}. There is no information in the literature about the time taken to process generic uPA/PAI-1 tests, but reasonably this could be variable.
There is more detail in question RC-ORG3 below about the impact on patient communication of introducing the tests.
The literature contains little information on the work flow and patient flow impact of using these tests. Some points that were made in the literature are summarised above. However, since quality criteria have not been applied to these studies (see domain methodology), the real impact of these points on work and patient flows is unknown.
Importance: Important
Transferability: Completely
Analysis of selected studies extracted from the basic literature search. Two articles were found to be relevant to this question.
MammaPrint
MammaPrint must be analysed exclusively by the manufacturer’s laboratory so no special staff, training or other human resources are needed within the centres, other than pathologists for the specimen preparation. Sample isolation and preparation must be performed by pathologists in the proper way, following the instructions of the manufacturer. Specimen preparation requires either fresh, fresh-frozen or FFPE tissue. {RC-TEC2, RC-TEC3, RC-TEC4}
In the logistics pilot study preceding the MINDACT trial {5} training activities were performed before introducing the 70-gene prognosis-signature into daily clinical practice. The study coordinator organised on-site instruction meetings in each participating hospital. These instruction meetings were attended by a multidisciplinary team, i.e. breast surgeons, medical oncologists, pathologists, data managers and research nurses. During this instruction visit, the logistical scheme was discussed and incorporated into the local standard procedures. Additionally, all study-specific standard procedures were explained in detail in a manual of operations and were summarised on provided pocket summaries, to support standardised procedures for tissue collection, freezing and shipment. The authors highlighted that training and repetition are very important to avoid sample failure and to achieve the balance between a sufficient amount of tumour cells and a limited amount of stromal tissue. {5}
Oncotype DX
Oncotype DX must be analysed exclusively by the manufacturer’s laboratory so no special staff, training or other human resources are needed within the centres, other than pathologists for the specimen preparation. Sample isolation and preparation must be performed by pathologists in the proper way, following the instructions of the manufacturer. The pathologist must be able to select the appropriate tumour block for Oncotype DX, given that results should reflect the invasive component of the tumour. Specimen preparation requires FFPE tissue. {6, RC-TEC4}
uPA/PAI-1 and FEMTELLE
If FEMTELLE is analysed in the centre’s own laboratory, the staff must be trained to an appropriate level (see RC-TEC13 or RC-ORG5 for more details). If the samples are sent to a laboratory recommended by the manufacturer, no special staff, training or other human resources are needed within the centres, other than pathologists for the specimen preparation. In both cases sample isolation and preparation must be performed by pathologists in the proper way, following the instructions of the manufacturer. Specimen preparation requires fresh-frozen tissue. {RC-TEC2}
No information was found about the staff, training or human resources requirements of using a generic (“home brew”) uPA/PAI-1 test.
If one particular tissue collection and preservation system (such as FFPE) is normally used in the clinical setting, use of a test which requires a different system (such as fresh-frozen) will have an impact on staff, training and human resource needs.
Importance: Important
Transferability: Completely
Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Five articles were found to be relevant to this question. We found additional information by an internet search of grey literature performed on 20 March 2012 via the search engine Google. It was performed by one investigator using key words specific to the Organisational Aspects domain (“communication”, “cooperation”, “network”, “teamwork”, “multidisciplinary team”, “multiprofessional team”) combined with each test (uPA/PAI-1/ Oncotype DX/ MammaPrint). Two grey literature sources are referred to in these results.
All of the literature refers to the generic uPA/PAI-1 test rather than to the brand FEMTELLE.
Cooperation activities
Tissue collection and preservation
If one particular tissue collection and preservation system is normally used in the clinical setting, use of a test that requires a different system will have an impact on inter-departmental cooperation. For example, Mook S et al. (2007) found that the logistics for the collection of fresh-frozen tissue are complex and vary from hospital to hospital{7}.Therefore, performing microarray analysis, especially on a real-time basis, can cause some logistical problems such as insufficient freezing procedures, or transport-related issues. The authors concluded that close collaboration between pathologists, surgeons and oncologists is of paramount importance.
Cooperation between units compared with standard care
Compared with standard care, these tests may require some additional forms of cooperation between hospital units, outpatient services and hospital structures. For instance, the National Cancer Institute states that performing and evaluating these tests will need the implementation of an integrated process involving different units of the organisation, clinical participants and stakeholders. An integrated process of care presumes the standardisation of coordination and communication mechanisms among the different participants. Multidisciplinary teams of pathologists, surgeons and oncologists are the best suited to lead the evaluation of cancer recurrence risk with these tests. Interdisciplinary cooperation will likely affect current practice patterns. Modern practices require a more customised examination with more cooperation between those who order the test, those who perform it and those who interpret it. Genetic counsellors may have a role to play. These specially trained health professionals are skilled at supporting individuals when testing is being considered, when test results are received, and during the weeks and months afterwards {8}.
The electronic survey of clinicians showed that the relationship between those who prescribe the test, those who administer it and those who interpret the results is usually very close. Six out of eight respondents (75%) said that those who prescribe the test and those who administer it are part of the same team. One respondent (13%) stated that the prescribers and those who administer the test are linked by a relationship of “supply of services” and one respondent (13%) said the relationship was “professional advice”. A similar pattern is reported by respondents about those who administer the test and those who interpret the results: for five out of eight (63%) it is within the same team, for two (25%) it is a relationship of “professional advice” and for one (13%) it is a relationship of “supply of services”. The units within organisations that are in charge of administering the test vary: for four respondents (50%) it is a laboratory or pathology department, for three (38%) it is an oncological unit, for one (13%) the test is sent away to be performed and for one (13%) it is carried out in the private sector.
MammaPrint
In a prospective community-based feasibility study (RASTER) for the use of the 70-gene signature, hospitals that wanted to be enrolled had to have uniformly structured multidisciplinary breast cancer care that used standard operating procedures, and had to have at least one dedicated physician (surgeon, pathologist, or medical oncologist) as a local coordinator. The coordinator’s role was to encourage and guarantee adequate information and communication activities among professionals involved in the patient pathway {9}.
Communication activities
Compared with standard care, the decision to introduce the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) in the clinical pathways of women with invasive breast cancer may need additional communication to all professionals involved and to eligible patients. Findings from the electronic survey show that in 75% of cases (6 out of 8) the availability of the test was communicated to clinicians. They were told about the need for careful identification of appropriate patients to use the test on and its rationale, or that the test would be discussed with relevant patients. One respondent from Spain reported also that clinicians were told that the test helps to make therapeutic decisions in some cases. In some places administrative staff and nursing staff were told about the need for careful identification of eligible patients and the rationale for the tests. (See {COL-3} for the full survey results.)
With patients
On the basis of patient interviews and questionnaires, Retal et al. (2007) felt that, given the level of knowledge on prognostic tests for cancer recurrence, there is room for improvement in the patient information {10}. The EGAPP (Evaluation of Genomic Applications in Practice and Prevention) working group (Berg et al. 2009) recommended that healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing, and should discuss with patients whether the test results are likely to change their decision about therapy {11}. (See the Social Aspects domain of this HTA for more details about training and information activities for patients.)
Among professionals involved in the patient pathway
The Breast Centres Network takes the view that communication among professionals is essential in order to ensure that all the information coming from the prognostic tests is available quickly and is correctly interpreted. They also highlight that a molecular geneticist should be accessible for consultation by the specialists in the clinic {12}.
The literature contains little information on the cooperation and communication requirements for using these tests. Some points that were made in the literature are summarised above. However, since quality criteria have not been applied to these studies (see domain methodology), the real impact of these points on cooperation and communication activities is unknown.
Importance: Important
Transferability: Completely
Analysis of selected studies extracted from the basic literature search. Three articles were found to be relevant to this question. The results of the Clinical Effectiveness domain of this HTA were also taken into account.
MammaPrint and Oncotype DX are currently offered as laboratory services subject to Clinical Laboratory Improvement Amendments (CLIA) general laboratory standards. Even if central laboratories offering the tests are certified and use reliable procedures, pre-analytic issues at the sending sites such as specimen acquisition and handling can potentially affect the results of the testing. Standardised protocols for sample processing, storage and preparation are important to ensure results {13}.
Marchionni L et al. (2007) have envisaged the potential for scale problems that may be faced in the future as a consequence of increased demand for these tests. They take the view that scientific or regulatory bodies should monitor whether the degree of accuracy seen in investigational settings can be maintained with increasing demands. Scaling up the tests could represent a challenge for the reproducibility and reliability of the tests in any setting, especially if more than one laboratory offers the assays, since procedures to ensure inter-laboratory reproducibility will be needed {13}.
The National Horizon Scanning Centre in the UK reported that the test could be taken in general, non-specialist hospitals (secondary care) or in highly specialist services or hospitals (tertiary care), but it did not recommend one setting over another {14}.
No information was found in the literature review about this question for either the generic uPA/PAI-1 test or the FEMTELLE brand.
The literature contains little information on the advantages and disadvantages of providing the tests centrally or locally. The potential impact on healthcare budgets or skill levels in hospital laboratories of the tests only being carried out at the company’s own laboratories was not discussed. The points made in the literature are summarised above. However, since quality criteria have not been applied to these studies (see domain methodology), the real impact of these points is unknown.
Importance: Important
Transferability: Partially
Analysis of selected studies extracted from the basic literature search. Five articles were found to be relevant to this question. Information provided by the manufacturers to the HTA was also reviewed.
In all cases, tissue must be extracted and handled with care, and appropriate staff must be available and trained to the appropriate level. {RC-TEC13}
MammaPrint
According to the manufacturer, centres that use fresh tissue can order MammaPrint Specimen Collection and Transportation Kits online, place the tumour biopsy specimens in RNARetain, a proprietary RNA stabilizing solution, and then courier it to Agendia in the Netherlands. FFPE tissue may also be sent. Results are delivered electronically within 10 days at a cost of $3200 {15}. In the EU the MammaPrint assay costs €2675 {COL-2}.
Oncotype DX
According to the manufacturer, the cost of the assay is $3450 (€3180 in the EU and £2580 in the UK) and the samples are processed by Genomic Health’s own laboratories. {COL-2}
Obtaining and preserving tissue samples does not require any additional investment in centres that handle FFPE tissue, as guidelines for selecting tissue samples for the Oncotype DX assay are consistent with those for selecting optimal tissue blocks for standard immunohistochemistry assays {16}.
uPA/PAI-1
The assay requires a substantial amount of fresh-frozen tissue sample. This will have an impact on costs in centres that normally use FFPE tissue.
The generic uPA/PAI-1 test costs approximately €150 {4, 17}.
FEMTELLE
According to the FEMTELLE manufacturer, in order to process the test, laboratories need the following equipment that is available as routine equipment at many diagnostic laboratories: homogeniser (e.g. dismembrator) to homogenise the tumour tissue; cooled laboratory centrifuge; enzyme-linked immunoassay (ELISA) plate reader. The laboratories that perform the test should be qualified to perform ELISA testing (e.g. private diagnostic laboratories, institutes of pathology, diagnostic laboratories at breast cancer centres etc.). Laboratories that want to establish FEMTELLE testing at their site must be trained in experienced ISO certified laboratories that have performed many FEMTELLE tests. To this end the technicians receive detailed technical training at selected laboratories. {COL-2}
The sample may also be shipped to any laboratory qualified to perform ELISA testing. The manufacturer has a list of recommended laboratories. {RC-TEC7}
The manufacturer supplies the FEMTELLE test kit to laboratories for approximately €300. {COL-2}
Importance: Important
Transferability: Partially
Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Twelve articles were found to be relevant to this question. Information provided by the manufacturers to the HTA was also reviewed.
MammaPrint
Management problems
Until recently MammaPrint required fresh or fresh-frozen tumour samples to preserve the quality of the RNA. Some of the potential difficulties in the implementation of the test in daily clinical practice have been the required change in routine work-up for tissue handling in centres that do not usually handle fresh tissue. This includes the onsite availability of the pathologist {10}. Mook et al. (2007) found that the logistics for the collection of fresh-frozen tissue are complex and vary from hospital to hospital. Therefore, performing microarray analysis, especially on a real-time basis, can cause some logistical problems such as insufficient freezing procedures, or transport-related issues. The authors concluded that close collaboration between pathologists, surgeons and oncologists is of paramount importance {7}. Centres that normally use FFPE tissue no longer face these issues now that MammaPrint can be used on FFPE tissue. {RC-TEC3}
Retèl et al. (2009) reported organisational issues faced during the implementation of MammaPrint in daily clinical practice in some community hospitals in the Netherlands (15 of the 16 participating hospitals in the RASTER study). All hospitals succeeded in implementing the required tumour sampling logistics. The duration of the implementation, measured from patient consent to first patient inclusion, varied from 0.2 to 9.4 months (median 1.2). The two outliers (4.3 and 9.4 months) had start-up problems especially in the pathology process.
