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.

Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX )

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)

HTA Core Model Application for Diagnostic Technologies (1.1)
Core HTA
Published
Tom Jefferson (age.na.s, Italy), Nicola Vicari (age.na.s, Italy), Heike Raatz (SNHTA, Switzerland)
Sarah Baggaley, NICE (Health problem and current use); Antonio Migliore, Agenas (Description and technical characteristics); Iris Pasternack, THL-FINOHTA (Safety); Mirjana Huic, AAZ (Clinical effectiveness), Isaura Vieira, INFARMED (Costs and economic evaluation); Dario Sacchini, A.Gemelli (Ethical analysis); Jennifer Butt, NICE (Organisational aspects); Marco Marchetti, A.Gemelli (Social and Legal aspects)
Agenzia nationale per i servizi sanitari regionali (age.na.s), Italy
A. Gemelli (Italy), AAZ (Croatia), Agenas (Italy), AHTAPol (Poland), AVALIA-t (Spain), INFARMED (Portugal), IPH-RS (Slovenia), NICE (United Kingdom), Regione Veneto (Italy), SNHTA (Switzerland), THL (Finland), UMIT (Austria)
13.6.2011 14.00.00
31.1.2013 18.05.00
Jefferson T, Vicari N, Raatz H [eds.]. Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX ) [Core HTA], Agenzia nationale per i servizi sanitari regionali (age.na.s), Italy ; 2013. [cited 14 November 2019]. Available from: http://meka.thl.fi/ViewCover.aspx?id=113

Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX )

Collection summary

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.



Collection methodology

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.

Introduction to collection

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:

  1. Health problem and current use of the technology (CUR)
  2. Description and technical characteristics of technology (TEC)
  3. Safety (SAF)
  4. Effectiveness  (EFF)
  5. Costs and economic evaluation  (ECO)
  6. Ethical analysis (ETH)
  7. Organisational aspects (ORG)
  8. Social aspects (SOC)
  9. Legal aspects (LEG)

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:

  • A. Gemelli, Italy
  • AAZ, Croatia
  • AETSA, Spain
  • Agenas,  Italy
  • AHTAPol, Poland
  • ASSR-RER, Italy
  • AVALIA-t, Spain
  • CAHIAQ, Spain
  • GÖG, Austria
  • HIQA, Ireland
  • IER (Slovenia)
  • INFARMED, Portugal
  • IQWIG, Germany
  • IPH-RS, Slovenia
  • Laziosanità, Italy
  • LBI-HTA, Austria
  • NICE, United Kingdom
  • Regione Veneto, Italy
  • SDU/CAST, Denmark
  • SNHTA, Switzerland
  • THL, Finland
  • UMIT, Austria
  • UTA, Estonia

Researchers:

  • Cari Almazan (CAHIAQ)
  • Ana Bação (Infarmed)
  • Sarah Baggaley (NICE)
  • Luciana Ballini (ASSR-RER)
  • Lidia Becla (AHTAPol)
  • Hanan Bell (NICE)
  • Jennifer Butt (NICE)
  • Angelica Carletto (A. Gemelli)
  • Marina Casini (A.Gemelli)
  • Emilio Chiarolla (Agenas)
  • Americo Cicchetti (A. Gemelli)
  • Mirella Corio (Agenas)
  • Chiara Filippi (Regione Veneto)
  • Teresa Gasparetto (Regione Veneto)
  • Massimo Gion (Regione Veneto)
  • Paolo Giorgi Rossi (Laziosanità)
  • Patricia Harrington (HIQA)
  • Mirjana Huic (AAZ)
  • Marjetka Jelenc (IPH-RS)
  • Gurleen Jhuti (NICE)
  • Eva-Maria Kernstock (GÖG)
  • Vesna Kovač (IER)
  • Stefan Lange (IQWIG)
  • Anne Lee (SDU/CAST)
  • Kristi Liiv (UTA)
  • Aurora Llanos-Mendez (AETSA)
  • Alessandro Lo Scalzo (Agenas)
  • Marco Marchetti (A.Gemelli)
  • Mirella Marlow (NICE)
  • Stefan Mathis-Endenhofer (LBI-HTA)
  • Emanuela Midolo (A.Gemelli)
  • Antonio Migliore (Agenas)
  • Roberta Minacori (A. Gemelli)
  • Judite Neves (Infarmed)
  • Monica O'Neill (HIQA)
  • Marco Oradei (A.Gemelli)
  • Monica Orzel (AHTAPol)
  • Anna Panasiuk (AHTAPol)
  • Iris Pasternack (THL)
  • Maria Rosaria Perrini (Agenas)
  • Heike Raatz (SNHTA)
  • Alexandra Ramssl-Sauer (GÖG)
  • Pietro Refolo, (A.Gemelli)
  • Matteo Ruggeri (A.Gemelli)
  • Katarzyna Sejbuk (AHTAPol)
  • Dario Sacchini (A.Gemelli)
  • Narine Sahakyan (UMIT)
  • Stefan Sauerland (IQWIG)
  • Petra Schnell-Inderst (UMIT)
  • Eva Turk (IPH-RS)
  • LeonorVarelaLema (AVALIA-t)
  • Isaura Vieira (INFARMED)
  • Luca Vignatelli (ASSR-RER)
  • Siw Waffenschmidt (IQWIG)
  • Claudia Wild (LBI-HTA)

Scope

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Health Problem and Current Use of the Technology

Authors: Sarah Baggaley, Massimo Gion

Summary

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}.

Introduction

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.

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
A0001Target ConditionWhich disease/health problem/potential health problem will the technology be used for?yesWhich disease/health problem/potential health problem will Genetic Test be used for?
A0002Target ConditionWhat, 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)?yesHow is the disease/health condition currently being diagnosed? Include a description of any relevant classification system
A0003Target ConditionWhich are the known risk factors for acquiring the condition?yesWhich are the known risk factors for acquiring the condition?
A0004Target ConditionWhat is the natural course of the condition?yesWhat is the natural course of the condition?
A0005Target ConditionWhat are the symptoms of the disease?yesWhat are the symptoms of the disease?
A0006Target ConditionWhat are the consequences of the condition?yesWhat are the consequences of the condition?
A0007Target ConditionHow many people belong at the moment (will belong) to the specific target group (describe according to sex, age)?yesHow many people belong at the moment (will belong) to the specific target group (describe according to sex, age)?
A0008Target ConditionWhat is the burden of disease (mortality, disability, life years lost)?yesWhat is the burden of disease (mortality, disability, life years lost)?
A0009Target ConditionWhat aspects of the burden of disease are targeted by the technology, i.e. are expected to be reduced by the technology?yesWhat aspects of the burden of disease are targeted by Genetic Test, i.e. are expected to be reduced by Genetic Test?
A0010Target ConditionHow long is the waiting time for diagnosis and/or treatment of the specific disease?noMerged withA0013
A0011UtilisationHow much is the technology being used?yesHow much is Genetic Test being used?
A0012UtilisationDescribe the variations in use across countries/regions/settings, if any?noMerged with A0011
A0013Current Management of the ConditionHow is the disease/health condition currently being diagnosed?yesHow is the disease/health condition currently being diagnosed?
A0014Current Management of the ConditionAccording to published algorithms/guidelines (if any), how should the condition be diagnosed?yesAccording to published algorithms/guidelines (if any), how should the condition be diagnosed?
A0015Current Management of the ConditionHow is the disease/health condition currently being managed?yesHow is the disease/health condition currently being managed?
A0016Current Management of the ConditionAccording to published algorithms/guidelines (if any), how should the condition be managed?yesAccording to published algorithms/guidelines (if any), how should the condition be managed?
A0017Current Management of the ConditionWhat are the differences in the management for different stages of disease, if any?noMerged with A0015
A0018Current Management of the ConditionWhat are the other evidence-based alternatives to the current technology, if any?noQuestion too broad
A0020Regulatory StatusWhich approval status has the technology in other countries, or international authorities?yesWhich approval status has Genetic Test in other countries, or international authorities?
A0021Regulatory StatusHas 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?)noMore relevant to other domains and can be merged with A0011
A0019Life-CycleIn which phase is the development of the technology (experimental, emerging, routine use, obsolete)?noMore relevant to technical characteristics domain
A0022OtherWho manufactures the technology?noMerged into A0009

Methodology description

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.

Result cards

Target Condition

Result card for CUR1: "Which disease/health problem/potential health problem will Genetic Test be used for?"

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CUR1: Which disease/health problem/potential health problem will Genetic Test be used for?
Method
Result

Importance: Critical

Transferability: Completely

Result card for CUR2: "How is the disease/health condition currently being diagnosed? Include a description of any relevant classification system"

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CUR2: How is the disease/health condition currently being diagnosed? Include a description of any relevant classification system
Method
Result

Importance: Important

Transferability: Completely

Result card for CUR3: "Which are the known risk factors for acquiring the condition?"

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CUR3: Which are the known risk factors for acquiring the condition?
Method
Result

Importance: Important

Transferability: Completely

Result card for CUR4: "What is the natural course of the condition?"

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CUR4: What is the natural course of the condition?
Method
Result

Importance: Important

Transferability: Completely

Result card for CUR5: "What are the symptoms of the disease?"

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CUR5: What are the symptoms of the disease?
Method
Result

Importance: Optional

Transferability: Completely

Result card for CUR6: "What are the consequences of the condition?"

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CUR6: What are the consequences of the condition?
Method
Result

Importance: Critical

Transferability: Completely

Result card for CUR7: "How many people belong at the moment (will belong) to the specific target group (describe according to sex, age)?"

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CUR7: How many people belong at the moment (will belong) to the specific target group (describe according to sex, age)?
Method
Result

Importance: Critical

Transferability: Completely

Result card for CUR8: "What is the burden of disease (mortality, disability, life years lost)?"

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CUR8: What is the burden of disease (mortality, disability, life years lost)?
Method
Result

Importance: Critical

Transferability: Completely

Result card for CUR9: "What aspects of the burden of disease are targeted by Genetic Test, i.e. are expected to be reduced by Genetic Test?"

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CUR9: What aspects of the burden of disease are targeted by Genetic Test, i.e. are expected to be reduced by Genetic Test?
Method
Result

Importance: Critical

Transferability: Completely

Utilisation

Result card for CUR11: "How much is Genetic Test being used?"

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CUR11: How much is Genetic Test being used?
Method
Result
Comment

Importance: Important

Transferability: Partially

Current Management of the Condition

Result card for CUR22: "How is the disease/health condition currently being diagnosed?"

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CUR22: How is the disease/health condition currently being diagnosed?
Method
Result

Importance: Critical

Transferability: Partially

Result card for CUR13: "According to published algorithms/guidelines (if any), how should the condition be diagnosed?"

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CUR13: According to published algorithms/guidelines (if any), how should the condition be diagnosed?
Method
Result

Importance: Critical

Transferability: Partially

Result card for CUR14: "How is the disease/health condition currently being managed?"

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CUR14: How is the disease/health condition currently being managed?
Method
Result
Comment

Importance: Important

Transferability: Partially

Result card for CUR15: "According to published algorithms/guidelines (if any), how should the condition be managed?"

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CUR15: According to published algorithms/guidelines (if any), how should the condition be managed?
Method
Result

Importance: Critical

Transferability: Partially

Regulatory Status

Result card for CUR21: "Which approval status has Genetic Test in other countries, or international authorities?"

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CUR21: Which approval status has Genetic Test in other countries, or international authorities?
Method
Result

Importance: Important

Transferability: Completely

Discussion

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.