The change in routine work-up for tissue handling (fresh-frozen tissue versus paraffin embedding) and the onsite availability of the pathologist were most difficult to achieve. However, if those logistics were in place, no other major problems appeared {10}.
Retel et al. (2009) also found that a potential increase in chemotherapy prescription, which was the result in the RASTER study, should be taken into account even though the initial expectation among the researchers and professionals involved was for the opposite to be the case{10}.
In one study, where all samples were obtained by surgical resection, a failure rate (i.e. the test produced no usable result) of 18% was observed due to non-representative tumour tissue (<50% tumour cells) {5}.
Opportunities
The MammaPrint assay has a larger gene number (70 genes) and could provide a greater opportunity to assess additional pathways and potentially provide additional pharmacogenomic information than the 21-gene Oncotype DX assay. It also has a wider indication than Oncotype DX by including both oestrogen-positive(ER+) and ER- patients, which also allows for the inclusion of a greater number of younger patients {18}.
Microarray based gene-expression profiling has also been used to define cellular functions, biochemical pathways, cell proliferation activity, and regulatory mechanisms {19}.
According to Retel et al. (2009) the introduction of this technology in hospitals, if well managed, does not change the time between surgery and the start of radiotherapy or adjuvant systemic treatment {10}.
Oncotype DX
Management problems
Failure rates in the range of 2.7 to 44.9% (mean 20.3% and median 11.8%) have been noted, some of which is due to insufficient tumour samples. This may in part be due to the use of archive samples and may not necessarily reflect the full sample normally available at the time of diagnosis {1}.
According to some researchers, Oncotype DX is an expensive test but it may save downstream costs of treatment by limiting chemotherapy to patients with higher risks of recurrence who are most likely to benefit from this regimen. Therefore immediate savings are expected because of reduced chemotherapy costs, supportive care costs, and management of adverse events per woman tested {20, 21}. This expectation have not been met in other contexts such as in Israel (Clalit Health Services, Tel Aviv, Israel) where testing 368 patients with ER+, lymph node negative (LN-), early stage breast cancer with Oncotype DX increased their health-care costs by $1,500,000. In the view of the study authors, these higher overall costs, relative to cost-savings that have been estimated for the USA, are likely to be a consequence of the higher expenditure per patient in Israel for adjuvant chemotherapy and its administration {22}.
uPA/PAI-1
Management problems
The uPA/PAI-1 assay requires a fresh-frozen tissue sample. The tissue-handling requirements make this assay challenging in current clinical practice if tissue is not normally collected and preserved in this way.
The prognostic significance of ELISA in small amounts of tissue, such as tissue collected by core biopsy, has not been confirmed {6}. Therefore, at present, this assay may not be practical for many women with small tumours, such as those who are detected by screening, for whom the decision about adjuvant chemotherapy is difficult {23}.
FEMTELLE: According to the manufacturer, training and quality assurance are needed for sample isolation. The pathologist should be trained to inspect breast cancer tumour tissue. Finally, the laboratories that perform the FEMTELLE test should participate in regular quality assurance rounds organised by a designated laboratory in Nijmegen in the Netherlands. {COL-2} These requirements could be considered a management problem.
Opportunities
FEMTELLE: The manufacturer states that FEMTELLE is performed in more than 30 centres in Europe (Germany, France, Spain, Slovenia) {24}. FEMTELLE can be also performed in any laboratory equipped with a tissue homogeniser, an ELISA reader, and a cooled centrifuge (16,000 g). {RC-TEC7} This could be considered a management opportunity. Laboratories that want to establish FEMTELLE testing at their site must be trained in experienced ISO certified laboratories that have performed many FEMTELLE tests. To this end the technicians receive detailed technical training at selected laboratories. {COL-2}
Potential for scale problems
Marchionni et al. (2007) have identified one problem that may be faced in the future: the consequences of an increase in demand for these tests. They consider that scientific or regulatory bodies should monitor whether the degree of accuracy seen in investigational settings can be maintained with increasing demands. Tissue sampling and processing may be a potential issue for broad implementation of testing {13}.
Possible need for databases
Marchionni et al. (2007) suggest that consideration should be given to developing databases with complete data on each patient tested with these and future tests. The data should include all the analyses performed, laboratory logs, the raw and processed data, and all the information about procedures and analyses that have been performed to produce a risk estimate from a tumour sample {13}.
Potential for problems with acceptability
The introduction of these tests in clinical practice could be hampered by some resistance of clinicians, nursing staff or administrative staff. As shown by the electronic survey of clinicians, resistance could be for economic and financial reasons (e.g. anxiety about offering a test to the patient that they would need to pay for). Moreover, the tests might not be strongly advocated by some clinicians because of their limited use or their cost. (See RC-ORG8 for more information about degree of acceptance of the tests.)
The literature contains little systematic information on the management problems and opportunities of using these tests. The main potential problems highlighted are: tissue-handling requirements (sample isolation, preparation, transport and processing); possible increase in chemotherapy costs; potentially high failure rates; possible challenges in scaling up use of the tests; and possible resistance to introduction of the tests. However, since quality criteria have not been applied to the studies used (see domain methodology), the real impact of these points on management problems and opportunities is unknown.
Importance: Critical
Transferability: Partially
Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Five articles were found to be relevant to this question. Well-conducted experimental and observational trials can give a picture of clinical decision-making and patient eligibility, which are too close to the ideal protocol. Results from the electronic survey give additional information from clinical practice.
Only anecdotal evidence was found in the literature.
The EGAPP working group (Berg et al. 2009) considered that, until more data are available, clinicians must decide on a case by case basis whether the use of a gene-expression profile test adds value beyond the use of the current prognostic markers (and how to weigh and combine these risks), and whether each test’s validation population is relevant to their patients’ age, disease status, and race/ethnicity {11}.
According to the European electronic survey, the folowing are responsible for deciding which women are eligible for the tests:
Six different reasons were given (by one respondent each) as the basis for making the eligibility decision: (1) on the basis of availability, funding and potential clinical benefit; (2) on a case by case basis to women at intermediate risk of breast cancer who are struggling to make a decision around adjuvant chemotherapy; (3) on the basis of evidence; (4) if they meet the local authorities’ inclusion criteria; (5) if they had the characteristics required to be enrolled on the MINDACT trial; and (6) on the basis of evidence, cost analysis and resource allocation prioritisation.
Oncotype DX
In one study of 44,079 tumour specimens from early-stage, ER+ breast cancer patients, surgeons ordered the Oncotype DX assay more frequently for HER2+, whereas medical oncologists ordered it more often for node-positive patients {25}.
In a round table discussion, expert opinion suggested that, although there is no set policy or algorithm for determining who should receive an assay, the typical patient for whom they would most likely order the test is an ER-positive patient with a tumour measuring between 1 and 3 cm. The participants in the discussion said that the Oncotype DX assay is validated in larger tumours, and is ordered for patients who have larger tumours, and athough it is by no means a universal practice, sometimes it was ordered for women with node-positive disease. The experts considered that the assay may also be useful for patients with minimal nodal involvement and for whom the clinician would normally recommend chemotherapy but where the patient may be hesitant to receive chemotherapy {26}.
From a data review over the past 6 months for a single centre, it was found that nearly 15% of requests for the Oncotype DX assay were for patients who had micrometastases {26}.
There is little information in the literature about clinical decision-making and patient eligibility. In conjunction with the electronic survey, the data lead us to conclude that the decision to use the tests rests mainly with clinicians, and that in reality the tests may not be used on the indicated patient population. Centres may not have a set policy for determining who should have the tests. However, these conclusions are not robust.
Importance: Important
Transferability: Partially
Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Seven articles were found to be relevant to this question.
The Clinical Effectiveness domain of this HTA has analysed the impact of use of the tests on clinicians’ decision-making. Here we consider only data about acceptance of the tests by clinicians.
All of the literature refers to the generic uPA/PAI-1 test rather than to the brand FEMTELLE.
The currently available literature suggests that risk stratification in breast cancer patients has not improved considerably over the past years. Clinicians still use tumour size, grade, and age, with the addition of biomarkers such as uPA/PAI-1, Oncotype DX or MammaPrint in some centres, to determine recurrence risk. Meanwhile, clinicians are eager to implement new techniques, including uPA/PAI-1 assessment, to better refine treatment decisions {4} but they tend to look for more confirmative data concerning the validity of the tests before implementing them in routine clinical practice. During a conference about the regular use of genetic assays in clinical practice in San Francisco in 2009, the audience members voted 50% in favour of regular use of multigene assays in low-risk, node-positive patients and 50% against. After the debate, the audience vote shifted away from regular use, with 33% in favour and 67% against {27}.
Results from the electronic survey show that clinicians and nursing staff have a good acceptance of the tests. (Seven out of eight respondents (88%) reported that both clinicians and nurses accepted or readily accepted the tests.) Nevertheless there was some resistance. Possible reasons for resistance were given by individual survey respondents as follows: lack of confidence in cost effectiveness; the fact the patient has to pay the cost of the test; lack of availability of patients (many are already involved in ongoing clinical trials on adjuvant therapy which do not use these tests); the desire to wait for published data from clinical trials (TailoRX, MINDACT) to define the role and necessity of these tests in therapeutic decision making. Some resistance comes also from administrative staff or nursing staff: some reported anxiety about offering a test to the patient that they would need to pay for or fear of an immediate cost increase due to a lack of confidence in the cost effectiveness of the tests. (See {COL-3} for the full survey results.)
Moreover, the uPA/PAI-1 assay and, until recently, MammaPrint require a fresh-frozen tissue sample, and there is some reluctance to adopt the tests in countries in which fresh-frozen tissue is not readily available after surgery. Core biopsy specimens are now more common and researchers are therefore trying to demonstrate that assays from core biopsies are reliable{4}.
Li et al. (2008) suggest that national or regional healthcare systems should develop supporting information systems that offer educational and consultation programmes for physicians and other healthcare providers, as well as for the general population, to guide the adoption and use of these tests {15}.
MammaPrint
A survey performed in 15 community hospitals (Retèl et al. 2009) showed that all the physicians interviewed expected that the MammaPrint signature will eventually become part of future regular diagnostics. Some expected the signature to be performed in all patients; others considered it as a complementary parameter especially in difficult cases. In general, the physicians rated the addition of the 70-gene signature as beneficial for patient management; however, several medical oncologists tended to look for more confirmative data concerning the validity of the signature {10}.
Oncotype DX
Some studies reported that the Oncotype DX Recurrence Score (RS) increased medical oncologists’ confidence in their treatment recommendation:
The quality of studies available is poor and the reliability of results, weak. Indeed, data on acceptance come from observational studies, surveys and expert opinions. Moreover, healthcare professionals who responded to the surveys may have had a systematically different impression of the clinical utility of the tests compared with non-respondents, so that acceptance results could be overestimates.
Importance: Important
Transferability: Partially
Analysis of selected studies extracted from the basic literature search and data from the electronic clinician survey. Two articles were found to be relevant to this question. A grey literature search was performed on 10 February 2012 via the search engine Google by one investigator using key words specific to the Organisational Aspects domain (“stakeholder”, “stakeholder involvement”, “genomic test”, “genetic test”) combined with each test (uPA/PAI-1/ Oncotype DX/ MammaPrint). One grey literature source is referred to in these results.
As highlighted in the electronic survey, all the relevant stakeholders within healthcare organisations usually work in close collaboration and as part of the same team. All those concerned are in charge of ordering, administering or interpreting the test and their decisions affect the spread of the tests in clinical practice. The electronic survey of clinicians showed that clinicians, and to a lesser extent also nursing staff and administrative staff, have a good acceptance of the tests. Nevertheless, some resistance was expressed because of economic and financial issues or the limited use of the tests. (See {COL-3} for the full survey results.)
Li et al. (2008) consider that cooperation is needed between third party payers and manufacturers, so that useful information and stronger evidence are produced or found by manufacturers in order to support the decision-making process. They suggest that manufacturers should develop supporting information systems that offer educational and advice programmes for physicians and other healthcare providers, as well as the general population, to spread knowledge and awareness about this kind of testing {15}.
In a review published by the American Society of Clinical Oncology in 2010 the authors examined the coverage policies of six private payers for the Oncotype DX 21-gene assay, highlighting that clinical evidence was the most important factor in decision making for all payers, even if they had different perceptions about the strength of evidence at the time of the coverage decision. Other factors influencing the decision about adoption were, for instance, physician adoption or medical society endorsement. Some payers reported that signs of broader adoption, such as increased number of claims, served as triggers for a closer policy review {31}.