References

  1. National Institute for Health and Clinical Excellence (2009) Early and locally advanced breast cancer. CG80. London: National Institute for Health and Clinical Excellence.
  2. Marchionni L, Wilson RF, Marinopoulos SS, Wolff AC, Parmigiani G, Bass EB, Goodman SN. Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes Evidence Report/Technology Assessment No 160. (Prepared by the John Hopkins University Evidence-based Practice Centre under contract No. 290-02-0018) AHRO Publication No. 08-E002. (January 2008) Rockville, MD: Agency for Healthcare Research and Quality.
  3. American Diagnostica [Internet]. Pfungstadt, Germany. [Accessed June 2012] Available from: http://www.femtelle.de/en/physicians/about-femtelle/benefits-of-femtelle/
  4. Agendia [Internet]. [Accessed June 2012] Available from: http://www.agendia.com/pages/mammaprint/21.php
  5. Genomic Health [Internet] [Accessed June 2012] Available from: http://www.oncotypedx.com/en-US/Breast/HealthcareProfessionalsInvasive
  6. National Cancer Institute [Internet] [Accessed June 2012] Available from: http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2
  7. Smartt, P. A comparison of gene expression profiling tests for breast cancer HSAC Report 2010; 3(16) Health Services Assessment Collaboration (HSAC), University of Canterbury ISBN 978-0-9864563-5-0 (online)
  8. Cancer Research UK [Internet] [Accessed June 2012] Available from: http://cancerhelp.cancerresearchuk.org/type/breast-cancer/treatment/number-stages-of-breast-cancer
  9. Cancer Research UK [Internet] [Accessed June 2012] Available from: http://cancerhelp.cancerresearchuk.org/type/breast-cancer/treatment/tnm-breast-cancer-staging
  10. American Cancer Society [Internet] [Accessed June 2012] Available from: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging
  11. Macmillan Cancer Support [Internet] [Accessed June 2012] Available from: http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/Stagingandgrading.aspx
  12. Macmillan Cancer Support [Internet] [Accessed June 2012] Available from: http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/HormoneandHER2receptors/HormoneandHER2receptors.aspx
  13. American Cancer Society [Internet] [Accessed June 2012] Available from: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-risk-factors
  14. Cancer Research UK [Internet] [Accessed June 2012] Available from: http://info.cancerresearchuk.org/cancerstats/types/breast/riskfactors/breast-cancer-risk-factors
  15. Medical Advisory Secretariat. Gene expression profiling for guiding adjuvant chemotherapy decisions in women with early breast cancer: an evidence-based and economic analysis. Ontario Health Technology Assessment 2010; 10(23) 1-57 [Internet] [Accessed June 2012] Available from: http://www.health.gov.on.ca/english/providers/program/mas/tech/reviews/pdf/gep_20101213.pdf
  16. Cancer Research UK [Internet] [Accessed June 2012] Available from: http://cancerhelp.cancerresearchuk.org/about-cancer/what-is-cancer/grow/how-a-cancer-spreads
  17. Macmillan Cancer Support [Internet] [Accessed June 2012] Available from: http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/Symptomsofbreastcancer.aspx
  18. NHS Choices [Internet] [Accessed June 2012] Available from: http://www.nhs.uk/Conditions/Cancer-of-the-breast-female/Pages/Symptoms.aspx
  19. Breast Cancer Care [Internet] [Accessed June 2012] Available from: http://www.breastcancercare.org.uk/breast-cancer-information/impact-breast-cancer-0
  20. D’Angelo-Donovan D., Dickson-Witmer D. and Petrelli N.J. Sentinel lymph node biopsy in breast cancer: A history and current clinical recommendations. Surgical Oncology (2012) 1-5
  21. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet] [Accessed June 2012].Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr/factsheets/cancers/breast.asp
  22. OECD (2011), Health at a Glance 2011: OECD Indicators, OECD Publishing.[Internet] [Accessed June 2012] Available from: http://dx.doi.org/10.1787/health_glance-2011-en
  23. American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011. [Internet] [Accessed June 2012] Available from: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-027766.pdf
  24. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Breast Cancer (Version 2.2011) http://www.nccn.org [Internet] [Accessed June 2012].
  25. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287-5312
  26. Gnant M., Harbeck N. and Thomssen C. St. Gallen 2011: Summary of the Consensus Discussion. Breast Care 2011; 6:136-141
  27. AGO Therapy Guidelines “Breast Cancer”. Guidelines of the “German Working Group of Gynecological Oncology” for diagnosis and treatment of patients with primary and metastatic breast cancer.2012 [Internet] [Accessed June 2012] Available from: www.ago-online.org
  28. American Diagnostica [Internet]. Pfungstadt, Germany. [Accessed June 2012] Available from: http://www.femtelle.de/en/physicians/publications/
  29. Sturgeon CM, Duffy MJ, Stenman UH, et al. National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin. Chem. (2008) 54(12), e11-79.
  30. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer? Genet Med. (2009) 11(1):66-73.

Description and technical characteristics of technology

Authors: Pseudo169 Pseudo169, Pseudo90 Pseudo90, Pseudo154 Pseudo154, Pseudo98 Pseudo98

Summary

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.

Introduction

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.

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
B0001Features of the technologyWhat is this technology?yesWhat is the FEMTELLE® uPA/PAI-1 ELISA test?
What is the MammaPrint® test?
What is the Oncotype DX™ test?
B0002Features of the technologyWhy is this technology used?yesWhy FEMTELLE®, MammaPrint®, and Oncotype DX™ are used?
B0003Features of the technologyPhase of the technology: When was it developed or introduced in health care?yesWhen FEMTELLE®, MammaPrint®, and Oncotype DX™ were developed or introduced in health care?
B0004Features of the technologyWho will apply this technology?yesWho will apply the FEMTELLE®, MammaPrint®, and Oncotype DX™ test?
B0005Features of the technologyWhat is the place and context for utilising the technologyyesWhat is the place and context for utilising FEMTELLE®, MammaPrint®, and Oncotype DX™?
B0017Features of the technologyIs the technology rapidly changing / improving?yesIs the technology rapidly changing / improving?
B0018Features of the technologyAre the reference values or cut-off points clearly established?yesAre the reference values or cut-off points clearly established?
B0006Features of the technologyAre there any special features relevant to this technology?noThis AE has been marked as IRRELEVANT. The technology is additive to the standard pathway for the treatment definition. No predecessors are defined.
B0016Features of the technologyWho are the persons this technology will be used on?noNot applicable. Moved to CUR (A0001).
B0007Investments and tools required to use the technologyWhat material investments are needed to use the technology?yesWhat material investments are needed to use FEMTELLE®, MammaPrint®, and Oncotype DX™?
B0008Investments and tools required to use the technologyWhat kind of special premises are needed to use the technology?noThis 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™).
B0009Investments and tools required to use the technologyWhat equipment and supplies are needed to use the technology?noThis AE has been integrated in B0007 (see B0007).
B0010Investments and tools required to use the technologyWhat kind of data and records are needed to monitor the use the technology?noWe believe that B0010 and B0011 are related to domain G (Organisational aspects).
B0011Investments and tools required to use the technologyWhat kind of registers is needed to monitor the use the technology?no
B0012Training and information needed for utilizing the technologyWhat kind of qualification, training and quality assurance are needed for the use or maintenance of the technology?yesWhat kind of qualification, training and quality assurance are needed for the use of FEMTELLE®, MammaPrint®, and Oncotype DX™?
B0014Training and information needed for utilizing the technologyWhat kind of training and information are needed for the patients receiving or using this technology & their families?yesWhat kind of information is needed for the patients receiving FEMTELLE®, MammaPrint®, and Oncotype DX™ and their families?
B0015Training and information needed for utilizing the technologyWhat information do patients outside the target group and the general public need on the technology?yesWhat information do patients outside the target group and the general public need on the use of FEMTELLE®, MammaPrint®, and Oncotype DX™?
B0020Training and information needed for utilizing the technologyHow does training and quality assurance affect the management or effectiveness?yesHow does training and quality assurance affect the management or effectiveness?

Methodology description

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}.

Information sources

– Manufacturers’ websites;

– Company brochures and data sheets;

– Guidelines;

– HTA reports;

– Regulatory authorities’ websites;

– Governmental institutions’ websites;

– Structured survey across manufacturers.

Quality assessment tools or criteria

Not applicable.

Analysis and synthesis

Not applicable.

Result cards

Features of the technology

Result card for TEC2: "What is the FEMTELLE&#174; uPA/PAI-1 ELISA test?", TEC3: "What is the MammaPrint&#174; test?" and TEC4: "What is the Oncotype DX™ test?"

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TEC2: What is the FEMTELLE&#174; uPA/PAI-1 ELISA test?
Method
Result

Importance: Critical

Transferability: Completely

TEC3: What is the MammaPrint&#174; test?
Method
Result

Importance: Critical

Transferability: Completely

TEC4: What is the Oncotype DX™ test?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC5: "Why FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ are used? "

View full card
TEC5: Why FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ are used?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC6: "When FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ were developed or introduced in health care?"

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TEC6: When FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ were developed or introduced in health care?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC7: "Who will apply the FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ test?"

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TEC7: Who will apply the FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ test?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC8: "What is the place and context for utilising FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?"

View full card
TEC8: What is the place and context for utilising FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC17: "Is the technology rapidly changing / improving?"

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TEC17: Is the technology rapidly changing / improving?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC18: "Are the reference values or cut-off points clearly established?"

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TEC18: Are the reference values or cut-off points clearly established?
Method
Result

Importance: Critical

Transferability: Completely

Investments and tools required to use the technology

Result card for TEC10: "What material investments are needed to use FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?"

View full card
TEC10: What material investments are needed to use FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?
Method
Result
Comment

Importance: Critical

Transferability: Completely

Training and information needed for utilizing the technology

Result card for TEC13: "What kind of qualification, training and quality assurance are needed for the use of FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?"

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TEC13: What kind of qualification, training and quality assurance are needed for the use of FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC14: "What kind of information is needed for the patients receiving FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ and their families?"

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TEC14: What kind of information is needed for the patients receiving FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™ and their families?
Method
Result

Importance: Critical

Transferability: Partially

Result card for TEC15: "What information do patients outside the target group and the general public need on the use of FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?"

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TEC15: What information do patients outside the target group and the general public need on the use of FEMTELLE&#174;, MammaPrint&#174;, and Oncotype DX™?
Method
Result

Importance: Critical

Transferability: Completely

Result card for TEC19: "How does training and quality assurance affect the management or effectiveness?"

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TEC19: How does training and quality assurance affect the management or effectiveness?
Method
Result

Importance: Critical

Transferability: Completely

Discussion

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.

References

  1. Mengele K, Harbeck N, Reuning U, Magdolen V, Schmitt M. Tumor-associated prognostic factors of the plasminogen activator family: determination and clinical value of u-PA, t-PA, PAI-1, and PAI-2. Hamostaseologie 2005; 25(3):301-10.
  2. www.femtelle.de/en/physicians/about-femtelle/clinical-routine-testing/
  3. www.agendia.com/filebin/pdf/Agendia_Sampling2.pdf
  4. www.oncotypedx.com/en-GB/Breast/HealthcareProfessional/Underlying.aspx
  5. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351: 2817-26.
  6. www.oncotypedx.com/en-US/Breast/HealthcareProfessional/OrderingOncotypeDX.aspx#b2
  7. www.american-diagnostica.de/index.php?id=20&L=1
  8. Diagnostics consultation document – Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat. Issue date: January 2012. http://guidance.nice.org.uk/DT/4/Consultation/Latest
  9. Smartt P. A comparison of gene expression profiling tests for breast cancer HSAC Report 2010; 3(16).
  10. www.femtelle.de/en/physicians/about-femtelle/
  11. www.americandiagnostica.com/html/products.asp
  12. www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm
  13. http://files.shareholder.com/downloads/GHDX/0x0x236212/8bdf35bd-7ca6-4102-ba6a-aec65c59a2e9/GHDX_News_2007_10_30_General.pdf
  14. http://www.medicallessons.net/2010/03/a-small-study-offers-insight-regarding-breast-cancer-patients-capacity-and-eagerness-to-participate-in-medical-decision-making
  15. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 Update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007 (25) 5287–5312.
  16. www.femtelle.de/en/physicians/faqs/
  17. Retel VP, Bueno-de-Mesquita JM, Hummel MJ, van de Vijver MJ, Douma KF, Karsenberg K et al. Constructive Technology Assessment (CTA) as a tool in coverage with evidence development: the case of the 70-gene prognosis signature for breast cancer diagnostics. International Journal of Technology Assessment in Health Care 2009; 25(1).
  18. Berg AO, Armstrong K, Botkin J, Calonge N, Haddow J, Hayes M et al. Recommendations from the EGAPP Working Group: Can tumor gene expression profiling improve outcomes in patients with breast cancer? Genetics in Medicine 2009; 11(1).
  19. Gwinn M, Grossniklaus DA, Yu W, Melillo S, Wulf A, Flome J, Dotson WD, Khoury MJ. Horizon scanning for new genomic tests. Genetics in Medicine 2011 13:2 (161–165).
  20. www.femtelle.de/en/physicians/about-femtelle/results/
  21. van't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature, 2002 415(6871), 530–536.