The Institute of Medicine (2012) believes that stakeholders representing regulators, payers and providers should share their perspectives on evidence. More dialogue and coordination among stakeholders is needed to facilitate the development of the necessary evidence base. Test development and reimbursement need to focus on the clinical utility of the test and the net benefit to patients. Moreover, the analysis of evidence must be adapted to the clinical setting and to the evidence needed for that particular application {32}.
The literature provides some insight into the influence of stakeholders on the adoption and diffusion of the prognostic tests for breast cancer recurrence in clinical practice. The degree of acceptance of these tests by clinicians, nursing staff and administrative staff, as shown by the electronic survey, was considered in this assessment element as it could be a factor influencing their diffusion. Cooperation between third party payers, regulators, providers and manufacturers could facilitate the development of further clinical evidence to support coverage decisions.
Importance: Important
Transferability: Partially
As described in the section on domain methodology, quality criteria were not applied to the studies identified for review. The real impact of the points identified in the literature on organisational issues is therefore unknown.
The response to the electronic survey of clinicians was too low (eight responses) to be statistically representative. The low response rate is likely to be at least in part due to the low use of the tests in European countries. {RC-CUR11}
Further research on all of the domain assessment elements would generate more certainty about the interpretations in the results cards above. However, issues such as communication or eligibility for tests vary culturally and in different countries, so it is not certain that it would be cost effective to undertake such research.
Authors: Pseudo85 Pseudo85, Pseudo84 Pseudo84
Feelings of distress and anxiety are frequently reported by patients undergoing prognostic tests and are related to the consequences of the tests on treatment decisions. It remains unclear whether and how these feelings affect the social areas of the patient. Some kind of emotional and psychological support could be useful, especially in cases where the results of prognostic tests and those of standard clinicopathological prognostic factors analysis are discordant. Communication with the patients is a delicate issue that deserves particular attention and requires further reflection on the most effective method of communicating risk information.
A number of studies showed that knowledge of some aspects of genetic and prognostic testing was low. Healthcare organisations should provide patients with counselling and educational support (verbal and printed information) so that they can gain a better understanding of genetic and prognostic tests in general, as well as about the specific test they undergo, and can participate in the decision-making process. In fact, as shown by different studies, most of the women with early breast cancer prefer having an active or shared role in medical decisions.
The social domain, according to the current version of Core HTA Model Handbook, takes the patient as a point of departure in its analysis of the manifold social implications of health technology. The task of the assessment is to map and describe the possible experiences, actions and reactions towards the technologies and the consequences of using a given technology. Application of prognostic tests may interact with patients’ social arenas in two ways: first, directly by application of the technology and second, by generating a prognostic result, the consequences of which the patient must face. Social interactions related to recurrence risk of breast cancer could involve communication and support needs before and after the examination, self-perception and future life planning (HTA Core Model Online Handbook).
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
H0001 | Major life areas | Which social areas does the use of the technology influence? | yes | In which social areas (e.g. working life, family life, social relations,…) of the patients may the use of Genetic Test for breast cancer generate change? |
H0002 | Major life areas | Who are the important others that the use of the technology may affect in addition to the patient? | yes | Who are the important others that the use of Genetic Test for breast cancer may affect in addition to the patient? |
H0003 | Major life areas | What kind of support and resources are needed or might be released as the technology is put to use? | yes | What kind of support and resources are needed or might be released as Genetic Test (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) is put to use for women with invasive breast cancer? |
H0004 | Major life areas | What kinds of changes does the use of the technology generate in the patient's role in the major life areas? | no | It is incorporated in question H0001. |
H0005 | Major life areas | What kind of changes does the implementation and use of the technology mean for the patients physical and psychological functioning in his or her major life areas? | no | It is incorporated in questions H0001 and H0003 |
H0006 | Individual | How do patients and important others react and act upon the technology? | yes | How do women with invasive breast cancer and important others react and act upon the Genetic Test for breast cancer ? |
H0007 | Communication | What is patients' and important others’ knowledge and understanding of the technology? | yes | What is patients' and important others’ knowledge and understanding of Genetic Test for breast cancer? |
H0008 | Communication | How is the information regarding the use of the technology processed and exchanged? | yes | How is the information regarding the use of Genetic Test for breast cancer processed and exchanged? |
H0009 | Communication | What are the consequences in decision making? | yes | What are the consequences in decision making? |
Domain frame
The project scope applies to this domain.
Information sources
Social and patient-related aspects of prognostic tests for breast cancer recurrence (uPA/PAI-1, Oncotype DX® and MammaPrint®) were analysed from the published scientific literature.
This domain used the information sources and search strategy undertaken for the Core HTA. Of the 616 articles identified, five studies were selected by one reviewer. Studies were eligible if they:
All the articles selected were retrieved and data extracted. Data extraction tables are reported in {SOC-1}.
Quality assessment tools or criteria
For assessing the quality of evidence the approach of the GRADE working group was applied by one investigator. (Guyatt GH, 2008)
The GRADE approach specifies four levels of quality: high—further research is very unlikely to change our confidence in the estimate of effect; moderate—further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates; low— further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low— we are very uncertain about the estimate.
The results of the quality assessment are reported in {SOC-1}.
Analysis and synthesis
Data extraction was done by one researcher. Analysis and synthesis of study designs and characteristics are reported in {SOC-1}.
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
According to literature review, the introduction of prognostic tests for breast cancer recurrence (PTBCRs) in clinical practice does not appear to have a direct impact on any of the social areas (e.g. working life, family life, social relations). Feelings of distress and anxiety are frequently reported and are related to the consequences of the tests on treatment decisions. It remains unclear whether and how these feelings affect the social areas of the patient.
Oncotype DX
According to Richman 2011 approximately 26% (17 of 65) of women agreed or strongly agreed that getting the test result made them worried and anxious. Greater endorsement of test-related distress was associated with higher actual recurrence risk based on the test, as the majority of women who experienced test-related distress had intermediate or high recurrence risks based on their test results (low = 18%, 6 of 33; intermediate = 30%, 7 of 23; high = 44%, 4 of 9). Stronger feelings of distress were also related to getting chemotherapy, not getting radiation, and having more frequent worries about breast cancer recurrence. {10}
Richman (2011) and Tzeng (2010), in their observational study on women’s experiences with genomic testing, reported that few women agreed that they had the test only because other family members wanted them to (8%); that the test had a negative effect on their family (5%); or that information about one’s cancer is better left unknown (3%). They did not report whether these experiences could affect the family life of patients. {10}, {11}
Lo et al. (2010) assessed the impact of Oncotype DX on total quality of life. The results showed that women’s quality of life remained stable over the year of diagnosis and treatment (P = 0.55) according to Functional Assessment of Cancer Therapy (FACT-B and FACT-G) surveys. Quality of life was assessed before the women obtained the results of the recurrence score (RS) assay (mean, 112.2; SD = 17.4) and 12 months after the assay (mean, 114.3; SD = 18.6). These data come from a questionnaire addressed to a small sample (89 patients) of American women with lymph-node-negative cancer. {6}
An indirect influence is due to the fact that genomic tests can help with making complex decisions about adjuvant treatment for cancer that, itself, has a strong impact on many of social areas. Following the tests, patients enrolled in the study by Lo et al. experienced reduced anxiety over their treatment decision and increased confidence in their choice of therapy. They reported significantly lower conflict about the decision about adjuvant treatment and had significantly decreased situational anxiety immediately after learning the results of the Oncotype DX test. 12-months after the assay most women continued to feel satisfied that they had used the RS assay, but those patients who were not satisfied (n = 5) noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and negative impact on self-image.{6}
The literature contains little information about the impact of using prognostic tests on different social areas. Some points were made in the literature about the impact of Oncotype DX on anxiety and quality of life, which are summarised above.
Importance: Optional
Transferability: Completely
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
There are no studies that address these questions.
Importance: Optional
Transferability: Unspecified
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
Evidence from literature review is all related to Oncotype DX. It showed a psychological impact and emotional reaction to the test results, such that the following types of support should be made available as the test is put to use for women with invasive breast cancer.
Emotional and psychological support
Since these tests may have a psychological impact on patients, emotional and psychological support should be provided.
Richman (2011) reported that most women experienced test-related distress. Stronger feelings of distress were also related to receiving chemotherapy, not receiving radiation, and having more frequent worries about breast cancer recurrence. {10}According to Tzeng et al. (2010), as women with intermediate and high genomic-based recurrence risks are more likely to worry about recurrence and be distressed about their test result, they deserve special attention. {11} Retèl et al. reported that the psychological impact on patients seems especially related to discordance between a low risk based on clinicopathological factors and a high genomic risk signatureand to its successive communication. {9}
Psychological impact was measured by Retèl et al. (2009) both through a questionnaire to 77 women, that was used to assess the respondents’ emotional reactions to the test results, also called “negative affects”, and by the Cancer Worries Scale which assessed how worried the women were after receiving the 70-gene prognosis signature. The scores for “thought about chances of getting cancer again influencing the mood” on the Cancer Worries scale differed significantly (p = 0.01; n = 77) according to risk group: 43% of patients with a clinically low risk but a poor genomic signature and 29% with a clinically high risk and no signature (due to failure in the testing process) often worried about recurrence, compared with 0% of the patients with a clinically high risk and a good signature, 20% of those with a clinically low risk and no signature, 13% with a clinically high risk and a poor signature and 3% with a clinically low risk and a good signature. {9}
Educational support (verbal and printed information)
A number of studies showed that knowledge about some aspects of the prognostic tests was low and having higher health literacy and numeracy increases patients’ ability to recall information about recurrence risk testing. {9},{10},{5} Healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing and should discuss whether the test results are likely to change the patient’s decision about therapy. {1} According to Richman et al. (2011), knowledge was higher among women who recalled receiving both verbal and printed information about the test and among women who recalled that their doctors described the results of the test using numbers. These findings offer preliminary information on communication approaches that may be most effective. For example, when communicating recurrence risk test information with patients, health professionals and educators should pay attention to patient health literacy and numeracy, and perhaps adjust the delivery of and time spent on communicating with patients. {10}
Importance: Important
Transferability: Completely
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
A number of studies reported how patients react and act upon the prognostic or genetic tests for breast cancer. Evidence from literature review is all related to Oncotype DX and MammaPrint; nothing was found about the uPA/PAI-1 test.
Oncotype DX
According to data presented at the 2007 and 2008 San Antonio Breast Cancer Symposia, following the use of the Oncotype DX assay patients usually experience reduced anxiety over their treatment decision, greater satisfaction, and increased confidence in their choice of therapy. The investigators reported that 95% of patients were glad that they had taken the Oncotype DX assay, and 83% of patients stated that the assay influenced their treatment decision. Patients reported significantly lower conflict about the decision for adjuvant treatment after obtaining the results of the RS assay. Decisional conflict was not repeated at 12 months, but it would have been interesting to see whether decisional conflict continued to be lower longer term. {6}
Good satisfaction about the Oncotype DX test is also reported by Richman et al. (2011). Women in this study had few concerns and were satisfied with the test, saying that they would recommend it to others and would still have the test if faced with the decision again today. In general, they perceived more benefits than concerns about the test. Approximately 26% (17 of 65) of women agreed or strongly agreed that getting the test result made them worried and anxious and test-related distress was associated with higher recurrence risk based on the test. {10}
MammaPrint
The satisfaction reported by Retèl et al. about receiving the 70-gene signature (MammaPrint) per risk-group was 76%. Of seventy patients 6 (8.6%) were very dissatisfied, of whom 4 had a discordant clinically low risk with a high risk signature, 2 (not discordant) were dissatisfied about the way the result of the 70-gene signature was communicated. Eleven patients had a neutral opinion. The overall satisfaction regarding the total trajectory, from diagnosis to the time of interviewing, around 2 months after surgery, was 82% (n = 77). Significant differences (P = 0.001) were found between the different risk groups for emotional reactions after receiving the 70-gene signature. Women with discordant clinically low risks with high genomic risk signatures and clinically high risks with no signature (due to failure in the testing process) had the highest negative affect-scores (n = 77). {9}
Data on satisfaction and existential experiences come from observational studies and surveys, so the reliability of results is not very high.
Importance: Important
Transferability: Completely
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
The introduction and diffusion of new prognostic or genetic tests raise the question of the extent to which patients are prepared to participate in informed decision making about their care. It is important to give information to patients, and others who may be affected that is at a low threshold, understandable and evidence based. (National Health and Medical Research Council, 2004)
Oncotype DX
Different studies using patient interviews and questionnaires showed that, given the level of knowledge on genetic tests for cancer, there is room for improvement in the patient information {9}. Healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing and should discuss whether the test results are likely to change the patient’s decision about therapy. {1}
Knowledge about genomic recurrence-risk testing was also assessed by Richman et al. (2011) and Tzeng et al. (2010) through a questionnaire with a 13-item scale mailed to 78 women, treated for early stage, oestrogen receptor-positive breast cancer with 0–3 positive lymph nodes, whose medical records indicated they received Oncotype DX testing earlier. They found low knowledge about many aspects of genomic recurrence risk testing. Most women understood the relationship between the test and chemotherapy (e.g. test aids decisions about chemotherapy) and general test procedures (e.g. it is done after surgery that removes the breast tumour). However, few understood that the test result indicates the likelihood of metastasis assuming additional treatment and that the test does not provide information about familial risk for breast cancer. The authors present the need to continue developing optimal ways to communicate and ensure both perceived and actual comprehension of genomic-based information. Further research is needed on the testing information provided to patients and best practices for patient education. {10, 11}
According to Lillie SE et al. (2008) health literacy may affect women’s capacity to learn about the new genomic tests (Oncotype DX). Women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Health literacy was not related to the amount of additional information women desired. {5}
MammaPrint
Questionnaires and interviews about knowledge and psychological impact of MammaPrint were conducted by Retèl et al. (2009). The results of the knowledge test show that important issues are the predictive accuracy of the test (87% wrong answers) and the consequences of the test (66% wrong answers). The authors stated that the number of patient questionnaires was too small to conduct extensive statistical analysis. {9}
Data on knowledge about genetic tests come from observational studies and surveys, so the reliability of results is not high. The limitations of some studies are reported below.
Importance: Important
Transferability: Partially
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
Oncotype DX
A clinical roundtable monograph funded by Genomic Health, manufacturers of Oncotype DX, about incorporating the Oncotype DX breast cancer assay into routine clinical practice, reported that the discussion generally begins in the surgeon’s office, where the Oncotype DX assay is first introduced as an evaluation tool. At this time, the patient is provided with basic information, so that they are familiar with Oncotype DX when they first meet with their medical oncologist. Therefore, the Oncotype DX assay is sometimes ordered by the surgeon before the patient ever meets with a medical oncologist. In most cases, the patient would then discuss the assay result with their medical oncologist. Pathologists generally have no communication with the patient about the Oncotype DX assay, because their main role is to select the most representative tumour block to send out after receiving a request. {2}
Palmer et al. stated that, given the anxiety that patients experience following surgery and prior to making an adjuvant treatment decision, there could be value in surgeons ordering the Oncotype DX assay as this is expected to reduce the time required for patients to receive results. Moreover, having RS results at the time of the first consultation with the medical oncologist can lead to a smoother and more meaningful conversation with the patient. {8}
Tzeng JP studied how women receive and incorporate the results of Oncotype DX into decisions about adjuvant treatment for early-stage breast cancer. Most of the women surveyed (77 women with early-stage, oestrogen receptor-positive breast cancer with 0 to 3 positive lymph nodes who received Oncotype DX between 2004 and 2009) preferred having an active (38%) or shared (49%) role in medical decisions. {11}
Although genomic tests can help inform treatment decisions, a challenge is how best to communicate and incorporate test results when making complex decisions about adjuvant treatment for cancer. Informed decision making about adjuvant treatments often involves discussions about patients’ chances of recurrence. To date, there is little consensus about the most effective method of communicating risk information. Moreover, cognitive constraints such as low health literacy or low numeracy may result in reduced understanding of medical and probabilistic information. {5, 11}
A recent US study assessed retention of information about genomic tests among a proxy population of breast cancer patients who had not received Oncotype DX, but who were provided with an oral and written description of the test immediately before completing the survey. According to Lillie et al. (2008) health literacy may affect women’s capacity to learn about the new genomic tests as well as their desire for informed participation in their medical care. The retention of information about the risk of recurrence of breast cancer is sensitive to the individual’s capacity for processing information; patient-oriented educational materials about the recurrence risk test must help to reduce this effect. These data suggest that clinicians and health educators should be concerned about patients’ health literacy levels when discussing genomic recurrence risk tests. {5}
The literature contains little information on how information about the use of prognostic tests for breast cancer is processed and exchanged. There are no studies that address these questions for the MammaPrint and uPA/PAI-1 tests.
Importance: Critical
Transferability: Completely
The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).
Oncotype DX
Genomic tests can help to inform treatment decisions, but a challenge is how best to communicate and incorporate test results when patients make complex decisions about adjuvant treatment for cancer. As shown in various studies most of the women preferred having an active or shared role in medical decisions. {5}, {11}
Lillie et al. (2008) investigated the effect of health literacy on desire for active participation in two decisions: the decision to have the recurrence risk test and the decision to use the test results to inform decisions about which adjuvants should be used after surgery. Interviews of 167 patients (recruited only post-surgery and post-treatment who either did not receive neoadjuvant or adjuvant chemotherapy or had completed it) showed that the women’s desires to be actively involved in both the decision to have the recurrence risk test done and in treatment decisions based on test results differed according to their health literacy levels. Women with higher health literacy indicated a preference for more active participation in the decision to have the recurrence risk test than did women with lower health literacy. This finding was statistically significant (P = 0.03). Similarly, women with higher health literacy more often indicated that they preferred active participation in the decision to use the results of the recurrence risk test to make treatment decisions than did women with lower health literacy (P<0.001). Women with lower health literacy reported an interest in passive decision making (34%) that those with higher health literacy did not have (6%). They showed there is a larger effect of health literacy on decision-making preferences for use of the recurrence risk test results to inform care than for being tested in the first place. Experiences with Oncotype DX and beliefs about the test are also potentially important because they can reduce breast cancer patients’ willingness to let the results guide treatment decisions. {5}
The results of the multicentre trial by Lo et al. confirm that the RS assay impacts patient treatment choice. The trial consecutively enrolled 89 women with lymph node-negative, oestrogen-positive breast cancer who were medically fit to receive adjuvant chemotherapy. Several authors declared financial ties to Genomic Health and the trial received direct funding from Genomic Health. Patients’ treatment decisions before and after Oncotype-DX testing were recorded and the results showed a change for 24 women (27%). Patients usually experience reduced anxiety over their treatment decision, greater satisfaction, and increased confidence in their choice of therapy. They reported significantly lower conflict about the decision for adjuvant treatment after the RS assay and had significantly decreased situational anxiety immediately after learning the results of the RS assay, which remained stable at 12 months. The perceived risk of recurrence was an important factor in women’s choice of treatment. On a scale of 0 to 100, with 100 indicating definite recurrence, patients ‘mean estimated risk before the RS assay was 22.4 and after the assay was 16.0 (P = 0.001). Patients’ estimated risk of recurrence post-RS was significantly correlated with their RS assay result (r = 0.42; P = 0.001) and significantly lower immediately after the RS assay, but lost significance at 12 months. {6}
The literature contains little information on the consequences of using prognostic tests in decision making. There are no studies that address this question for the MammaPrint and uPA/PAI-1tests.
Importance: Important
Transferability: Completely
The literature contains little information on social issues about prognostic tests and all the available data come from observational studies, surveys and interviews. More research is needed on how to measure the influence on social aspects when patients undergo prognostic tests for breast cancer and what the impact of the tests could be.
Further research on all of the domain assessment elements would generate more certainty about the interpretations in the result cards above.
Appendix SOC-1 Data extraction and quality level of selected studies
Publication details: |
Lo SS et al. J Clin Oncol. 2010 Apr 1;28(10):1671-6. Epub 2010 Jan 11. | |
Social topic(s)/issue(s): |
Patient perceptions, preferences and satisfaction | |
Nature of the study: aims/objectives |
Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. | |
Methods: |
Observational study - prospective, pre-post design (patients and physicians served as their own controls at two time-points, pre- and post-RS assay). Multicentre (one community and three academic practices) | |
Participant characteristics: |
89 women with LN–negative, ER positive breast cancer Age 55 (35-77); Tumour size: Mean 1.7 cm (range 0.6-3.5) | |
Features the studied intervention (when applicable): |
Oncotype DX. Central analysis: Genomic Health Inc. | |
Outcomes and results: |
Perceived risk of recurrence: on a scale of 0 to 100, with 100 indicating definite recurrence, patients’ mean estimated risk pre-RS was 22.4 and post-RS was 16.0 (P = 0.001). Change in patient adjuvant therapy selection: 24 (27%) patients changed their treatment decision on the basis of the results of RS assay. Impact on quality of life: before obtaining the results of the Recurrence Score assay (mean, 112.2; SD = 17.4) and 12 months post-RS (mean, 114.3; SD = 18.6). | |
Reviewers' comments or other notes |
Genomic Health (Research funding: Consultant or Advisory Role: Honoraria) | |
Quality level (GRADE) |
Low | |
Publication details: |
Richman AR et al. Psycho-Oncology. 2011;20:28-35. | |
Social topic(s)/issue(s): |
Social area affected by prognostic genetic tests Knowledge and information Patient perceptions, preferences and satisfaction | |
Nature of the study: aims/objectives |
To identify correlates of knowledge about genomic tests, including patient characteristics, experiences with breast cancer treatment, and experiences with genomic testing, whether different ways of presenting test results was associated with higher knowledge | |
Methods: |
Observational study: cross-sectional study (questionnaire), supplemented by medical chart review. | |
Participant characteristics: |
N = 104 invited women N = 78 completed the survey; Age 58 (38-83). Tumour size not reported. | |
Features the studied intervention (when applicable): |
Oncotype DX | |
Outcomes and results: |
Knowledge of genomic testing: low knowledge about many aspects of genomic recurrence risk testing. Change in patient satisfaction - Most women (96%, 74/77) said that they would have the test if they had to decide again today. - 95%, 73/77 would recommend the test to other women. - 95%, 73/77 agreed that having the test gave them a better understanding of their treatment options’ chances of success. - 26% (17/65) of women agreed or strongly agreed that getting the test result made them worried and anxious - Few women had concerns about the test. - 8% (6/77) of women said that they had the test only because other family members wanted them to; 5% (4/77) said that having the test had a negative effect on their family; only 3% (2/76) agreed that this information about one’s cancer is better left unknown. | |
Reviewers' comments or other notes |
No conflict of interest | |
Quality level (GRADE) |
Very Low | |
Publication details: |
Tzeng JP et al. Cancer. 2010;116:1992-2000 | |
Social topic(s)/issue(s): |
Knowledge and information | |
Nature of the study: aims/objectives |
To study: patient numeracy and literacy; breast cancer worries; how patients learn about the test; how patients get the test results; patients’ attitudes toward Oncotype DX testing; participants’ recall of recurrence risk; perceived recurrence risk; patients’ treatment decisions. | |
Methods: |
Observational study: cross-sectional study (questionnaire), supplemented by medical chart review | |
Participant characteristics: |
N = 104 invited women N = 78 completed the survey; Age 58 (38-83). Tumour size not reported. | |
Features of the studied intervention (when applicable): |
Oncotype DX | |
Outcomes and results: |
- Most women said that they would have the test if they had to decide again today (96%). - 95% would recommend the test to other women in the same situation. - Almost all women (95%) agreed that having the test gave them a better understanding of their treatment options’ chances of success. - Few women agreed that they had the test only because other family members wanted them to (8%); that the test had a negative effect on their family (5%); that information about one’s cancer is better left unknown (3%, 2 of 76). - About 25% of women recalled experiencing test-related distress. - Approximately 26% (17 of 65) of women agreed or strongly agreed that getting the test result made them worried and anxious. - Greater endorsement of test-related distress was associated with higher actual recurrence risk based on the test, as the majority of women who experienced test-related distress had intermediate or high recurrence risks | |
Reviewers' comments or other notes |
None | |
Quality level (GRADE) |
Very low | |
Publication details: |
Retèl et al. International Journal of Technology Assessment in Health Care, 25:1 (2009), 73–83. | |
Social topic(s)/issue(s): |
Patient perceptions, preferences and satisfaction Knowledge and information | |
Nature of the study: aims/objectives |
To analyse the organisational efficiency (logistics and teamwork) and patients’ satisfaction as a consequence of the introduction of the 70-gene signature. | |
Methods: |
Semi-structured baseline and post-survey interviews. Pre-post structured surveys were conducted in 15 community hospitals. Patient-centredness was measured by questionnaires and interviews regarding knowledge and psychological impact of the test (by the Cancer Worries-scale). | |
Participant characteristics: |
Node-negative breast cancer patients, n = 77, response 78%; | |
Features the studied intervention (when applicable): |
70-gene prognosis signature (MammaPrint) | |
Outcomes and results: |
Questionnaire to 77 patients: - Patient perceptions and psychological impact: 43% of patients with a clinically low risk but a poor genomic signature and 29% with a clinically high risk and no signature (due to failure in the testing process) often worried about recurrence, compared with 0% of the patients with a clinically high risk but a good signature, 20% with a clinically low risk and no signature, 13% with a clinically high risk and a poor signature and 3% with a clinically low risk and a good signature. - Patients’ satisfaction: Satisfaction about receiving the 70-gene signature (MammaPrint) was 76%. Six of 70 patients (8.6%) were very dissatisfied, four of whom had a discordant clinically low risk and a high risk-signature, two (no discordant patients) were dissatisfied about the way the result of the 70-gene signature was communicated. Eleven patients had a neutral opinion. - Knowledge: Important issues were the predictive accuracy of the test (87% wrong answers) and the consequences of the test (66% wrong answers). | |
Reviewers' comments or other notes |
None | |
Quality level (GRADE) |
Low | |
Publication details: |
Lillie S. et al. Cancer Epidemiol Biomarkers Prev 2007;16:249-255. Published online January 30, 2007. |
Social topic(s)/issue(s): |
Knowledge and information |
Nature of the study: aims/objectives |
To measure patients’ health literacy (using the Rapid Estimate of Adult Learning in Medicine), knowledge of and attitudes towards the Oncotype DX test |
Methods: |
Interviews were conducted between February 2005 and August 2005. |
Participant characteristics: |
Of 339 eligible patients, 108 could not be contacted. Of the patients contacted, 65 declined to participate, either via mail (n = 48) or at the clinic (n = 17). The response rate was 72% (166 of 231). Adult women (mean age 59 years) previously diagnosed with stage I or II primary breast cancer who were patients at the University of North Carolina Breast Center, post-surgery and post-treatment patients who either did not receive neoadjuvant/adjuvant chemotherapy or had completed it. |
Features the studied intervention (when applicable): |
Oncotype DX |
Outcomes and results: |
- Health Literacy - Retention of Information about the Recurrence Risk Test - Desire for Additional Health Information.