Appendices

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.

Safety

Authors: Iris Pasternack, Emilio Chiarolla, Narine Sahakyan, Leonor Varela

Summary

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.

Introduction

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.

Methodology

Frame

A modified collection scope is used in this domain.

TechnologyuPA/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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
C0001Patient safetyWhat kind of harms can use of the technology cause to the patient and what is the incidence, severity and duration of harms?yesWhat 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®?
C0002Patient safetyWhat is the dose relatedness of the harms to patients?noThere is no dose relatedness
C0003Patient safetyWhat is the timing of onset of harms to patients: immediate, early or late?noNo obvious changes expected.
C0004Patient safetyIs the incidence of the harms to patients likely to change over time?noPsychological 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.
C0005Patient safetyAre there susceptible patient groups that are more likely to be harmed through use of the technology?noNo obvious risk groups for harms.
C0006Patient safetyWhat 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?noThe aim was to look at the prognostic value of the tests and not their effectiveness in the test-treatment intervention.
C0007Patient safetyWhat are the special features in using (applying/interpreting/maintaining) the technology that may increase the risk of patient safety?noUnspecific question.
C0008Patient safetyWhat is the safety of the technology in comparison to alternative technologies used for the same purpose?noThese 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.
C0020Occupational safetyWhat kind of occupational harms may exist through using the technology?yesWhat kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint®?
C0040Environmental safetyWhat kind of environmental risks may use of the technology cause?yesWhat kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint®?
C0062Safety risk managementHow can one reduce safety risks for patients (including technology-, user-, and patient-dependent aspects)?yesHow can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint® (including technology-, user-, and patient-dependent aspects)?
C0063Safety risk managementHow can one reduce safety risks for professionals (including technology-, user-, and patient-dependent aspects)?yesHow can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint® (including technology-, user-, and patient-dependent aspects)?
C0060Safety risk managementHow does the safety profile of the technology vary between different generations, versions or products?noThe technologies are in their early developmental phase.
C0061Safety risk managementIs there evidence that harms increase or decrease in different organizational settings?noHowever, there could be differences between specialized breast cancer care centers versus regular oncology hospitals
C0064Safety risk managementHow can one reduce safety risks for environment (including technology-, user-, and patient-dependent aspects)?noLargely same as occupational safety procedures. Will be handeled in C0063.

Methodology description

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}.

Result cards

Patient safety

Result card for SAF1: "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&#174;? " and SAF14: "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&#174;?"

View full card
SAF1: 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&#174;?
Method
Frame
Result

Importance: Important

Transferability: Completely

SAF14: 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&#174;?
Method
Result

Importance: Important

Transferability: Partially

Occupational safety

Result card for SAF7: "What kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint&#174;? "

View full card
SAF7: What kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?
Method
Frame
Result
Comment

Importance: Important

Transferability: Partially

Environmental safety

Result card for SAF8: "What kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?"

View full card
SAF8: What kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?
Method
Frame
Result

Importance: Optional

Transferability: Completely

Safety risk management

Result card for SAF11: "How can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?"

View full card
SAF11: How can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?
Method
Frame
Result

Importance: Important

Transferability: Partially

Result card for SAF12: "How can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?"

View full card
SAF12: How can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?
Method
Frame
Result

Importance: Important

Transferability: Partially

Discussion

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.

References

  1. Raab SS, Grzybicki DM. Quality in Cancer Diagnosis. CA: A Cancer Journal for Clinicians 2010;60(3):139-165.
  2. Valenstein P. Promoting Patient Safety through Risk Reduction and Continuous Improvement. Northfield, IL: College of American Pathologists 2005.
  3. Meier FA, Varney RC, Zarbo RJ. Study of amended reports to evaluate and improve surgical pathology processes. Adv Anat Pathol 2011 Sep;18(5):406-413.
  4. Valenstein PN, Sirota RL. Identification errors in pathology and laboratory medicine. Clin Lab Med 2004 12;24(4):979-996.
  5. 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):969-974.
  6. Layfield LJ, Anderson GM. Specimen labeling errors in surgical pathology: an 18-month experience. Am J Clin Pathol 2010 Sep;134(3):466-470.
  7. Makary MA, Epstein J, Pronovost PJ, Millman EA, Hartmann EC, Freischlag JA. Surgical specimen identification errors: A new measure of quality in surgical care. Surgery 2007 4;141(4):450-455.
  8. Longo MS, O'Neill MJ, O'Neill RJ. Abundant human DNA contamination identified in non-primate genome databases. PLoS One 2011 Feb 16;6(2):e16410.
  9. Richman AR, Tzeng JP, Carey LA, Retèl VP, Brewer NT. Knowledge of genomic testing among early-stage breast cancer patients. Psychooncology 2011;20(1):28-35.
  10. Retel VP, Bueno-de-Mesquita JM, Hummel MJ, van de Vijver MJ, Douma KF, Karsenberg K, et al. Constructive Technology Assessment (CTA) as a tool in coverage with evidence development: the case of the 70-gene prognosis signature for breast cancer diagnostics. Int J Technol Assess Health Care 2009 Jan;25(1):73-83.
  11. Oncotype DX web site: ordering the Oncotype DX test. Available at: http://www.oncotypedx.com/en-US/Breast/HealthcareProfessionalsDCIS/Ordering/OrderingTest. Accessed June 20, 2012.
  12. Agendia web site: How to order tests with Agendia. Available at: http://www.agendia.com/pages/ordering_symphony/38.php. Accessed June 20, 2012.
  13. National Toxicology Program. Final Report on Carcinogens: Background Document for Formaldehyde. Rep Carcinog Backgr Doc 2010 Jan;10-5981:1-521.
  14. Dimenstein IB. A pragmatic approach to formalin safety in anatomical pathology. LABMEDICINE 2009;40(12):740-746.
  15. International Agency for Research on Cancer (IARC). Formaldehyde. 2006; Available at: http://monographs.iarc.fr/ENG/Monographs/vol88/mono88-6A.pdf). Accessed June 20, 2012.
  16. Donnay C, Denis M, Magis R, Fevotte J, Massin N, Dumas O, et al. Under-estimation of self-reported occupational exposure by questionnaire in hospital workers. Occupational and Environmental Medicine 2011 August 01;68(8):611-617.
  17. Wilhelmsson B, Holmström M. POSITIVE FORMALDEHYDE-RAST AFTER PROLONGED FORMALDEHYDE EXPOSURE BY INHALATION. The Lancet 1987 7/18;330(8551):164.
  18. Dapson JC, Dapson RW. Hazardous Materials in the Histopathology laboratory: regulations, risks, handling and disposal. 4th ed. Battle Creek, MI: Anatech LTD; 2005.
  19. Arif AA, Delclos GL. Association between cleaning-related chemicals and work-related asthma and asthma symptoms among healthcare professionals. Occupational and Environmental Medicine 2012 January 01;69(1):35-40.
  20. Kilburn KH, Warshaw R, Thornton JC. Pulmonary function in histology technicians compared with women from Michigan: effects of chronic low dose formaldehyde on a national sample of women. Br J Ind Med 1989 Jul;46(7):468-472.
  21. Paustenbach D, Alarie Y, Kulle T, Schachter N, Smith R, Swenberg J, et al. A recommended occupational exposure limit for formaldehyde based on irritation. J Toxicol Environ Health 1997 Feb 21;50(3):217-263.
  22. Saurel-Cubizolles MJ, Hays M, Estryn-Behar M. Work in operating rooms and pregnancy outcome among nurses. Int Arch Occup Environ Health 1994;66(4):235-241.
  23. Titford ME, Horenstein MG. Histomorphologic assessment of formalin substitute fixatives for diagnostic surgical pathology. Arch Pathol Lab Med 2005 Apr;129(4):502-506.
  24. 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 7/15;408(16):3092-3095.
  25. Berton F, Novi CD. Occupational hazards of hospital personnel: assessment of a safe alternative to formaldehyde. J Occup Health 2012;54(1):74-78.

Appendices

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

  • 23 Add Search (#22) AND #21 35 04:45:29 > 35 hits listed below
  • 22 Add Search hospital[Title/Abstract] 550947 04:43:16
  • 21 Add Search (#20) AND #17 1505 04:42:46
  • 20 Add Search (#19) OR #18 546515 04:42:22
  • 19 Add Search work[Title/Abstract] 483270 04:41:54
  • 18 Add Search occupational[Title/Abstract] 79830 04:41:35
  • 17 Add Search (#16) OR #15 39041 04:41:15
  • 16 Add Search formaldehyde[Title/Abstract] 14641 04:40:39
  • 15 Add Search formalin[Title/Abstract] 24748 04:40:15
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Appendix SAF-4. Search for SAF1 and SAF11

15 March 2012 Iris Pasternack

Search strategy

  • 3 Add Search (safety[Title/Abstract]) AND #2 >18 references listed below
  • 2 Add Search (surgical pathology[Title/Abstract]) AND #1 246
  • 1 Add Search quality[Title/Abstract] 449032
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  3. 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. PubMed PMID: 21809987.
  4. Raab SS, Grzybicki DM. Cytologic-histologic correlation. Cancer Cytopathol. 2011 Oct 25;119(5):293-309. doi: 10.1002/cncy.20165. Epub 2011 Jul 5. Review. PubMed PMID: 21732549.
  5. Minato H, Nojima T, Nakano M, Yamazaki M. [Safety management in pathology laboratory: from specimen handling to confirmation of reports]. Rinsho Byori. 2011 Mar;59(3):299-304. Review. Japanese. PubMed PMID: 21560413.
  6. Silverman JF. Recent trends in quality, patient safety, and error reduction in nongyn cytology. Adv Anat Pathol. 2010 Nov;17(6):437-44. Review. PubMed PMID: 20966649.
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  9. Nakhleh RE. Patient safety and error reduction in surgical pathology. Arch Pathol Lab Med. 2008 Feb;132(2):181-5. Review. PubMed PMID: 18251572.
  10. Association of Directors of Anatomic and Surgical Pathology. Recommendations for quality assurance and improvement in surgical and autopsy pathology. Am J Surg Pathol. 2006 Nov;30(11):1469-71. Erratum in: Am J Surg Pathol. 2007 Jan;31(1):160. PubMed PMID: 17063090.
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  12. Association Of Directors Of Anatomic And Surgical Pathology, Nakhleh R, Coffin C, Cooper K. Recommendations for quality assurance and improvement in surgical and autopsy pathology. Hum Pathol. 2006 Aug;37(8):985-8. Epub 2006 Jun 19. PubMed PMID: 16867860.
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  15. Raab SS, Nakhleh RE, Ruby SG. Patient safety in anatomic pathology: measuring discrepancy frequencies and causes. Arch Pathol Lab Med. 2005 Apr;129(4):459-66. PubMed PMID: 15794667.
  16. Morales AR, Nassiri M, Kanhoush R, Vincek V, Nadji M. Experience with an automated microwave-assisted rapid tissue processing method: validation of histologic quality and impact on the timeliness of diagnostic surgical pathology. Am J Clin Pathol. 2004 Apr;121(4):528-36. PubMed PMID: 15080304.
  17. Chillemi S, Sinardi D, Marino A, Mantarro G, Campisi R. The use of remifentanil for bloodless surgical field during vertebral disc resection. Minerva Anestesiol. 2002 Sep;68(9):645-9. PubMed PMID: 12370680.
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Clinical Effectiveness

Authors: Authors: Mirjana Huic, Narine Sahakyan, Gurleen Jhuti, Anna Panasiuk, Heike Raatz, Petra Schnell-Inderst, Katarzyna Sejbuk, Eva Turk, Marjetka Jelenc

Summary

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.