- Preference for Active Participation in Decision Making.
|
Reviewers' comments or other notes |
None |
Quality level (GRADE) |
Low/Moderate |
Authors: Marina Casini, Emanuela Midolo, Marco Marchetti
Analysis of legal aspects highlighted three points that, in our opinion, have shortcomings and should be developed at the European level:
1) the lack of an ad hoc European directive on medical devices —in vitro predictive tests. In fact, in our analysis we could not refer to specific EC legislation, but we referred, by analogy, to other documents such as the Directive 98/79 EC on in vitro diagnostic medical devices.
2) the absence of the FEMTELLE® uPA/PAI-1 test, MammaPrint® and Oncotype DX® from the Eudamed register (European registry). This registration is important in order to improve control of sales, use and movement within the EC of such tests.
3) the need to ensure equitable access to these tests, if their clinical utility and validity is confirmed by good quality evidence. This point is especially important particularly in respect of the principle of "equitable access to care", included in most of the European conventions.
Legal issues related to prognostic tests for breast cancer are discussed in this domain. Some issues are directly related to the patient and his/her basic rights, such as autonomy, informed consent, privacy and confidentiality. Other issues are linked to the technology, such as authorisations, patents/licenses, acquisition process, price and reimbursement regulations, product safety, guarantee and liability. Some assessment elements in this domain were considered not relevant and they were not translated into research questions.
The analysis of legal aspects was carried out at a European level, so regulations and documents of the European Union and Council of Europe were taken into account.
The collection scope is used in this domain.
Technology | uPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
DescriptionUrokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}. Technical details: - Inspection of unfixed tissue - Removal of a representative piece of tumour tissue (>50 mg) - Freezing of the unfixed tissue (-20°C or colder) - Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks Clinical Laboratory (Pathology, Hospital) - Transport of frozen tumour tissue on dry ice - Extraction of uPA and PAI-1 - Perform FEMTELLE uPA/PAI-1 ELISA - Transfer of test results to physician Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200. Possible logistic issues to consider are {2}: - Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation. - Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process. Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com). The test requires a fresh sample of tissue composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline] Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors. Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400. RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.) MeSH Terms: There are no MeSH-Terms for Oncotype DX and MammaPrint. |
---|---|
Intended use of the technology | Defining an existing health condition in further detail to assist selection of appropriate or optimal treatment Assessment of risk of breast cancer recurrence Target conditionBreast cancer recurrenceTarget condition descriptionAssessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy). As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question. Target populationTarget population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition. Target population descriptionWomen with invasive breast cancer in whom adjunctive treatment might be indicated |
Comparison | Standard of care
DescriptionStandard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX). Depending on manpower and time resources the three index tests may also be compared with each other. |
Topic | Issue | Relevant | Research questions or rationale for irrelevance | |
---|---|---|---|---|
I0002 | Autonomy of the patient | Can patients understand the implications of using/not using the technology? | yes | Can patients understand the implications of using/not using Genetic Test for breast cancer? |
I0003 | Autonomy of the patient | Are there relevant optional technologies that future patients should be allowed to consider? | yes | Are there relevant optional technologies that future patients should be allowed to consider? |
I0004 | Autonomy of the patient | Is it possible to give future patients enough time to consider their decisions? | yes | Is it possible to give future patients enough time to consider their decisions? |
I0005 | Autonomy of the patient | Is it possible to obtain an advance directive on the use of the technology? | no | Not applicable for genetic tests. |
I0009 | Privacy of the patient | Can the access to the patient data secured properly? | yes | Can the access to the patient data secured properly? |
I0010 | Privacy of the patient | What levels of access to which kind of patient information exist in the chain of care? | yes | What levels of access to which kind of patient information exist in the chain of care? |
I0007 | Privacy of the patient | Does the use of the technology produce some additional (i.e. diagnostically or therapeutically irrelevant) information on the patient? | yes | Does the use of Genetic Tests for breast cancer produce some additional (i.e. diagnostically or therapeutically irrelevant) information on the patient? |
I0008 | Privacy of the patient | Does the use of the technology produce information that would be relevant for the relatives of the patient? | yes | Does the use of Genetic Test for breast cancer produce information that would be relevant for the relatives of the patient? |
I0033 | Privacy of the patient | Does the use of the technology produce such information on the patient that is not directly relevant to the current disease/condition? | no | It is incorporated in question I0007. |
I0011 | Equality in health care | Is the technology equally accessible to all needing members in a given society? | yes | Are the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) equally accessible to all women with invasive breast cancer in the society? |
I0012 | Equality in health care | Is the technology subsidized by the society? | yes | Are the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) subsidized by the society? |
I0013 | Equality in health care | Is there a wide variation in the acceptability of the technology across Europe? | yes | Is there a wide variation in the acceptability of Genetic Test for breast cancer across Europe? |
I0014 | Equality in health care | Is health-care tourism expected from/to other European countries? | yes | Is health-care tourism expected from/to other European countries? |
I0015 | Authorisation & safety | Has the technology national/EU level authorisation? | yes | Have Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) national/EU level authorisation? |
I0016 | Authorisation & safety | Does the technology need to be listed in a national/EU register? | yes | Do Genetc Tests for breast cancer need to be listed in a national/EU register? |
I0017 | Authorisation & safety | Does the technology fulfil product safety requirements? | yes | Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill product safety requirements? |
I0018 | Authorisation & safety | Does the technology fulfil tissue safety requirements? | yes | Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill tissue safety requirements? |
I0019 | Ownership & liability | Does the technology infringe some intellectual property right? | yes | Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) infringe some intellectual property right? |
I0020 | Ownership & liability | Does the introduction of the technology presume some additional licensing fees to be paid? | yes | Does the introduction of Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) presume some additional licensing fees to be paid? |
I0021 | Ownership & liability | What are the width, depth and length of the manufacturers guarantee? | yes | What are the width, depth and length of the manufacturers guarantee? |
I0022 | Ownership & liability | Is the user guide of the technology comprehensive enough? | yes | Is the user guide of Genetic Test (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) comprehensive enough? |
I0023 | Regulation of the market | Is the technology subject to price control? | yes | Are Genetic Tests for beast cancer subject to price control? |
I0024 | Regulation of the market | Is the technology subject to acquisition regulation? | yes | Are Genetic Tests for breast cancer subject to acquisition regulation? |
I0025 | Regulation of the market | Is the marketing of the technology to the patients restricted? | yes | Is the marketing of Genetic Tests for breast cancer to the patients restricted? |
I0026 | Legal regulation of novel/experimental techniques | Is the technology so novel existing legislation was not designed to cover its regulation? | yes | Are Genetic Tests for breast cancer so novel existing legislation was not designed to cover its regulation? |
I0027 | Legal regulation of novel/experimental techniques | How the liability issues are solved according to existing legislation? | yes | How the liability issues are solved according to existing legislation? |
I0028 | Legal regulation of novel/experimental techniques | Are new legislative measures needed? | yes | Are new legislative measures needed? |
I0029 | Legal regulation of novel/experimental techniques | Is the voluntary participation of patients guaranteed properly? | yes | Is the voluntary participation of patients guaranteed properly? |
I0030 | End-user | Who is the intended end-user of the technology? | yes | Who is the intended end-user of Genetic Test for breast cancer? |
I0031 | End-user | Is the use of the technology limited in legislation? | yes | Is the use of Genetic Test for breast cancer limited in legislation? |
I0032 | End-user | Is the health care personnel using the technology according the professional standards? | yes | Is the health care personnel using Genetic Test for breast cancer according the professional standards? |
Information sources
Legal aspects of prognostic tests for breast cancer were analysed from legal texts in the European area.
Our work is based on finding the main sources of European regulations. This is a large, complex and varied biojuridical material formed within the European Union and Council of Europe. The documentation is diversified in terms of cogency (some documents have binding authority, others simply address) and origins (different bodies of enactment). However, unless more or less detail, we found common elements in the discipline of information and consent, privacy protection, and access to treatment.
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
The principle of informed consent is a right of patients to obtain all the necessary information in order to take a well informed and responsible decision, and to have greater participation in their treatment. According to Article 5 of the Oviedo Convention {1} the information must be appropriate in relation to the goals, to the nature of the intervention and to the potential consequences and risks for the patient. Under Article 5 of the Oviedo Convention, information given must be adequate in relation to the purpose, nature and risks of surgery and all potential consequences.
Article 10 of the Oviedo Convention, Private life and right to information {1}, affirms “Everyone has the right to respect for private life in relation to information about his or her health. Everyone is entitled to know any information collected about his or her health. However, the wishes of individuals not to be so informed shall be observed. In exceptional cases, restrictions may be placed by law on the exercise of the rights contained in paragraph 2 in the interests of the patient”.
With regard to genetic tests, we maintain that information is an integral part of the substance of these tests. Moreover, for genetic testing we can assume that the information falls under the provisions of Article 12 of the same Convention: “Tests which are predictive of genetic diseases or which serve either to identify the subject as a carrier of a gene responsible for a disease or to detect a genetic predisposition or susceptibility to a disease may be performed only for health purposes or for scientific research linked to health purposes, and subject to appropriate genetic counselling”.
Regarding genetic information, another important regulation is the Additional Protocol to the Convention on Human Rights and Biomedicine concerning Genetic Testing for health purposes {2} where Article 8 declares: “When a genetic test is envisaged, the person concerned shall be provided with prior appropriate information in particular on the purpose and the nature of the test, as well as the implications of its results”. In the norm just cited, reference is made to Article 12 of the Oviedo Convention {1} with respect to appropriate genetic counselling for the person concerned: “For predictive genetic tests as referred to in Article 12 of the Convention on Human Rights and Biomedicine, appropriate genetic counselling shall also be available for the person concerned. The tests concerned are: tests predictive of a monogenic disease; tests serving to detect a genetic predisposition or genetic susceptibility to a disease; tests serving to identify the subject as a healthy carrier of a gene responsible for a disease. The form and extent of this genetic counselling shall be defined according to the implications of the results of the test and their significance for the person or the members of his or her family, including possible implications concerning procreation choices. Genetic counselling shall be given in a non-directive manner”.
Another relevant normative reference concerning the information that must be given to the patient is the Additional Protocol to the Oviedo Convention relating to biomedical research (25/01/2005).{3}
Article 13 of the same Oviedo Convention concerning biomedical research {1} affirms that the information must be adequate, documented and furnished in an understandable way. The content of the information should cover the goals, the entire research project and the possible risks and benefits of the same. Moreover, the rule indicates a number of elements that enrich the content of the information: “the persons concerned shall be specifically informed, according to the nature and purpose of the research:
In addition, the persons being asked to participate in a research project shall be informed of the rights and safeguards prescribed by law for their protection, and specifically of their right to refuse consent or to withdraw consent at any time without being subject to any form of discrimination, in particular regarding the right to medical care”.
Another document that is very important concerning informed consent is the Declaration of Helsinki{4}, where paragraph 24 affirms; “In medical research involving competent human subjects, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information. After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject's freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed”; and in paragraph 34 declares that; “The physician must fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study or the patient's decision to withdraw from the study must never interfere with the patient-physician relationship”.