Introduction

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}.

Methodology

Frame

A modified collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
D0010Change-in managementHow does the technology modify the need for hospitalization?yesDoes 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?
D0023Change-in managementHow does the technology modify the need for other technologies and use of resources?yesDo 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?
D0021Change-in managementDoes the use of the technology lead to a change in the physicians' management decisions?yesDid 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?
D0020Change-in managementDoes the use of the technology lead to improved detection of the disease?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D0022Change-in managementDoes the use of technology detect other health conditions which have impact on the treatment decisions concerning the target condition?noOur tests are prognostic tests, not diagnostic tests.
D0012Function / HRQL (Health-related quality of life)What is the effect of the technology on health-related quality of life?yesWhat 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?
D0016Function / HRQL (Health-related quality of life)How does the use of technology affect activities of daily living?yesDoes 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?
D0017Patient satisfactionWas the use of technology worth it?yesDo 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?
D0018Patient satisfactionWould the patient be willing to use the technology again?yesWould the patient be willing to use the technology (uPA/PAI or Mammaprint or Oncotype test) again?
D0030Patient satisfactionDoes the knowledge of the test result improve the patient's quality of life?yesDoes 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?
D0025Test-treatment chainWhat is the effect of the test-treatment intervention on mortality?yesWhat 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)?
D0032Test-treatment chainHow does the test-treatment intervention modify the magnitude and frequency of morbidity?yesHow 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?
D0024Test-treatment chainIs there an effective treatment for the condition the technology is detecting?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D0026MorbidityHow does the technology modify the effectiveness of subsequent interventions?yesDoes 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?
D0004MortalityWhat is the mortality related to the technology studied?noAs 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.
D0027Test accuracyWhat are the negative consequences of further testing and delayed treatment in patients with false negative test result?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D0028Test accuracyWhat are the negative consequences of further testing and treatments in patients with false positive test result?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D0029Test accuracyWhat are the overall benefits and harms in health outcomes considering the amount of false positive and false negative test results.noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1001Test accuracyWhat is the accuracy of the test against reference standard?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1002Test accuracyHow does the technology compare to other optional diagnostic technologies in terms of accuracy measures?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1003Test accuracyWhat is the reference standard and how likely does it classify the target condition correctly?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1004Test accuracyWhat are the requirements for accuracy in the context the technology will be used?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1005Test accuracyWhat is the optimal threshold value in this context?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1006Test accuracyDoes the technology have the potential to reliably rule in or rule out the target condition?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1007Test accuracyHow does test accuracy vary in different settings?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1008Test accuracyWhat is known about the intra- and inter-observer variation in test interpretation?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D1019Test accuracyIs there evidence that the replacing technology is more specific or safer than the old one?noOur tests are prognostic tests, not diagnostic tests. Prognostic/predictive accuracy will not be assessed in this HTA Core Model for diagnostic technologies.
D0031SafetyWhat is the mortality and morbidity related to the diagnostic technology?noOur tests are prognostic tests, not diagnostic tests. This question belongs to safety domain and seems not to be relevant to genetic test.

Methodology description

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:

  1. included women who had been diagnosed with early invasive breast cancer;
  2. compared at least one of the following prognostic tests: uPA/PAI-1, MammaPrint or  Oncotype DX with standard/current practice;
  3. addressed questions on clinical (health) outcomes like 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;
  4. reported sufficient methodological details to allow critical appraisal of study quality;
  5. were in English;
  6. reported on humans only.

Exclusion criteria were studies that:

  1. did not involve women with early stage invasive breast cancer;
  2. did not compare use of at least one of the following tests: uPA/PAI-1, MammaPrint, and Oncotype DX to standard/current practice;
  3. did not provide data on at least one of the domain questions on clinical (health) outcomes like 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;
  4. assessed only the prognostic/predictive accuracy of the test;
  5. papers with RCTs and observational studies without sufficient methodological details to allow critical appraisal of study quality;
  6. papers (publications) published in a language other than English;
  7. duplicated the original publication;
  8. reported studies relating to these tests in the neo-adjuvant setting only.

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}

113.EFF Figure 1
Quality assessment tools or criteria

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:

  • 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
Analysis and synthesis

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.

Result cards

Change-in management

Result card for EFF15: "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?"

View full card
EFF15: 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?
Result

Importance: Critical

Transferability: Completely

Result card for EFF7: "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?"

View full card
EFF7: 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?
Result

Importance: Important

Transferability: Completely

Result card for EFF6: "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?"

View full card
EFF6: 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?
Result

Importance: Important

Transferability: Completely

Function / HRQL (Health-related quality of life)

Result card for EFF3: "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?"

View full card
EFF3: 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?
Result

Importance: Critical

Transferability: Completely

Result card for EFF4: "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?"

View full card
EFF4: 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?
Result

Importance: Optional

Transferability: Partially

Patient satisfaction

Result card for EFF5: "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?"

View full card
EFF5: 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?
Result

Importance: Important

Transferability: Partially

Result card for EFF14: "Would the patient be willing to use the technology (uPA/PAI or Mammaprint or Oncotype test) again?"

View full card
EFF14: Would the patient be willing to use the technology (uPA/PAI or Mammaprint or Oncotype test) again?
Result

Importance: Critical

Transferability: Partially

Result card for EFF12: "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?"

View full card
EFF12: 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?
Result

Importance: Important

Transferability: Partially

Test-treatment chain

Result card for EFF9: "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)?"

View full card
EFF9: 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)?
Result

Importance: Critical

Transferability: Completely

Result card for EFF13: "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?"

View full card
EFF13: 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?
Result

Importance: Critical

Transferability: Completely

Morbidity

Result card for EFF11: "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?"

View full card
EFF11: 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?
Result

Importance: Critical

Transferability: Completely

Discussion

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.

References

  1. HTA Core Model Online Handbook, Version 1.3, from 20 Oct 2011.
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Appendices

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

pdf113.EFF Appendix 5

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

pdf113.EFF Appendix 6

Costs and economic evaluation

Authors: Isaura Vieira, Mirella Corio, Maria Rosaria Perrini, Matteo Ruggeri

Summary

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.

Introduction

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.

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
E0001Resource utilizationWhat types of resources are used when delivering the assessed technology and its comparators (resource use identification)?yesWhat 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?
E0002Resource utilizationWhat amounts of resources are used when delivering the assessed technology and its comparators (resource use measurement)?yesWhat 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?
E0003Unit costsWhat are the unit costs of the resources used when delivering the assessed technology and its comparators?yesWhat 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?
E0004Indirect CostsWhat is the impact of the technology on indirect costs?yesWhat is the impact of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® on indirect costs?
E0005OutcomesWhat are the incremental effects of the technology relative to its comparator(s)?yesWhat are the incremental effects of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® relative to standard clinical practice?
E0006Cost-effectivenessWhat is the incremental cost-effectiveness ratio?yesWhat is the incremental cost-effectiveness ratio of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint® compared to standard clinical practice?

Methodology description

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:

  • abstracts that referred to the project scope (PICO description above);
  • abstracts that referred to domain-specific issues (identification and quantification of resources, existence of economic model, reference to indirect costs, treatment guidelines);
  • studies presented in conferences or meetings that were only available in abstract or poster format were excluded.

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.

Result cards

Resource utilization

Result card for ECO1: "What types of resources are used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; and what types of resources are used when delivering standard clinical practice?"

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ECO1: What types of resources are used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; and what types of resources are used when delivering standard clinical practice?
Method
Frame
Result
Comment

Importance: Critical

Transferability: Completely

Result card for ECO2: "What quantity of resources is used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; and what quantity of resources are used when delivering standard clinical practice?"

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ECO2: What quantity of resources is used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; and what quantity of resources are used when delivering standard clinical practice?
Method
Result

Importance: Critical

Transferability: Partially

Unit costs

Result card for ECO3: "What are the unit costs of the resources used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; and what are the unit costs of the resources used when delivering standard clinical practice?"

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ECO3: What are the unit costs of the resources used when delivering uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; and what are the unit costs of the resources used when delivering standard clinical practice?
Method
Result

Importance: Critical

Transferability: Not

Indirect Costs

Result card for ECO4: "What is the impact of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; on indirect costs?"

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ECO4: What is the impact of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; on indirect costs?
Method
Result
Comment

Importance: Optional

Transferability: Not

Outcomes

Result card for ECO5: "What are the incremental effects of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; relative to standard clinical practice?"

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ECO5: What are the incremental effects of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; relative to standard clinical practice?
Method
Result
Comment

Importance: Critical

Transferability: Completely

Cost-effectiveness

Result card for ECO6: "What is the incremental cost-effectiveness ratio of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; compared to standard clinical practice?"

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ECO6: What is the incremental cost-effectiveness ratio of uPA/PAI-1 (Femtelle), OncotypeDx™ or MammaPrint&#174; compared to standard clinical practice?
Method
Result
Comment

Importance: Critical

Transferability: Partially

Discussion

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.

References

  1. Klang SH, Hammerman A, Liebermann N, Efrat N, Doberne J, Hornberger J. Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli-managed health-care organization. Value in Health. 2010; 13(4).
  2. Kondo M, Hoshi SL, Ishiguro H, Yoshibayashi H, Toi M. Economic evaluation of 21-gene reverse transcriptase-polymerase chain reaction assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer inJapan. Breast cancer research and treatment. 2008; 112(1): 175-187.
  3. Kondo M, Hoshi SL, Yamanaka T, Ishiguro H, Toi M. Economic evaluation of the 21-gene signature (Oncotype DX) in lymph node-negative/positive, hormone receptor-positive early-stage breast cancer based on Japanese validation study (JBCRG-TR03). Breast cancer research and treatment. 2011; 127(3): 739-749.
  4. Tsoi DT, Inoue M, Kelly CM, Verma S, Pritchard KI. Cost-effectiveness analysis of recurrence score-guided treatment using a 21-gene assay in early breast cancer. Oncologist. 2010; 15(5): 457- 465.
  5. Retel VP, Joore MA, Knauer M, Linn SC, Hauptmann M, Harten WH. Cost-effectiveness of the 70-gene signature versus St. Gallen guidelines and Adjuvant Online for early breast cancer. European Journal of Cancer. 2010; 46(8): 1382 - 1391.
  6. Chen E, Tong KB, Malin JL. Cost-effectiveness of 70-gene MammaPrint signature in node-negative breast cancer. American Journal of Managed Care. 2010 December; 16(12): e333-e342.
  7. Vanderlaan BF, Broder MS, Chang EY, Oratz R, Bentley TG. Cost-effectiveness of 21-gene assay in node-positive, early-stage breast cancer. American Journal of Managed Care. 2011 July; 17(7): 455- 464.
  8. Hornberger J, Cosler LE, Lyman GH. Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer. American Journal of Managed Care. 2005 May; 11(5): 313 – 324.
  9. Bacchi CE, Prisco F, Carvalho FM, Ojopi EB, Saad ED. Potential economic impact of the 21-gene expression assay on the treatment of breast cancer inBrazil. Revista da Associacao Medica Brasileira. 2010; 56(2): 186 – 191.
  10. Eng-Wong J, Isaacs C. Prediction of benefit from adjuvant treatment in patients with breast cancer. Clinical Breast Cancer. 2010 June; 10, Supplement 1: E32-E37.
  11. Kelly CM, Warner E, Tsoi DT, Verma S, Pritchard KI. Review of the clinical studies using the 21-gene assay. Oncologist. 2010; 15(5): 447 – 456.
  12. Drummond M, O’Brien B, Stoddart GL, TorranceGW. Methods for the economic evaluation of health care programs. Second edition.United States:OxfordUniversityPress; 1997
  13. NICE. Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat - Diagnostics consultation document [Internet]. 2012 January. Available from: http://www.nice.org.uk/nicemedia/live/13283/58040/58040.pdf

Appendices

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

   

Ethical analysis

Authors: Dario Sacchini, Roberta Minacori, Pietro Refolo

Summary

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.

  1. In this context, clinical utility is the likelihood that using a PTBCR 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.
  2. 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. It seems plausible that more women will benefit (i.e., to 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) who are moved to a lower level of risk as a result of using these tests, 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 the proportion of women with moderate to high risk, based on conventional risk assessments, that will have a “low enough” score to affect their decision about chemotherapy.

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:

  1. Up to now, through the studies available, 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 heterogeneous for these three tests. In addition, the three tests so far have had different frequencies of use in the USA and Europe.
  2. The few studies available suggest that, although both Oncotype DX and MammaPrint are costly and have high incremental cost-effectiveness ratios (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, and are, so far, inconclusive.

Introduction

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.

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
F0001Principal questions about the ethical aspects of technologyIs 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?yesAre 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?
F0002Principal questions about the ethical aspects of technologyCan the technology challenge religious, cultural or moral convictions or beliefs of some groups or change current social arrangements?yesCan uPA/PAI-1, Oncotype or Mammaprint challenge religious, cultural or moral convictions or beliefs of some groups or change current social arrangements?
F0003Principal questions about the ethical aspects of technologyWhat can be the hidden or unintended consequences of the technology and its applications for different stakeholders.yesWhat can be the hidden or unintended consequences of uPA/PAI-1, Oncotype or Mammaprint and its applications for different stakeholders?
F0005AutonomyIs the technology used for patients/people that are especially vulnerable?yesAre uPA/PAI-1, Oncotype or Mammaprint used for patients that are especially vulnerable?
F0006AutonomyCan the technology entail special challenges/risk that the patient/person needs to be informed of?yesCan uPA/PAI-1, Oncotype or Mammaprint entail special challenges/risk that the patient/person needs to be informed of?
F0007AutonomyDoes the implementation challenge or change professional values, ethics or traditional roles?yesDoes the use of uPA/PAI-1, Oncotype or Mammaprint challenge or change professional values, ethics or traditional roles?
F0004AutonomyDoes the implementation or use of the technology challenge patient autonomy?noThe 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
F0008Human DignityDoes the implementation or use of the technology affect human dignity?yesDoes the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human dignity?
F0009Human integrityDoes the implementation or use of the technology affect human integrity?yesDoes the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human integrity?
F0010Beneficence/nonmaleficenceWhat 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?yesWhat 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?
F0011Beneficence/nonmaleficenceCan 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?yesCan 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?
F0012Justice and EquityWhat are the consequences of implementing / not implementing the technology on justice in the health care system? Are principles of fairness, justness and solidarity respected?yesWhat 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?
F0013Justice and EquityHow are technologies presenting with relevantly similar (ethical) problems treated in health care system?yesHow are technologies presenting with relevantly similar (ethical) problems treated in health care system?
F0014RightsDoes the implementation or use of the technology affect the realisation of basic human rights?yesDoes the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect the realisation of basic human rights?
F0016LegislationIs legislation and regulation to use the technology fair and adequate?yesIs legislation and regulation to use Genetic Test fair and adequate?
F0017Questions about effectiveness and accuracyWhat are the proper end-points for assessment and how should they be investigated?yesWhat are the proper end-points for assessment and how should they be investigated?
F0018Questions about effectiveness and accuracyAre the accuracy measures decided and balanced on a transparent and acceptable way?yesAre the accuracy measures decided and balanced on a transparent and acceptable way?

Methodology description

Information sources

The Ethical domain relies on information from the following sources.

  1. The result cards of other domains in this project (from published data, preferably) for most of the ethical issues involved.
  2. “ad hoc” specific ethics literature (from published data, preferably) directly or indirectly linked to the object of the analysis, if available on general and specific databases (cf. below). If not, literature on issues analogous to the matter under discussion was considered. Particularly, on 19 and 26 March 2012 The search strategy for PubMed (www.pubmed.gov) was constructed using a search module for “ethics” literature and combining it with a search module of medical subjects headings (MESH) and other relevant terms as: ethics OR bioethics; breast cancer, early stage, recurrence risk, adjuvant therapy, decision making, risk communication gene expression profiling, and Oncotype DX, Mammaprint, uPA/PAI-1. We supplemented this search by updating searches in PubMed and by hand searching additional publications that appeared after the initial search (March 2012–April 2012). We reviewed titles and abstracts to identify original data studies or systematic reviews or recommendations from a scientific group, that involved the use of any of the three assays in women with early-stage breast cancer.

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.

Result cards

Principal questions about the ethical aspects of technology

Result card for ETH1: "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?"

View full card
ETH1: 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?
Result

Importance: Critical

Transferability: Completely

Result card for ETH2: "Can uPA/PAI-1, Oncotype or Mammaprint challenge religious, cultural or moral convictions or beliefs of some groups or change current social arrangements?"

View full card
ETH2: Can uPA/PAI-1, Oncotype or Mammaprint challenge religious, cultural or moral convictions or beliefs of some groups or change current social arrangements?
Result

Importance: Unspecified

Transferability: Unspecified

Result card for ETH3: "What can be the hidden or unintended consequences of uPA/PAI-1, Oncotype or Mammaprint and its applications for different stakeholders?"

View full card
ETH3: What can be the hidden or unintended consequences of uPA/PAI-1, Oncotype or Mammaprint and its applications for different stakeholders?
Result

Importance: Unspecified

Transferability: Unspecified

Autonomy

Result card for ETH4: "Are uPA/PAI-1, Oncotype or Mammaprint used for patients that are especially vulnerable?"

View full card
ETH4: Are uPA/PAI-1, Oncotype or Mammaprint used for patients that are especially vulnerable?
Result

Importance: Unspecified

Transferability: Unspecified

Result card for ETH5: "Can uPA/PAI-1, Oncotype or Mammaprint entail special challenges/risk that the patient/person needs to be informed of?"

View full card
ETH5: Can uPA/PAI-1, Oncotype or Mammaprint entail special challenges/risk that the patient/person needs to be informed of?
Result

Importance: Critical

Transferability: Completely

Result card for ETH6: "Does the use of uPA/PAI-1, Oncotype or Mammaprint challenge or change professional values, ethics or traditional roles?"

View full card
ETH6: Does the use of uPA/PAI-1, Oncotype or Mammaprint challenge or change professional values, ethics or traditional roles?
Result

Importance: Important

Transferability: Completely

Human Dignity

Result card for ETH7: "Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human dignity?"

View full card
ETH7: Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human dignity?
Result

Importance: Unspecified

Transferability: Unspecified

Human integrity

Result card for ETH8: "Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human integrity?"

View full card
ETH8: Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect human integrity?
Result

Importance: Unspecified

Transferability: Unspecified

Beneficence/nonmaleficence

Result card for ETH9: "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?"

View full card
ETH9: 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?
Result

Importance: Critical

Transferability: Completely

Result card for ETH10: "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?"

View full card
ETH10: 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?
Result

Importance: Unspecified

Transferability: Unspecified

Justice and Equity

Result card for ETH11: "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?"

View full card
ETH11: 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?
Result

Importance: Important

Transferability: Completely

Result card for ETH12: "How are technologies presenting with relevantly similar (ethical) problems treated in health care system?"

View full card
ETH12: How are technologies presenting with relevantly similar (ethical) problems treated in health care system?
Result

Importance: Unspecified

Transferability: Unspecified

Rights

Result card for ETH13: "Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect the realisation of basic human rights?"

View full card
ETH13: Does the implementation or use of uPA/PAI-1, Oncotype or Mammaprint affect the realisation of basic human rights?
Result

Importance: Unspecified

Transferability: Unspecified

Legislation

Result card for ETH14: "Is legislation and regulation to use Genetic Test fair and adequate?"

View full card
ETH14: Is legislation and regulation to use Genetic Test fair and adequate?
Result

Importance: Unspecified

Transferability: Unspecified

Questions about effectiveness and accuracy

Result card for ETH15: "What are the proper end-points for assessment and how should they be investigated?"

View full card
ETH15: What are the proper end-points for assessment and how should they be investigated?
Result

Importance: Important

Transferability: Partially

Result card for ETH16: "Are the accuracy measures decided and balanced on a transparent and acceptable way?"

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ETH16: Are the accuracy measures decided and balanced on a transparent and acceptable way?
Result

Importance: Important

Transferability: Completely

Discussion

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.

References

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Organisational aspects

Authors: Jennifer Butt, Marco Marchetti, Angelica Carletto, Americo Cicchetti, Chiara Filippi

Summary

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:

  • Care must be taken with the excision of the tissue sample.
  • If tissue is normally gathered and selected in one way (such as formalin-fixed paraffin embedded), then the need for a different process (such as fresh frozen) could be a significant obstacle for introducing a given test.
  • Coordination is needed between the various units involved in carrying out the tests and using the results.
  • Cost may be a deterrent factor, particularly in the case of MammaPrint® and Oncotype DX®.
  • Additional effort may be needed in communicating with patients to ensure that they understand about genetic and prognostic tests in general, as well as about the specific test they undergo.

Introduction

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.

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
G0001ProcessWhat kind of work flow and patient flow processes are needed?yesWhat work flow and patient flow processes are needed to use the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) on women with invasive breast cancer?
G0003ProcessWhat kind of staff, training and other human resources is required?yesWhat 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?
G0004ProcessWhat kind of co-operation and communication of activities have to be mobilised?yesWhat 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?
G0002ProcessWhat kind of patient and relative involvement in treatment or care has to be mobilized?noThis is appropriate for the social domain, not the organisational domain
G0005StructureWhat consequences the implementation of the new technology will have in respect of decentralisation or centralisation?yesWhat are the advantages and disadvantages of providing the tests centrally or locally?
G0006StructureWhat kinds of investments are needed (material or premises)?yesWhat 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?
G0007StructureWhat is the likely budget impact of the implementation of the technology for the payers (e.g. government)?noThis question should be included in the ECO domain, not the ORG domain
G0008ManagementWhat management problems and opportunities are attached to the new technology?yesWhat management problems and opportunities are attached to use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)?
G0009ManagementWho decides which patients are to undergo a treatment and on what basis?yesWho decides which women are eligible for the tests and on what basis (e.g. likelihood of cancer recurrence)?
G0010CultureHow is the new technology accepted?yesHow are the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) accepted by healthcare professionals and other staff?
G0011CultureHow will the other interest groups of the new technology be taken into account in the planning / implementation of the new technology?yesHow 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)?