Among the documents of the European Union, Directive 2001/20/CE of the European Parliament and of the Council of 4 April 2001{5}, states that the person must be informed of the nature, the risks and the meaning of the specific intervention: “if the individual is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation”. Concerning informed consent, for competent and incompetent patients to give consent, it is very important to cite articles n. 11-16-20 of the Additional Protocol concerning genetic tests{2}, and also the important Article 6 of The UNESCO Declaration. {6}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
At present, the prognostic tests: uPA/PAI-1, MammaPrint®, and Oncotype DX® are the most advanced prognostic tests for breast cancer. Healthcare professionals are required to provide certain information and patients have a corresponding right to know what must be revealed to them and what is available. It is therefore not an omission on the part of the doctor if he/she does not provide information that they do not have and only explain what technology is being used and the possible consequences and implications for the patient. If, in the future, physicians are aware of new technological options, they are obliged to provide information about these as indicated in the documents cited in the RC-LEG1.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
The European legal situation does not establish time limits for the provision of informed consent about therapies or treatments. There are situations, however, where the state of health of the patient requires emergency action, but these situations are not considered in the fundamental texts on genetic tests examined. True informed consent implies allowing the patient time to consider decisions. We believe that sufficient time is implied in adequate and appropriate informed consent. It is also true that informed consent may require more time for certain subjects. The tests in question are not characterised by an urgency as to when they must be performed, therefore patients have the time to consider their decision. The European normative documents are the same as those cited in the result card RC-LEG1. {1},{2},{3},{4},{5},{6}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
The right of the patient to full information about their personal data and the right to privacy with regard to them would impose a duty, not only the possibility of proper and safe access to their data as affirmed in Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 {8} on the protection of individuals with regard to the processing of personal data and on the free movement of such data, Article 8 “The processing of special categories of data”:
(a) the data subject has given his explicit consent to the processing of those data, except where the laws of the Member State provide that the prohibition referred to in paragraph 1 may not be lifted by the data subject's giving his consent; or (b) processing is necessary for the purposes of carrying out the obligations and specific rights of the controller in the field of employment law in so far as it is authorized by national law providing for adequate safeguards; or (c) processing is necessary to protect the vital interests of the data subject or of another person where the data subject is physically or legally incapable of giving his consent; or (d) processing is carried out in the course of its legitimate activities with appropriate guarantees by a foundation, association or any other non-profit-seeking body with a political, philosophical, religious or trade-union aim and on condition that the processing relates solely to the members of the body or to persons who have regular contact with it in connection with its purposes and that the data are not disclosed to a third party without the consent of the data subjects; or (e) the processing relates to data which are manifestly made public by the data subject or is necessary for the establishment, exercise or defence of legal claims.
and Article 8 of the European Convention on Human Rights “Right to respect for private and family life” :{7}
Finally, we remind the Sentence of the European Court of Justice of the 20 May of 2003 C-465/00, C-138/01, C-139/01. {9}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
To speak of levels of access may seem discriminatory to individual patients (some are allowed greater access than others). This appears to contradict the right to full information. Since these are prognostic tests aimed at evaluating the likelihood of recurrence of a tumour and therefore the necessity to initiate or not chemotherapy treatment, the relevant information is substantially providing the patient with the complete test results. Therefore, the problem of levels of access does not arise.
The legal framework of reference is cited at the end of the response to the result card RC-LEG1.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
If additional information from prognostic testing is irrelevant to the current state of health of the patient the physician has an obligation to inform the patient and to report exactly any data of which the doctor is aware. This obligation of the physician is less strong when the patient expresses a desire not to be informed. The European normative documents relevant here are the same as those cited in the result card RC-LEG1. {1},{2},{3},{4},{5},{6}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
As far as we know, the genetic tests in question do not provide important information for relatives of the patient. Nevertheless, from a legal perspective, information regarding the health of a patient that also concerns relatives is important. When the patient does not give consent for third parties to be given information that regards them, there is a conflict between opposing rights: the right to privacy of the patient and the right to know of the relatives. Protection of privacy regarding personal health data has an important relevance to Article 8 of the European Convention on Human Rights.{7} Also with reference to the treatment of personal data, it is important to reference Article 8 “The processing of special categories of data” of Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995{8} on the protection of individuals with regard to the processing of personal data and on the free movement of such data which states the following.
(a) the data subject has given his explicit consent to the processing of those data, except where the laws of the Member State provide that the prohibition referred to in paragraph 1 may not be lifted by the data subject's giving his consent; or (b) processing is necessary for the purposes of carrying out the obligations and specific rights of the controller in the field of employment law in so far as it is authorized by national law providing for adequate safeguards; or (c) processing is necessary to protect the vital interests of the data subject or of another person where the data subject is physically or legally incapable of giving his consent; or (d) processing is carried out in the course of its legitimate activities with appropriate guarantees by a foundation, association or any other non-profit-seeking body with a political, philosophical, religious or trade-union aim and on condition that the processing relates solely to the members of the body or to persons who have regular contact with it in connection with its purposes and that the data are not disclosed to a third party without the consent of the data subjects; or (e) the processing relates to data which are manifestly made public by the data subject or is necessary for the establishment, exercise or defence of legal claims.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
We believe that this type of test should be equally accessible to all women, from the healthcare, legal and economic points of view. From the first two perspectives access is guaranteed because the principle of non-discrimination is applied with reference to human dignity. And medically there is a guarantee of the possibility of performing these genetic tests for all women with breast cancer. There are, however, some concerns with regard to the economic aspects. The list prices for these tests are €3180 for most of Europe and £2580 for the UK. Furthermore, using online searches, we discovered that the price of MammaPrint is €2675 and for the Oncotype DX test the cost is $3400. The MammaPrint test is reimbursed only by some private institutions as follows:
This data supports, in our opinion, the essential need for the adoption of a European norm to ensure equal access to care that would provide for lowering the costs of the tests or a total reimbursement of the costs. Currently, the legislative framework on equal access to healthcare is given by Article 3 of the Oviedo Convention,{1} and Articles 1 and 4 of the Additional Protocol to the Oviedo Convention on genetic testing. {2} as for access to European health we must refer to the White Paper of the Commission of the European Communities of the 23.10.2007 “Together for Health: A Strategic Approach for the EU 2008-2013”. {10}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
It seems that currently only MammaPrint is reimbursed. The funds are provided through two private institutions in Europe, ACHMEA (Netherlands) and INTRA (Switzerland). In the USA MammaPrint is covered by the following private institutions: United Healthcare, Humana, Coventry, Three Rivers, NPPN, Galaxy, Multiplan, Beech Street, Global Claims, Medicare, Railroad Medicare, Aetna, Cigna, BCBS, and Blue Cross and Blue Shield.
We refer readers to the answer to the preceding question which proposed that European institutions provide access for all to these tests because of the right to health and to treatment without economic discrimination. A review of European jurisprudence calls our attention to the ruling of the European Court of Justice of 16.05.2006 (C-372/04) {11}. From among the information collected, we think it important to report the following answer given by manufacturers of the tests:
We think that the principle of equal access to healthcare necessarily implies a guarantee of European subsidies and / or reimbursement of the costs of such tests, especially if their clinical effectiveness can be ascertained.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
On the specific subject of genetic tests we must remember the Additional Protocol to the Convention on Human Rights and Biomedicine concerning Genetic Testing for Health Purposes from 27.11.2008.{2} The object and scope of the Additional Protocol to the Convention on Human Rights and Biomedicine concerning Genetic Testing are:
Article 1 “Parties to this Protocol shall protect the dignity and identity of all human beings and guarantee everyone, without discrimination, respect for their integrity and other rights and fundamental freedoms with regard to the tests to which this Protocol applies in accordance with Article 2”
Article 2 “This Protocol applies to tests, which are carried out for health purposes, involving analysis of biological samples of human origin and aiming specifically to identify the genetic characteristics of a person which are inherited or acquired during early prenatal development (hereinafter referred to as “genetic tests”).{2}
This Protocol does not apply to genetic tests carried out:
For the purposes of paragraph 1 “analysis” refers to:
Through careful research we have found certain documents of the European Union dedicated to the fight against cancer. These show that more than a wide variation in non acceptance of genetic testing is the need to use all tools available to fight cancer in its various forms. These documents are: the document of the European Commission of the 24.06.2009 entitled Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on action against cancer: European Partnership; of the European Parliament Resolution concerning the Commission communication “Action against Cancer: European Partnership” {12}, European Code Against Cancer {13}.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
The European Union produces many documents on healthcare in all Member States, such as: Decision n. 1350/2007/EC of the European Parliament and of the Council of 23 October 2007 establishing a second program of Community Action in the field of health (2008–2013);{10} the White paper of the European Commission “Together for Health: A Strategic Approach for the EU 2008–2013”{14}; the Communication from the Commission to the Council, the European Parliament, the European economic and social Committee and the Committee of the Regions e-Health - making healthcare better for European citizens: An action plan for a European e-Health Area{15}; the Decision of the Commission of the 23 February of 2009 that adopted the second program of Community Action in the field of health (2008–2013){16} and establishes the selection and attribution criteria, and other criteria for financial contributions to the actions of this; the Council Recommendation on a European action in the field of rare diseases from 11.11.2008{17}; the P5_TA(2003)0270 breast cancer, the Resolution of European Parliament on breast cancer in the EU (2002/2279(INI)){18}; the Recommendation no. R (89) 13 of the Committee of Ministers to Member States on the Organization of Multidisciplinary care for cancer patients of the 24.10.1989{19}; the Recommendation no. r (80) 6 of the Committee of Ministers to Member States concerning cancer control from 30.4.1980{20}; Directive CEE/CEEA/CE n° 79 of the 27/10/1998 98/79/ce: the Directive of the European Parliament and the Council of the 27 October 1998 on in vitro diagnostic medical devices{21}; the Communication from the Commission Consultation regarding Community action on health services, 26.9.2006{22}.
With regard to foreign health tourism in Europe there are some documents: 2011/24/UE Directive of the European Parliament and the Council of 9 March 2011 concerning the application of patients' rights in cross-border healthcare{23}; the Recommendation Rec(2006)18 of the Committee of Ministers to member states on health services in a multicultural society from 8.11.2006{24}; the Council of the European Union Directive on cross-border healthcare adopted 28.2.2011{25}. A look at the European Court calls our attention to the judgment of the Court of Justice of the European Union 28.04.1998 (C-120/95). {26}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
Our research has found that in Europe only the MammaPrint test has been commercially available since July 2005 when the Dutch Healthcare Inspectorate approved it as a medical device presenting low risks. The US Food and Drug Administration (FDA) also approved it. The references substantiating this are contained in the bibliography {27}. The uPA/PAI-1 test is recommended in the guidelines of the American Society of Clinical Oncology (ASCO) and the guidelines of the German Association of Gyneclogical Oncology (AGO). Oncotype DX is approved by the US FDA and has been commercially available since 2004. It is also recommended by the ASCO guidelines. The Oncotype DX collection kit received an EC stamp of approval and may be distributed in every country of the European Economic Area. Furthermore, regarding authorisation of medicinal products for human use one may refer to the Guidelines 2010 / C 82/01 of the European Commission on an application for a permit for a clinical trial of a medicinal product for human use {28}. These guidelines are addressed to the competent authorities and also cover the notification of substantial changes and the declaration of the end of the trial. The legal framework on the subject in question must also take into account of the ruling of the Court of Justice of the European Union (fourth section) 03.07.2002, in Case T-179/00, A. Menarini vs. Commission of European Communities{29}.We call attention to the Sentence of the European Court of Justice of 3 July 2002 T-179/00. We report what the producers of this kind of test affirmed: “The Genomic Health Clinical Laboratory is regularly inspected by the College of American Pathologists and federal and state agencies. Audits include a complete review of the Oncotype DX assays, including a thorough assessment of assay validation reports, the procedure manual, and the quality control and quality assurance processes described above. In nine on-site audits since its opening in 2004, the Genomic Health Clinical Laboratory has never received a deficiency, and all requests to add new assays to our test menu have been granted”.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms, sentences and EUnetHTA documents.
In general it is possible affirm that according to the Commission website:{27}
“The Medical Device Directives contain provisions on a European databank for medical devices, which has been developed under the name Eudamed. The aim of Eudamed is to strengthen market surveillance and transparency in the field of medical devices by providing Member State competent authorities with fast access to information on manufacturers and authorised representatives, on devices and certificates and on vigilance and clinical investigation data, as well as to contribute to a uniform application of the Directives, in particular in relation to registration requirements.