Methodology description

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. A literature search and review of the results
  2. An electronic survey of clinicians and administrators
  3. Grey literature searches

1.  Literature search and review

The literature search was carried out in two stages:

  1. A literature search was carried out for the Core HTA (see {COL-1} for more details). This search identified 616 articles that were appropriate for this HTA.
  2. The 616 articles were reviewed by hand by one reviewer who used the following inclusion criteria:
  • include all HTA reports
  • include all economic studies (in case they contained information about work flow, patient flow, investment needed, etc)
  • include articles where the abstract referred to organisational issues
  • include studies that were carried out to detect the acceptability of the test among professionals

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.

Result cards

Process

Result card for ORG1: "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? "

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ORG1: 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?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for ORG2: "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? "

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ORG2: 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?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for ORG3: "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?"

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ORG3: 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?
Method
Result
Comment

Importance: Important

Transferability: Completely

Structure

Result card for ORG4: "What are the advantages and disadvantages of providing the tests centrally or locally?"

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ORG4: What are the advantages and disadvantages of providing the tests centrally or locally?
Method
Result
Comment

Importance: Important

Transferability: Partially

Result card for ORG5: "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?"

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ORG5: 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?
Method
Result

Importance: Important

Transferability: Partially

Management

Result card for ORG7: "What management problems and opportunities are attached to use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)?"

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ORG7: What management problems and opportunities are attached to use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)?
Method
Result
Comment

Importance: Critical

Transferability: Partially

Result card for ORG8: "Who decides which women are eligible for the tests and on what basis (e.g. likelihood of cancer recurrence)?"

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ORG8: Who decides which women are eligible for the tests and on what basis (e.g. likelihood of cancer recurrence)?
Method
Result
Comment

Importance: Important

Transferability: Partially

Culture

Result card for ORG9: "How are the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) accepted by healthcare professionals and other staff?"

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ORG9: How are the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) accepted by healthcare professionals and other staff?
Method
Result
Comment

Importance: Important

Transferability: Partially

Result card for ORG10: "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)?"

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ORG10: 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)?
Method
Result
Comment

Importance: Important

Transferability: Partially

Discussion

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.

References

  1. Medical AS. Gene expression profiling for guiding adjuvant chemotherapy decisions in women with early breast cancer : an evidence-based and economic analysis 9. 2010. Canada, Toronto: Medical Advisory Secretariat, Ontario Ministry of Health and Long-Term Care (MAS).
  2. Mayordomo JI, Roig AM, Rolfo CD, Morales S, Glas A, Floore A et al. Feasibility of using core needle biopsies for the 70-gene prognosis signature 1282. Annals of Oncology 2008; Conference: 34th Congress of the European Society for Medical Oncology(ESMO).
  3. American Diagnostica FEMTELLE product insert, ref. 899CEIE©ADI2005rev0524
  4. Harbeck N, Thomssen C. A new look at node-negative breast cancer. Oncologist 2010; 15.
  5. Mook S, Bonnefoi H, Pruneri G, Larsimont D, Jaskiewicz J, Sabadell MD et al. Daily clinical practice of fresh tumour tissue freezing and gene expression profiling; logistics pilot study preceding the MINDACT trial. European Journal of Cancer 2009; 45(7).
  6. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal of Clinical Oncology 2007; 25(33).
  7. Mook S, Van't Veer LJ, Rutgers EJ, Piccart-Gebhart MJ, Cardoso F. Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics & Proteomics 2007; 4(3).
  8. National Cancer Institute [Internet]. Bethesda, MD, USA. [Accessed 20 March 2012] Available from: http://www.cancer.gov/cancertopics/understandingcancer/genetesting.
  9. Bueno-de-Mesquita JM, van Harten WH, Retel VP, Van't Veer LJ, van Dam FS, Karsenberg K et al. Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER).[Erratum appears in Lancet Oncol. 2008 Jan;9(1):10]. Lancet Oncology 2007; 8(12).
  10. Retel VP, Bueno-de-Mesquita JM, Hummel MJ, van de Vijver MJ, Douma KF, Karsenberg K et al. Constructive Technology Assessment (CTA) as a tool in coverage with evidence development: the case of the 70-gene prognosis signature for breast cancer diagnostics. International Journal of Technology Assessment in Health Care 2009; 25(1).
  11. Berg AO, Armstrong K, Botkin J, Calonge N, Haddow J, Hayes M et al. Recommendations from the EGAPP Working Group: Can tumor gene expression profiling improve outcomes in patients with breast cancer? Genetics in Medicine 2009; 11(1).
  12. Breast Centres Network [Internet]. Milan, Italy. [Accessed 20 March 2012] Available from: http://www.breastcentresnetwork.org/.
  13. Marchionni L, Wilson RF, Marinopoulos SS, Wolff AC, Parmigiani G, Bass EB et al. Impact of gene expression profiling tests on breast cancer outcomes. Evidence Report/Technology Assessment 2007;(160).
  14. National Horizon Scanning Centre. MammaPrint (gene test) for breast cancer - prognostic test: horizon scanning technology briefing (Project record) 94. Birmingham: National Horizon Scanning Centre (NHSC) 2009.
  15. Li X, Quigg RJ, Zhou J, Gu W, Nagesh RP, Reed EF. Clinical utility of microarrays: Current status, existing challenges and future outlook 1319. Current Genomics 2008; 9(7).
  16. Cronin M, Sangli C, Liu ML, Pho M, Dutta D, Nguyen A et al. Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. Clinical Chemistry 2007; 53(6).
  17. Colozza M, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ. Bringing molecular prognosis and prediction to the clinic. Clinical Breast Cancer 2005; 6(1).
  18. Ross JS, Hatzis C, Symmans WF, Pusztai L, Hortobagyi GN. Commercialized multigene predictors of clinical outcome for breast cancer. Oncologist 2008; 13(5).
  19. Ross JS. Multigene classifiers, prognostic factors, and predictors of breast cancer clinical outcome. Advances in Anatomic Pathology 2009; 16(4).
  20. Hornberger J, Chien R, Kreb K, Hochheiser LI. Economics of a multi-gene assay to predict recurrence of early stage breast cancer: Experience of a large United States insurance program 97. Value in Health 2011; Conference: 16th Annual International Meeting of the International Society for Pharmacoeconomics and Outcomes Research, ISPOR 2011 Baltimore, MD United States.
  21. Kondo M, Hoshi SL, Ishiguro H, Yoshibayashi H, Toi M. Economic evaluation of 21-gene reverse transcriptase-polymerase chain reaction assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer in Japan 1369. Breast cancer research and treatment 2008; 112(1).
  22. Klang SH, Hammerman A, Liebermann N, Efrat N, Doberne J, Hornberger J. Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli-managed health-care organization. Value in Health 2010; 13(4).
  23. Hayes DF. Markers of increased risk for failure of adjuvant therapies. Breast 2003; 12(6).
  24. American Diagnostica [Internet]. Pfungstadt, Germany. [Accessed 21 May 2012] Available from: http://www.femtelle.de/en/physicians/about-femtelle/clinical-routine-testing/
  25. Palmer G, Baehner FL, Bugarini R, Harness JK. The distribution of recurrence scores and other parameters in oncotype DX submissions by surgeons compared to medical oncologists 513. Annals of Surgical Oncology 2010; Conference: 11th Annual Meeting of the American Society of Breast Surgeons Las Vegas, NV United States.
  26. Gradishar WJ, Hansen NM, Susnik B. A multidisciplinary approach to the use of Oncotype DX in clinical practice 1179. Clinical Advances in Hematology and Oncology 2009; 7(4 SUPPL. 9).
  27. Tuma RS, Chlebowski R, Elias AD. Should breast cancer patients with low-risk, node-positive disease have gene profiling to help with decision making? Oncology Times 2009; 31(18).
  28. Henry LR, Stojadinovic A, Swain SM, Prindiville S, Cordes R, Soballe PW. The influence of a gene expression profile on breast cancer decisions. Journal of Surgical Oncology 2009; 99(6).
  29. Lo SS, Mumby PB, Norton J, Rychlik K, Smerage J, Kash J 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. Journal of Clinical Oncology 2010; 28(10).
  30. Oratz R, Kim B, Chao C, Skrzypczak S, Ory C, Bugarini R 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/American Society of Clinical Oncology 2011; 7(2).
  31. Trosman JR, Van Bebber SL, Phillips KA. Coverage policy development for personalized medicine: private payer perspectives on developing policy for the 21-gene assay. Journal of oncology practice/American Society of Clinical Oncology 2010; 6(5).
  32. Institute of Medicine. Generating Evidence for Genomic Diagnostic Test Development. Workshop Summary. Institute of Medicine (US) Roundtable on Translating Genomic-Based Research for Health. Washington (DC): National Academies Press (US); 2011.

Social aspects

Authors: Pseudo85 Pseudo85, Pseudo84 Pseudo84

Summary

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.

Introduction

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).

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
H0001Major life areasWhich social areas does the use of the technology influence?yesIn 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?
H0002Major life areasWho are the important others that the use of the technology may affect in addition to the patient?yesWho are the important others that the use of Genetic Test for breast cancer may affect in addition to the patient?
H0003Major life areasWhat kind of support and resources are needed or might be released as the technology is put to use?yesWhat 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?
H0004Major life areasWhat kinds of changes does the use of the technology generate in the patient's role in the major life areas?noIt is incorporated in question H0001.
H0005Major life areasWhat 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?noIt is incorporated in questions H0001 and H0003
H0006IndividualHow do patients and important others react and act upon the technology?yesHow do women with invasive breast cancer and important others react and act upon the Genetic Test for breast cancer ?
H0007CommunicationWhat is patients' and important others’ knowledge and understanding of the technology?yesWhat is patients' and important others’ knowledge and understanding of Genetic Test for breast cancer?
H0008CommunicationHow is the information regarding the use of the technology processed and exchanged?yesHow is the information regarding the use of Genetic Test for breast cancer processed and exchanged?
H0009CommunicationWhat are the consequences in decision making?yesWhat are the consequences in decision making?

Methodology description

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:

  • included women diagnosed with early invasive breast cancer (stage I, II or III)
  • investigated at least one of these  prognostic tests: uPA/PAI-1, Oncotype DX or MammaPrint
  • analysed and reported results of any of these social issues: support and communication needs, working life, family life, social life, values, attitudes, self-concept, patient preferences, knowledge about prognostic tests
  • study designs: systematic reviews or any kind of empirical studies that studied some of the social issues

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}.

Result cards

Major life areas

Result card for SOC1: "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?"

View full card
SOC1: 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?
Method
Result
Comment

Importance: Optional

Transferability: Completely

Result card for SOC2: "Who are the important others that the use of Genetic Test for breast cancer may affect in addition to the patient?"

View full card
SOC2: Who are the important others that the use of Genetic Test for breast cancer may affect in addition to the patient?
Method
Result

Importance: Optional

Transferability: Unspecified

Result card for SOC3: "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? "

View full card
SOC3: 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?
Method
Result

Importance: Important

Transferability: Completely

Individual

Result card for SOC4: "How do women with invasive breast cancer and important others react and act upon the Genetic Test for breast cancer ?"

View full card
SOC4: How do women with invasive breast cancer and important others react and act upon the Genetic Test for breast cancer ?
Method
Result
Comment

Importance: Important

Transferability: Completely

Communication

Result card for SOC5: "What is patients&#39; and important others’ knowledge and understanding of Genetic Test for breast cancer?"

View full card
SOC5: What is patients&#39; and important others’ knowledge and understanding of Genetic Test for breast cancer?
Method
Result
Comment

Importance: Important

Transferability: Partially

Result card for SOC6: "How is the information regarding the use of Genetic Test for breast cancer processed and exchanged?"

View full card
SOC6: How is the information regarding the use of Genetic Test for breast cancer processed and exchanged?
Method
Result
Comment

Importance: Critical

Transferability: Completely

Result card for SOC7: "What are the consequences in decision making?"

View full card
SOC7: What are the consequences in decision making?
Method
Result
Comment

Importance: Important

Transferability: Completely

Discussion

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.

References

  1. Berg AO, Armstrong K, Botkin J, Calonge N, Haddow J, Hayes M et al. Recommendations from the EGAPP Working Group: Can tumor gene expression profiling improve outcomes in patients with breast cancer? Genetics in Medicine 2009; 11(1).
  2. Gradishar WJ, Hansen NM, Susnik B. A multidisciplinary approach to the use of Oncotype DX in clinical practice 1179. Clinical Advances in Hematology and Oncology 2009; 7(4 SUPPL. 9).
  3. Guyatt Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P et al. GRADE: an emerging consensus on rating quality of evidence and strength of reccomendations. BMJ. 2008;336:924-6
  4. HTA Core Model Online Handbook, Version 1.3, from 20 Oct 2011.
  5. Lillie SE, Brewer NT, O'Neill SC. Literacy Information from Genomic Tests: The Role of Health Retention and Use of Breast Cancer Recurrence Risk. Cancer Epidemiol Biomarkers Prev 2007;16:249-255. Published online January 30, 2007.
  6.  Lo SS, Mumby PB, Norton J, Rychlik K, Smerage J, Kash J 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. Journal of Clinical Oncology 2010; 28(10).
  7. National Health and Medical Research Council, Australian Government. Communicating with Patients. Advice for medical practitioners. Commonwealth of Australia, 2004. Available on: http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/e58.pdf (April 2012).
  8. Palmer G, Baehner FL, Bugarini R, Harness JK. The distribution of recurrence scores and other parameters in oncotype DX submissions by surgeons compared to medical oncologists 513. Annals of Surgical Oncology 2010; Conference: 11th Annual Meeting of the American Society of Breast Surgeons Las Vegas, NV United States. Conference Start: 20100428 Conference End: 20100502. Conference Publication:(var.pagings).
  9. Retel VP, Bueno-de-Mesquita JM, Hummel MJ, van de Vijver MJ, Douma KF, Karsenberg K et al. Constructive Technology Assessment (CTA) as a tool in coverage with evidence development: the case of the 70-gene prognosis signature for breast cancer diagnostics. International Journal of Technology Assessment in Health Care 2009; 25(1).
  10. Richman AR, Tzeng JP, Carey LA, Rete VP, Brewer NT. Knowledge of genomic testing among early-stage breast cancer patients. Psycho-Oncology 20: 28–35 (2011)
  11. Tzeng JB, Mayer D, Richman AR, Lipkus I, Han PK, Valle CG, Carey LA, Brewer NT. Women’s Experiences With Genomic Testing for Breast Cancer Recurrence Risk. Cancer April 15, 2010.

Appendices

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.

  • The topic for which women (over 90%) wanted the most information was treatment

- Preference for Active Participation in Decision Making.

  • 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 (P = 0.03).
  • women with higher health literacy indicated they preferred active participation in the decision to use the results of the recurrence risk test to make treatment decisions more than women with lower health literacy (P <0.001).

Reviewers' comments or other notes

None

Quality level (GRADE)

Low/Moderate


Authors: Marina Casini, Emanuela Midolo, Marco Marchetti

Summary

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.

Introduction

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.

Methodology

Frame

The collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description

Urokinase 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 technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment 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 population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard 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.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
I0002Autonomy of the patientCan patients understand the implications of using/not using the technology?yesCan patients understand the implications of using/not using Genetic Test for breast cancer?
I0003Autonomy of the patientAre there relevant optional technologies that future patients should be allowed to consider?yesAre there relevant optional technologies that future patients should be allowed to consider?
I0004Autonomy of the patientIs it possible to give future patients enough time to consider their decisions?yesIs it possible to give future patients enough time to consider their decisions?
I0005Autonomy of the patientIs it possible to obtain an advance directive on the use of the technology?noNot applicable for genetic tests.
I0009Privacy of the patientCan the access to the patient data secured properly?yesCan the access to the patient data secured properly?
I0010Privacy of the patientWhat levels of access to which kind of patient information exist in the chain of care?yesWhat levels of access to which kind of patient information exist in the chain of care?
I0007Privacy of the patientDoes the use of the technology produce some additional (i.e. diagnostically or therapeutically irrelevant) information on the patient?yesDoes the use of Genetic Tests for breast cancer produce some additional (i.e. diagnostically or therapeutically irrelevant) information on the patient?
I0008Privacy of the patientDoes the use of the technology produce information that would be relevant for the relatives of the patient?yesDoes the use of Genetic Test for breast cancer produce information that would be relevant for the relatives of the patient?
I0033Privacy of the patientDoes the use of the technology produce such information on the patient that is not directly relevant to the current disease/condition?noIt is incorporated in question I0007.
I0011Equality in health careIs the technology equally accessible to all needing members in a given society?yesAre the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) equally accessible to all women with invasive breast cancer in the society?
I0012Equality in health careIs the technology subsidized by the society?yesAre the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) subsidized by the society?
I0013Equality in health careIs there a wide variation in the acceptability of the technology across Europe?yesIs there a wide variation in the acceptability of Genetic Test for breast cancer across Europe?
I0014Equality in health careIs health-care tourism expected from/to other European countries?yesIs health-care tourism expected from/to other European countries?
I0015Authorisation & safetyHas the technology national/EU level authorisation?yesHave Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) national/EU level authorisation?
I0016Authorisation & safetyDoes the technology need to be listed in a national/EU register?yesDo Genetc Tests for breast cancer need to be listed in a national/EU register?
I0017Authorisation & safetyDoes the technology fulfil product safety requirements?yesDo Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill product safety requirements?
I0018Authorisation & safetyDoes the technology fulfil tissue safety requirements?yesDo Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill tissue safety requirements?
I0019Ownership & liabilityDoes the technology infringe some intellectual property right?yesDo Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) infringe some intellectual property right?
I0020Ownership & liabilityDoes the introduction of the technology presume some additional licensing fees to be paid?yesDoes the introduction of Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) presume some additional licensing fees to be paid?
I0021Ownership & liabilityWhat are the width, depth and length of the manufacturers guarantee?yesWhat are the width, depth and length of the manufacturers guarantee?
I0022Ownership & liabilityIs the user guide of the technology comprehensive enough?yesIs the user guide of Genetic Test (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) comprehensive enough?
I0023Regulation of the marketIs the technology subject to price control?yesAre Genetic Tests for beast cancer subject to price control?
I0024Regulation of the marketIs the technology subject to acquisition regulation?yesAre Genetic Tests for breast cancer subject to acquisition regulation?
I0025Regulation of the marketIs the marketing of the technology to the patients restricted?yesIs the marketing of Genetic Tests for breast cancer to the patients restricted?
I0026Legal regulation of novel/experimental techniquesIs the technology so novel existing legislation was not designed to cover its regulation?yesAre Genetic Tests for breast cancer so novel existing legislation was not designed to cover its regulation?
I0027Legal regulation of novel/experimental techniquesHow the liability issues are solved according to existing legislation?yesHow the liability issues are solved according to existing legislation?
I0028Legal regulation of novel/experimental techniquesAre new legislative measures needed?yesAre new legislative measures needed?
I0029Legal regulation of novel/experimental techniquesIs the voluntary participation of patients guaranteed properly?yesIs the voluntary participation of patients guaranteed properly?
I0030End-userWho is the intended end-user of the technology?yesWho is the intended end-user of Genetic Test for breast cancer?
I0031End-userIs the use of the technology limited in legislation?yesIs the use of Genetic Test for breast cancer limited in legislation?
I0032End-userIs the health care personnel using the technology according the professional standards?yesIs the health care personnel using Genetic Test for breast cancer according the professional standards?

Methodology description

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.

Result cards

Autonomy of the patient

Result card for LEG1: "Can patients understand the implications of using/not using Genetic Test for breast cancer?"

View full card
LEG1: Can patients understand the implications of using/not using Genetic Test for breast cancer?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG2: "Are there relevant optional technologies that future patients should be allowed to consider?"

View full card
LEG2: Are there relevant optional technologies that future patients should be allowed to consider?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG3: "Is it possible to give future patients enough time to consider their decisions?"

View full card
LEG3: Is it possible to give future patients enough time to consider their decisions?
Method
Result

Importance: Important

Transferability: Completely

Privacy of the patient

Result card for LEG6: "Can the access to the patient data secured properly?"

View full card
LEG6: Can the access to the patient data secured properly?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG7: "What levels of access to which kind of patient information exist in the chain of care?"

View full card
LEG7: What levels of access to which kind of patient information exist in the chain of care?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG4: "Does the use of Genetic Tests for breast cancer produce some additional (i.e. diagnostically or therapeutically irrelevant) information on the patient?"

View full card
LEG4: Does the use of Genetic Tests for breast cancer produce some additional (i.e. diagnostically or therapeutically irrelevant) information on the patient?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG5: "Does the use of Genetic Test for breast cancer produce information that would be relevant for the relatives of the patient?"

View full card
LEG5: Does the use of Genetic Test for breast cancer produce information that would be relevant for the relatives of the patient?
Method
Result

Importance: Important

Transferability: Completely

Equality in health care

Result card for LEG8: "Are the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) equally accessible to all women with invasive breast cancer in the society?"

View full card
LEG8: Are the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) equally accessible to all women with invasive breast cancer in the society?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG9: "Are the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) subsidized by the society?"

View full card
LEG9: Are the Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) subsidized by the society?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for LEG10: "Is there a wide variation in the acceptability of Genetic Test for breast cancer across Europe?"

View full card
LEG10: Is there a wide variation in the acceptability of Genetic Test for breast cancer across Europe?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG11: "Is health-care tourism expected from/to other European countries?"

View full card
LEG11: Is health-care tourism expected from/to other European countries?
Method
Result

Importance: Important

Transferability: Completely

Authorisation & safety

Result card for LEG12: "Have Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) national/EU level authorisation?"

View full card
LEG12: Have Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) national/EU level authorisation?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG13: "Do Genetc Tests for breast cancer need to be listed in a national/EU register?"

View full card
LEG13: Do Genetc Tests for breast cancer need to be listed in a national/EU register?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for LEG14: "Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill product safety requirements?"

View full card
LEG14: Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill product safety requirements?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG15: "Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill tissue safety requirements?"

View full card
LEG15: Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) fulfill tissue safety requirements?
Method
Result

Importance: Important

Transferability: Completely

Ownership & liability

Result card for LEG16: "Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) infringe some intellectual property right?"

View full card
LEG16: Do Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) infringe some intellectual property right?
Method
Result

Importance: Optional

Transferability: Partially

Result card for LEG17: "Does the introduction of Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) presume some additional licensing fees to be paid?"

View full card
LEG17: Does the introduction of Genetic Tests (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) presume some additional licensing fees to be paid?
Method
Result

Importance: Critical

Transferability: Completely

Result card for LEG18: "What are the width, depth and length of the manufacturers guarantee?"

View full card
LEG18: What are the width, depth and length of the manufacturers guarantee?
Method
Result

Importance: Optional

Transferability: Completely

Result card for LEG19: "Is the user guide of Genetic Test (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) comprehensive enough?"

View full card
LEG19: Is the user guide of Genetic Test (uPA/PAI-1 ELISA/ Oncotype DX/ MammaPrint) comprehensive enough?
Method
Result

Importance: Important

Transferability: Completely

Regulation of the market

Result card for LEG20: "Are Genetic Tests for beast cancer subject to price control?"

View full card
LEG20: Are Genetic Tests for beast cancer subject to price control?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG21: "Are Genetic Tests for breast cancer subject to acquisition regulation?"

View full card
LEG21: Are Genetic Tests for breast cancer subject to acquisition regulation?
Method
Result

Importance: Important

Transferability: Not

Result card for LEG22: "Is the marketing of Genetic Tests for breast cancer to the patients restricted?"