Depending on the applicable directive, Eudamed contains data on:
In conclusion we can affirm that in our research we did not find an official comprehensive European registry of these prognostic tests for breast cancer recurrence. It is desirable that the competent organisations should resolve this deficiency.
The producers of these tests responded “Not in Europe” when asked if their products were present in European registries. (Genomic Health – questions document of EUnetHTA Core HTA on Genetic Tests for Breast Cancer, Draft-Confidential).
When it is proved the clinical validity of these tests is necessary to create registers ad hoc for monitoring the use of the tests.
Under the present discussion of the medical devices legal framework, the need to reinforce the post-market clinical follow-up by the manufacturer is being considered, namely in the IVDD, as well as registration systems for the health professionals/users. This necessity to reinforce the post-market clinical follow-up by the manufacturer applies particularly to the prognostic tests, which are not really covered by the European legislation.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
Since there are not yet any specific EU Directives relating to the safety requirements of the three tests (uPA/PAI-1, Oncotype DX, MammaPrint), it is necessary to make analogical references to norms such as Directive 2001/20/CR of the European Parliament and the Council from 4 April 2001 regarding the application of good clinical practices in the execution of clinical experimentation of medicines for human use{30}; Directive CEE/CEEA/CE 79 from 27/10/1998 98/79/CE: Directive of the European Parliament and the Council from 27 October 1998 relating to in vitro medical diagnostic devices{21}, that indicate all the requirements for the use of medicines for human use in a way that truly respects human dignity and that establishes the essential requirements needed to guarantee the quality, safety and good performance of the in vitro device placed in the European market.
Thereof, the essential requirements determined in Annex I of the In Vitro Diagnostic Device IVDD concern:
A. Safety and performance general requirements;
B. Design and manufacturing requirements:
The presumption of conformity with the essential requirements is achieved by the implementation of technical specifications given by European harmonised standards. Harmonised standards are European standards, which are adopted by European standards organisations, prepared in accordance with the General Guidelines agreed between the Commission and the European standards organisations, and follow a mandate issued by the Commission after consultation with the Member States.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
Since EU Directives specific to the safety requirements of these three tests (uPA/PAI-1, Oncotype DX, MammaPrint ) have not been issued it is necessary to make analogical references to norms such as Directive 2001/20/CR of the European Parliament and the Council from 4 April 2001 regarding the application of good clinical practices in the execution of clinical experimentation of medicines for human use {30}; and Directive CEE/CEEA/CE 79 from 27/10/1998 98/79/CE: Directive of the European Parliament and the Council from 27 October 1998 relating to in vitro medical diagnostic devices {21}. The requirements of this latter Directive indicate “(33) Whereas, in view of the need to protect the integrity of the human person during the sampling, collection and use of substances derived from the human body, it is appropriate to apply the principles laid down in the Convention of the Council of Europe for the protection of human rights and dignity of the human being with regard to the application of biology and medicine;{1} whereas, furthermore, national regulations relating to ethics continue to apply”.
Other norms relating to this issue are: the Committee of Experts on trafficking in human organs, tissues and cells PC-TO (2011)1 Preliminary draft Council of Europe Convention against trafficking in human organs {32} and the Common Position of the European Parliament and the Council in view of the directive on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (2003/C 240 E/02).
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
In the light of the information collected on genetic testing and the legal documents identified, some infringements of intellectual property rights may arise.
At the European level, the reference standard for the patentability of biotechnological inventions is Directive 98/44/EC of the European Parliament and of the Council from 6 July 1998 on the legal protection of biotechnological inventions. {26}
Importance: Optional
Transferability: Partially
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
As these tests do not presume the need of Notified Body assessment (which is paid) in this context there is no associated fee.
Nevertheless, there are some Member States that require registration fees for all medical devices.
Importance: Critical
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
This question does not have juridical relevance.
Importance: Optional
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
According to the research carried out by us, there are complete, clear and understandable user guides on MammaPrint and Oncotype DX. We did not find any explanatory guide for professionals or patients for uPA/PAI-1.
It is desirable to have such a guide for uPA/PAI-1, which would assist greater awareness and protection of patients and better knowledge among professionals. http://www.mammaprint.co.uk/MammaPrint_Patient_Brochure_EU_lowres.pdf/ http://www.oncotypedx.com/enUS/Breast/HealthcareProfessionalsInvasive/ScientificPublication/ http://www.femtelle.de/en/physicians/publications/
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
The cost of the genetic tests in question is in our response to question LEG8. How to control the uniformity of prices in various countries in which these tests are in use is the subject of several European directives such as: Decision n. 1350/2007/EC of the European Parliament and of the Council del 23 October 2007 establishing a second programme of Community Action in the field of health (2008–2013){10}; the White paper of the European Commission “Together for Health: A Strategic Approach for the EU 2008–2013”{14}; the Communication from the Commission to the Council, the European parliament, the European economic and social committee and the committee of the regions e-Health -making healthcare better for European citizens: An action plan for a European e-Health Area{15}; the Decision of the Commission of the 23 February of 2009 that adopted the action plan for 2009 for the actualization of the second Community action plan for the health care (2008–2013){16}. This Decision establishes the selection and attribution criteria, and other criteria for financial contributions to the actions of this program; the Council Recommendation on a European action in the field of rare diseases from 11.11.2008{17}; the P5_TA(2003)0270 breast cancer, the Resolution of European Parliament on breast cancer in the EU (2002/2279(INI) {18}; the Recommendation no. R (89) 13 of the Committee of Ministers to Member States on the Organisation of Multidisciplinary care for cancer patients of the 24.10.1989{19}; the Recommendation no. r (80) 6 of the Committee of Ministers to Member States concerning cancer control from 30.4.1980{20}; Directive CEE/CEEA/CE n° 79 from 27/10/1998 98/79/EC: the Directive of the European Parliament and the Council of the 27 October of 1998 on in vitro diagnostic medical devices (21); the Commission communication concerning community action on health services from 26.9.2006 {22}. Foreign tourism within Europe is referred to in some documents: 2011/24/UE Directive of the European Parliament and the Council of 9 March 2011 concerning the application of patients' rights in cross-border healthcare {23}; the Recommendation Rec (2006)18 of the Committee of Ministers to member states on health services in a multicultural society from 8.11.2006 {24}; the Council of the European Union Directive on cross-border healthcare adepte 28.2.2011{25}. We report the response of the test manufacturers: “France has a formal process of price control. Other countries do not have a formal pricing control but have HTAs in place (e.g. Ireland, UK, Spain) where cost-effectiveness and budget impact matter in the decision making”.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
At the European level there are different norms on the subject of breast cancer: P5_TA(2003)0270 the Resolution of European Parliament on breast cancer in the EU (2002/2279(INI){18}; The Recommendation of the Council concerning screening for cancer from 2.12.2003, whose implementation came with the Report of the Commission of the Council of the European Parliament to the European economic and social committee of the regions from 22.12.2008; The European Code vs. Cancer; the Recommendation concerning cancer screening in the European Union by the consultative committee on the prevention of cancer after the conference on screening and on the first appearance of cancer held at Vienna the 18–19 November 1999; and the Resolution of the European Parliament of 6.05.2010 on the communication of the Commission “Action against cancer a European partnership”.
Importance: Important
Transferability: Not
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
The state of our knowledge leads us to conclude that in fact the marketing of genetic testing is limited to those patients who have the economic resources to afford access to these tests. Precisely for this reason we consider it necessary, as already mentioned above, to make these tests accessible to all, under the principle of equal access to treatment. The many Directives that declare the principle of equal access to care, include: Articles 1 and 4 of the Additional Protocol to the Convention on Human Rights and Biomedicine concerning Genetic Testing {2}; Article 14 of the European Convention of Human Rights “The enjoyment of the rights and freedoms set forth in this Convention shall be secured without discrimination on any ground such as sex, race, colour, language, religion, political or other opinion, national or social origin, association with a national minority, property, birth or other status” (7); Sentence of the European Court of Justice from the 28 April of 1998 C-158/96 (32); Sentence of the Queen for Yvonne Watts vs. Bedford Primary Care Trust & Secretary of State for Health C-372/04.{11}
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
Our research found a lack of European legislation specifically for these genetic tests, but there are European standards of health policy regarding breast cancer, aimed at the creation of tools to implement the prevention, diagnosis and treatment of these tumours: Decision n. 1350/2007/EC of the European Parliament and of the Council from 23 October 2007 establishing a second program of Community Action in the field of health (2008–2013){10}; the White paper of the European Commission “Together for Health: A Strategic Approach for the EU 2008–2013”{14}; the Communication from the Commission to the Council, the European parliament, the European economic and social committee and the committee of the regions e-Health - making healthcare better for European citizens: An action plan for a European e-Health Area{15}; the Decision of the Commission of the 23 February of 2009 that adopted the plan of action for 2009 for the actualization of the second Community action plan for the health care (2008–2013){16}; the Council Recommendation on a European action in the field of rare diseases from 11.11.2008{17}; the P5_TA(2003)0270 breast cancer, the Resolution of European Parliament on breast cancer in the EU (2002/2279(INI)){18}; the Recommendation no. R (89) 13 of the Committee of Ministers to Member States on the Organization of Multidisciplinary care for cancer patients of the 24.10.1989{19}; the Recommendation no. r (80) 6 of the Committee of Ministers to Member States concerning cancer control of the 30.4.1980{20}; the Directive CEE/CEEA/CE n° 79 of the 27/10/1998 98/79/EC of the European Parliament and the Council of the 27 October of 1998 concerning in vitro diagnostic medical devices (21); and the Communication from the Commission Consultation regarding Community action in health services, 26.9.2006{22}.
Importance: Critical
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
As stated in result card RC-LEG23, there are no norms on prognostic tests for breast cancer, but interesting points may be drawn, by analogy, from other norms covering similar areas such as; Directive 2001/20/EC of the European Parliament and of the Council from 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use{5}.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
In our opinion it is necessary to have European regulations uniformly governing all Member States covering all aspects involved in the use of these prognostic tests for breast cancer recurrence: conditions of use (informed consent of competent patients, informed consent of patients unable to give consent, therapeutic indications, protection of privacy, equal access to care...), the processing of personal data, medical liability and insurance coverage.
The elaboration of European Union legislative measures appropriate to these new prognostic tests for breast cancer recurrence is necessary.
Importance: Critical
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
To the extent that prognostic testing for breast cancer respects the fundamental principles of medical activity, including the principle of autonomy in the choice of treatments, the voluntary participation of patients is adequately protected. The principle of autonomy is actualised principally with informed consent, so it is evident that the clarity, completeness and comprehensibility of information plays a key role.
Importance: Important
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
We consider that the question is not of legal relevance, because there are no regulations yet on this subject.
Importance: Optional
Transferability: Unspecified
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
As stated in result card RC-LEG23, there is no specific legislation on genetic testing for breast cancer, so we cannot yet speak about legislative limits.
Importance: Critical
Transferability: Completely
The domain methodology used for this question has been collection, selection and analysis of European norms and sentences.
Certainly, all health professionals, including those who use genetic testing are subject to compliance with the standards of professional ethics and the law. Some of these standards can be found in the following documents: the European guidelines for quality assurance in breast cancer screening and diagnosis{33}; Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use{34}, as well as the requirements for the authorisation of the manufacturing or importation of such products and the Additional Protocol of the Oviedo Convention on Human Rights and Biomedicine concerning Genetic Tests{2}.
Importance: Important
Transferability: Completely
We found a range of documents, varying in nature and origin, published by European Union bodies about issues and profiles that are not directly related to the prognostic tests in question, but on general areas of the doctor-patient relationship, on information and consent, and on privacy. The most relevant documents are those related to breast cancer.
We believe that the European Commission should implement all measures necessary to create an ad hoc directive on in vitro medical devices with predictive purposes, in order to provide greater clarity to individual Member States and uniformity of national laws on access to and use of these tests. Among the measures that the European Commission could adopt we mention the inclusion of these tests in European registries allowing better control of their use in clinical practice, and the provision of European economic measures ensuring fair access to these tests.
Acknowledgments: Jayne Hickton (Information Specialist, NICE)
Literature search
The systematic literature search was performed for the whole Core HTA (9 Domains), according to the Search strategy described below in Appendix COL-1 1, in October 2011, by the Information specialist from NICE (JH), in the following databases: Ovid MEDLINE(R) <1948 to September Week 4 2011>; Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <October 07, 2011>; Embase <1980 to 2011 Week 40>; Cochrane Issue 4 of 4, Oct 2011; Cinahl (Accessed 12/10/2011); CRD databases: DARE, NHS EED, HTA (Accessed 13/10/2011). In addition, further clinical trials registries were assessed (13/10/2011), for registered ongoing clinical trials or observational studies: ClincalTrials.gov, ISRCTN, metaRegister of Controlled Trials (mRCT) and International Clinical Trials Registry Platform (ICTRP). Last databases update was on 19 December 2011.
Selection of literature
Relevant references available for screening after duplicates removed were screened and assessed for eligibility by two reviewers from Clinical Effectiveness Domain (MH, NS) independently, according Inclusion/ Exclusion criteria (Appendix COL-1 2), in the second part of October 2011. Different selection results were discussed in order to achieve consensus, a third person was involved in case of uncertainty. There were 4508 references. Three additional references were found through hand-search (total of 4511 references). After the title and abstract screening, 616 references which met Inclusion/ Exclusion criteria (Appendix COL-1 2) were retrieved (marked as Included and Ambiguous, for which whole text was needed for final inclusion) (Figure COL-1 1).
Figure COL-1 1. Selection process for all 9 Domains according the PRISMA flowchart
The screening results were saved in the word document, in EndNote and Reference Manager databases, and sent to the investigators of all Domains on 31 10 2011.
All further databases updates, till 19 December 2011, with total of 28 additional references were sent to Primary investigators of all Domains to assess them further for eligibility in their Domains.
Appendix COL-1 1. Literature Search strategy for all Domains
Database: Ovid MEDLINE(R) <1948 to September Week 4 2011> Search Strategy: |
|
Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <October 07, 2011> Search Strategy: |
|
Database: Embase <1980 to 2011 Week 40> Search Strategy: |
|
Database: Cochrane Issue 4 of 4, Oct 2011 Search Strategy: | ||
1 |
7171 | |
2 |
(breast* or mamma*) near/3 (neoplasm* or tumor* or tumour* or cancer* or carcinoma*):ti,ab,kw |
13822 |
3 |
13822 | |
4 |
13 | |
5 |
57 | |
6 |
8 | |
7 |
15 | |
8 |
0 | |
9 |
MeSH descriptor Plasminogen Activator Inhibitor 1 explode all trees |
436 |
10 |
MeSH descriptor Urokinase-Type Plasminogen Activator explode all trees |
309 |
11 |
MeSH descriptor Receptors, Urokinase Plasminogen Activator explode all trees |
6 |
12 |
3107 | |
13 |
14 | |
14 |
MeSH descriptor Enzyme-Linked Immunosorbent Assay explode all trees |
1849 |
15 |
4149 | |
16 |
(#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15) |
7269 |
17 |
96 | |
Cochrane Reviews [1] Other Reviews [0] Clinical (Controlled) Trials [78] Methods Studies [0] Technology Assessments [9] Economic Evaluations [8] Cochrane Groups [0] | ||
Database: Cinahl (Accessed 12/10/2011) Search Strategy: | ||
1 |
exp BREAST NEOPLASMS/ | |
2 |
(breast* ADJ3 neoplasm*).ti,ab | |
3 |
(breast* ADJ3 tumor*).ti,ab | |
4 |
(breast* ADJ3 tumour*).ti,ab | |
5 |
(breast* ADJ3 cancer*).ti,ab | |
6 |
(breast* ADJ3 carcinoma*).ti,ab | |
7 |
1 OR 2 OR 3 OR 4 OR 5 OR 6 | |
8 |
oncotype*.ti,ab | |
9 |
(21-gene* OR (21 ADJ gene*)).ti,ab | |
10 |
(mammaprint* OR (mamma* ADJ print*)).ti,ab | |
11 |
(70-gene* OR (70 ADJ gene*)).ti,ab | |
12 |
femtelle*.ti,ab | |
13 |
exp UROKINASE/ OR exp PLASMINOGEN ACTIVATORS/ | |
14 |
(urokinase* OR (plasminogen* adj3 activator*)).ti,ab | |
15 |
(upa* adj3 pai-1*).ti,ab | |
16 |
ENZYME-LINKED IMMUNOSORBENT ASSAY/ | |
17 |
(elisa* OR enzyme-linked AND immunosorbent AND assay*).ti,ab | |
18 |
8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 | |
19 |
7 AND 18 | |
20 |
19 [Limit to: (Language English)] |
Database: CRD databases: DARE, NHS EED, HTA (Accessed 13/10/2011) Search Strategy: | ||
1 |
MeSH DESCRIPTOR Breast Neoplasms EXPLODE ALL TREES |
985 |
2 |
MeSH DESCRIPTOR Carcinoma, Ductal, Breast EXPLODE ALL TREES |
16 |
3 |
(breast* near neoplasm*) OR (breast* near tumor*) OR (breast* near tumour*) OR (breast* near cancer*) OR (breast* near carcinoma*) |
1471 |
4 |
(mamma* near neoplasm*) OR (mamma* near tumor*) OR (mamma* near tumour*) OR (mamma* near cancer*) OR (mamma* near carcinoma*) |
10 |
5 |
#1 OR #2 OR #3 OR #4 |
1471 |
6 |
(oncotype*) OR (21-gene*) OR (21 near gene*) |
43 |
7 |
(mammaprint*) OR (mamma* near print*) OR (70-gene*) OR (70 near gene*) |
30 |
8 |
(femtelle*) OR (urokinase* near plasminogen*) OR (urokinase* near activator* ) OR (upa* near pai-1*) |
32 |
9 |
MeSH DESCRIPTOR Plasminogen Activator Inhibitor 1 EXPLODE ALL TREES |
2 |
10 |
MeSH DESCRIPTOR Receptors, Urokinase Plasminogen Activator EXPLODE ALL TREES |
0 |
11 |
MeSH DESCRIPTOR Enzyme-Linked Immunosorbent Assay EXPLODE ALL TREES |
67 |
12 |
(elisa*) OR (enzyme-linked immunosorbent assay*) |
121 |
13 |
#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 |
255 |
14 |
#5 AND #13 |
24 |
Appendix COL-1 2. Inclusion/Exclusion criteria for references eligibility
[1] Eligible (YES): according Inclusion criteria (below)-INCLUDED
[2] Unclear/No abstract (full text article is needed to make final decision)-AMBIGUOUS
[3] NOT eligible (exclude): indicate reason for exclusion (below)-EXCLUDED
Reason for EXCLUSION? (choose any that apply)
Appendix COL-2 Survey across manufacturers
The manufacturers of the 3 tests (Agendia, American Diagnostica, and Genomic Health) were contacted by Agenas (lead partner of the Strand B within the EUnetHTA WP4). A list of specific questions for each test (FEMTELLE, MammaPrint, and Oncotype DX) was sent. Questions were grouped by domain; they were formulated by all the researchers involved in the project and collated by the PI of each domain. The lists of questions for the three tests are in the following pages. First contact with manufacturers was on 14 February 2012; they had 2 weeks to answer the questions (deadline was then changed after a direct request form two manufacturers). Information collected by the survey was used to answer the questions of this core HTA and reference is made as Appendix COL-2; detailed answers from manufacturers are not included in the public report.
Questions about health problem and current use of the technology:
1. In which European countries do you market your test for breast cancer recurrence?
2. If possible, please state in which European countries your test is most widely used.
3. If possible, please state how many tests are sold in each country.
Questions about technical description and characteristics of the technology:
4. How much time has to be allowed for shipping the samples?
5. Are the equipment and supplies required for the specimen preparation commonly available by the cancer centres / hospitals across EU?
6. Are there particular qualification, training and quality assurance needed for sample isolation and preparation?
7. What kind of qualification, training and quality assurance are needed for those centres that decide to perform the test in their own labs?
Questions about safety issues:
8. What are the safety standards that the technology must follow (e.g. UNI, ISO)?
9. What is the statistical, percentage of sampling error?
10. What systems are used to minimise or eliminate the risk of the sample contamination?
11. Is there a product data sheet, application for product license, safety reports or other documentation of the products including safety information available for us?
12. Are there technology or patient registries managed by the manufacturer regarding the test in question?
13. Are you aware of discussion forums, in professional or patient organizations, or in social media, about your product?
Questions about clinical effectiveness of the technology:
14. Are you aware of any unpublished study?
Especially with prospective design, reporting on clinical effectiveness, clinical utility, health outcomes (morbidity, mortality), safety (adverse events according adjuvant chemotherapy), quality of life, clinical decision making on treatment choice with adjuvant chemotherapy, patients satisfactions, overall benefit and harms in health outcomes, in comparison of standard (or current) care, or direct (head-to-head) comparison.
Questions about market and regulation:
15. In which European country is your test reimbursed by the National Health Service?
16. In which European country is your test subject to price control?
17. In which European country is your test subject to acquisition regulation?
18. Is the marketing of genetic tests for breast cancer to the patients restricted?
Questions about prices:
19. At what price do you sell the test?
20. Are the prices different among countries? If yes, please specify the price for each EU country.
Please could you help us produce a factually correct, fair and balanced report by providing the information requested from your own databases if the information exists. |
Questions for the manufacturer of the technology: MammaPrint® (Agendia BV)
Questions about health problem and current use of the technology:
1. In which European countries do you market your test for breast cancer recurrence?
2. If possible, please state in which European countries your test is most widely used.
3. If possible, please state how many tests are sold in each country.
Questions about technical description and characteristics of the technology:
4. What are the clinicopathological factors that need to be considered together with the test results?
5. How much time has to be allowed for shipping the samples?
6. Are the equipment and supplies required for the specimen preparation commonly available by the cancer centres / hospitals across EU?
7. Are there particular qualification, training and quality assurance needed for sample isolation and preparation?
Questions about safety issues:
8. What are the safety standards that the technology must follow (e.g. UNI, ISO)?
9. What is the statistical, percentage of sampling error?
10. What systems are used to minimise or eliminate the risk of the sample contamination?
11. Is there a product data sheet, application for product license, safety reports or other documentation of the products including safety information available for us?
12. Are there technology or patient registries managed by the manufacturer regarding the test in question?
13. Are you aware of discussion forums, in professional or patient organizations, or in social media, about your product?
Questions about clinical effectiveness of the technology:
14. Are you aware of any unpublished study?
Especially with prospective design, reporting on clinical effectiveness, clinical utility, health outcomes (morbidity, mortality), safety (adverse events according adjuvant chemotherapy), quality of life, clinical decision making on treatment choice with adjuvant chemotherapy, patients satisfactions, overall benefit and harms in health outcomes, in comparison of standard (or current) care, or direct (head-to-head) comparison.
Questions about market and regulation:
15. In which European country is your test reimbursed by the National Health Service?
16. In which European country is your test subject to price control?
17. In which European country is your test subject to acquisition regulation?
18. Is the marketing of genetic tests for breast cancer to the patients restricted?
Questions about prices:
19. At what price do you sell the test?
20. Are the prices different among countries? If yes, please specify the price for each EU country.
Please could you help us produce a factually correct, fair and balanced report by providing the information requested from your own databases if the information exists. |
Questions for the manufacturer of the technology: Oncotype DX™ (Genomic Health, Inc.)
Questions about health problem and current use of the technology:
1. In which European countries do you market your test for breast cancer recurrence?
2. If possible, please state in which European countries your test is most widely used.
3. If possible, please state how many tests are sold in each country.
Questions about technical description and characteristics of the technology:
4. How much time has to be allowed for shipping the samples?
5. Are the equipment and supplies required for the specimen preparation commonly available by the cancer centres / hospitals across EU?
6. Are there particular qualification, training and quality assurance needed for sample isolation and preparation?
Questions about safety issues:
7. What are the safety standards that the technology must follow (e.g. UNI, ISO)?
8. What is the statistical, percentage of sampling error?
9. What systems are used to minimise or eliminate the risk of the sample contamination?
10. Is there a product data sheet, application for product license, safety reports or other documentation of the products including safety information available for us?
11. Are there technology or patient registries managed by the manufacturer regarding the test in question?
12. Are you aware of discussion forums, in professional or patient organizations, or in social media, about your product?
Questions about clinical effectiveness of the technology:
13. Are you aware of any unpublished study?
Especially with prospective design, reporting on clinical effectiveness, clinical utility, health outcomes (morbidity, mortality), safety (adverse events according adjuvant chemotherapy), quality of life, clinical decision making on treatment choice with adjuvant chemotherapy, patients satisfactions, overall benefit and harms in health outcomes, in comparison of standard (or current) care, or direct (head-to-head) comparison.
Questions about market and regulation:
14. In which European country is your test reimbursed by the National Health Service?
15. In which European country is your test subject to price control?
16. In which European country is your test subject to acquisition regulation?
17. Is the marketing of genetic tests for breast cancer to the patients restricted?
Questions about prices:
18. At what price do you sell the test?
19. Are the prices different among countries? If yes, please specify the price for each EU country.
Please could you help us produce a factually correct, fair and balanced report by providing the information requested from your own databases if the information exists. |
Appendix COL-3 Survey Report for retrieving information on the use of technology in European countries
Appendix COL-4 Abbreviations list