View full card
LEG22: Is the marketing of Genetic Tests for breast cancer to the patients restricted?
Method
Result

Importance: Important

Transferability: Completely

Legal regulation of novel/experimental techniques

Result card for LEG23: "Are Genetic Tests for breast cancer so novel existing legislation was not designed to cover its regulation?"

View full card
LEG23: Are Genetic Tests for breast cancer so novel existing legislation was not designed to cover its regulation?
Method
Result

Importance: Critical

Transferability: Completely

Result card for LEG24: "How the liability issues are solved according to existing legislation?"

View full card
LEG24: How the liability issues are solved according to existing legislation?
Method
Result

Importance: Important

Transferability: Completely

Result card for LEG25: "Are new legislative measures needed?"

View full card
LEG25: Are new legislative measures needed?
Method
Result
Comment

Importance: Critical

Transferability: Completely

Result card for LEG26: "Is the voluntary participation of patients guaranteed properly?"

View full card
LEG26: Is the voluntary participation of patients guaranteed properly?
Method
Result

Importance: Important

Transferability: Completely

End-user

Result card for LEG27: "Who is the intended end-user of Genetic Test for breast cancer?"

View full card
LEG27: Who is the intended end-user of Genetic Test for breast cancer?
Method
Result

Importance: Optional

Transferability: Unspecified

Result card for LEG28: "Is the use of Genetic Test for breast cancer limited in legislation?"

View full card
LEG28: Is the use of Genetic Test for breast cancer limited in legislation?
Method
Result

Importance: Critical

Transferability: Completely

Result card for LEG29: "Is the health care personnel using Genetic Test for breast cancer according the professional standards?"

View full card
LEG29: Is the health care personnel using Genetic Test for breast cancer according the professional standards?
Method
Result

Importance: Important

Transferability: Completely

Discussion

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.

References

  1. COUNCIL OF EUROPE, Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine, Oviedo, 4-IV-1997.
  2. COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Genetic Testing for Health Purposes, Strasbourg, 27-XI-2008.
  3. COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, Strasbourg, 25-I-2005.
  4. WORLD MEDICAL ASSOCIATION, Declaration of Helsinki, Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, South Africa, October 1996; 52nd WMA General Assembly, Edinburgh, Scotland, October 2000; 53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification on paragraph 29 added); 55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification on Paragraph 30 added); 59th WMA General Assembly, Seoul, Korea, October 2008.
  5. EUROPEAN PARLIAMENT AND COUNCIL, Directive 2001/20/EC of 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.
  6. UNESCO, Universal Declaration on the Human Genome and Human Rights, 11 November 1997.
  7. EUROPEAN CONVENTION FOR THE PROTECTION OF HUMAN RIGHTS AND FUNDAMENTAL FREEDOMS, Rome 4.XI.1950.
  8. EUROPEAN PARLIAMENT AND COUNCIL, Directive 95/46/EC of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data.
  9. COURT OF JUSTICE OF EUROPEAN UNION, Judgement 20 May 2003, Joined Case C-465/00, C-138/01, C-139/01.
  10. COMMISSION, White Paper "Together for Health: A Strategic Approach for the EU 2008-2013, COM (2007) 630.
  11. EUROPEAN COURT OF JUSTICE, Sentence of 16.05.04 (C-372/04).
  12. COMMISSION OF THE EUROPEAN COMMUNITIES, Brussels 24.06.2009, Communication From The Commission To The European Parliament, The Council, The European Economic And Social Committee And The Committee Of The Regions: An Action Against Cancer: European Partnership.
  13. EUROPEAN CODE AGAINST CANCER.
  14. EUROPEAN COMMISSION, White paper of the “Together for Health: A Strategic Approach for the EU 2008-2013”.
  15. COMMISSION TO THE COUNCIL, THE EUROPEAN PARLIAMENT, THE EUROPEAN ECONOMIC AND SOCIAL COMMITTEE AND THE COMMITTEE OF THE REGIONS E-HEALTH - Communication making healthcare better for European citizens: An action plan for a European e-Health Area.
  16. 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)
  17. Council Recommendation on a European action in the field of rare diseases from 11.11.2008.
  18. P5_TA(2003)0270 breast cancer, the Resolution of European Parliament on breast cancer in the UE (2002/2279(INI))
  19. Recommendation no. R (89) 13 of the Committee of Ministers to Member States on the Organisation of Multidisciplinary care for cancer patients del 24.10.1989
  20. Recommendation no. r (80) 6 of the Committee of Ministers to Member States concerning cancer control del 30.4.1980
  21. Directive CEE/CEEA/CE n° 79 del 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
  22. Communication from the Commission Consultation regarding Community action in health services, 26.9.2006
  23. 2011/24/UE Directive of the European Parliament and the Council of 9 March 2011concerning the application of patients' rights in cross-border healthcare
  24. Recommendation Rec (2006)18 of the Committee of Ministers to member states on health services in a multicultural society from 8.11.2006
  25. Council of the European Union Directive on cross-border healthcare adopted 28.2.2011
  26. European Court calls our attention to the judgment of the Court of Justice of the European Union 28.04.1998 (C-120/95).
  27. EUNETHA, Core HTA on Genetic Tests for Breast Cancer- Draft confidential.
  28. 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
  29. COURT OF JUSTICE OF THE EUROPEAN UNION (fourth section) Sentence in Case T-179/00, A. Menarini vs. Commission of European Communities, 03.07.2002.
  30. EUROPEAN PARLIAMENT - COUNCIL OF THE EUROPEAN UNION, Directive 2001/20/CR of the from 4 April 2001 regarding the application of good clinical practices in the execution of clinical experimentation of medicines for human use
  31. EUROPEAN PARLIAMENT AND COUNCIL, Directive 2004/23/EC of the of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.
  32. Sentence of the European Court of Justice from the 28 April of 1998 C-158/96
  33. European guidelines for quality assurance in breast cancer screening and diagnosis
  34. 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

Collection appendices

Appendix COL-1 Common literature search strategy

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

113.EFF Figure 1

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:

  1. exp Breast Neoplasms/ or exp Inflammatory Breast Neoplasms/ or exp Carcinoma, Lobular/ or exp Carcinoma, Ductal, Breast/ (190871)
  2. ((breast* or mamma*) adj3 (neoplasm* or tumor* or tumour* or cancer* or carcinoma*)).tw. (187456)
  3. or/1-2 (236372)
  4. oncotype*.tw. (139)
  5. (21-gene* or ("21" adj gene*)).tw. (999)
  6. (mammaprint* or (mamma* adj print*)).tw. (58)
  7. (70-gene* or ("70" adj gene*)).tw. (610)
  8. femtelle*.tw. (0)
  9. exp Plasminogen Activator Inhibitor 1/ or exp Plasminogen Activators/ or exp Urokinase-Type Plasminogen Activator/ or exp Receptors, Urokinase Plasminogen Activator/ (38146)
  10. (urokinase* or (plasminogen* adj3 activator*)).tw. (31468)
  11. (upa* adj3 pai-1*).tw. (639)
  12. exp Enzyme-Linked Immunosorbent Assay/ (111107)
  13. (elisa* or enzyme-linked immunosorbent assay*).tw. (119190)
  14. or/4-13 (214620)
  15. 3 and 14 (3455)
  16. Animals/ not Humans/ (3606824)
  17. 15 not 16 (3223)
  18. limit 17 to english language (3026)

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <October 07, 2011>

Search Strategy:

  1. ((breast* or mamma*) adj3 (neoplasm* or tumor* or tumour* or cancer* or carcinoma*)).tw. (7287)
  2. oncotype*.tw. (4)
  3. (21-gene* or ("21" adj gene*)).tw. (31)
  4. (mammaprint* or (mamma* adj print*)).tw. (5)
  5. (70-gene* or ("70" adj gene*)).tw. (35)
  6. femtelle*.tw. (0)
  7. (urokinase* or (plasminogen* adj3 activator*)).tw. (818)
  8. (upa adj3 pai-1).tw. (16)
  9. (elisa* or enzyme-linked immunosorbent assay*).tw. (4722)
  10. or/2-9 (5577)
  11. 1 and 10 (98)
  12. limit 11 to english language (93)

Database: Embase <1980 to 2011 Week 40>

Search Strategy:

  1. exp breast tumor/ or exp breast cancer/ or exp breast carcinoma/ or exp inflammatory breast cancer/ (267013)
  2. ((breast* or mamma*) adj3 (neoplasm* or tumor* or tumour* or cancer* or carcinoma*)).tw. (219643)
  3. or/1-2 (298799)
  4. oncotype.tw. (215)
  5. (21-gene* or ("21" adj gene*)).tw. (1225)
  6. (mammaprint* or (mamma* adj print*)).tw. (116)
  7. (70-gene* or ("70" adj gene*)).tw. (738)
  8. femtelle*.tw. (1)
  9. exp plasminogen activator/ or exp urokinase receptor/ or exp urokinase/ or exp plasminogen activator inhibitor 1/ or exp plasminogen activator inhibitor/ (65349)
  10. (urokinase* or (plasminogen* adj3 activator*)).tw. (35789)
  11. (upa* adj3 pai-1*).tw. (749)
  12. exp enzyme linked immunosorbent assay/ (158646)
  13. (elisa* or enzyme-linked immunosorbent assay*).tw. (145438)
  14. or/4-13 (265469)
  15. 3 and 14 (4630)
  16. Nonhuman/ not Human/ (3037332)
  17. 15 not 16 (4361)
  18. limit 17 to english language (4002)

Database: Cochrane Issue 4 of 4, Oct 2011

Search Strategy:

1

MeSH descriptor Breast Neoplasms explode all trees

7171

2

(breast* or mamma*) near/3 (neoplasm* or tumor* or tumour* or cancer* or carcinoma*):ti,ab,kw

13822

3

(#1 OR #2)

13822

4

oncotype*

13

5

21 next gene*

57

6

mammaprint* or (Mamma* next print*)

8

7

70 next gene*

15

8

femtelle*

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

urokinase* or (plasminogen* near/3 activator*):ti,ab,kw

3107

13

upa* near/3 pai-1*

14

14

MeSH descriptor Enzyme-Linked Immunosorbent Assay explode all trees

1849

15

elisa* or enzyme-linked immunosorbent assay*:ti,ab,kw

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

(#3 AND #16)

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/

29061

2

(breast* ADJ3 neoplasm*).ti,ab

39

3

(breast* ADJ3 tumor*).ti,ab

604

4

(breast* ADJ3 tumour*).ti,ab

119

5

(breast* ADJ3 cancer*).ti,ab

20900

6

(breast* ADJ3 carcinoma*).ti,ab

776

7

1 OR 2 OR 3 OR 4 OR 5 OR 6

31964

8

oncotype*.ti,ab

25

9

(21-gene* OR (21 ADJ gene*)).ti,ab

197

10

(mammaprint* OR (mamma* ADJ print*)).ti,ab

13

11

(70-gene* OR (70 ADJ gene*)).ti,ab

136

12

femtelle*.ti,ab

0

13

exp UROKINASE/ OR exp PLASMINOGEN ACTIVATORS/

1972

14

(urokinase* OR (plasminogen* adj3 activator*)).ti,ab

1471

15

(upa* adj3 pai-1*).ti,ab

25

16

ENZYME-LINKED IMMUNOSORBENT ASSAY/

5035

17

(elisa* OR enzyme-linked AND immunosorbent AND assay*).ti,ab

3407

18

8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17

9642

19

7 AND 18

155

20

19 [Limit to: (Language English)]

153

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

  1. Women diagnosed with early invasive breast cancer;
  2. The papers (publications) which include at least one of the following prognostic tests: OncotypeDX, MammaPrint und uPA/PA1 test;
  3. Papers (publications) published in English;
  4. Papers (publications) on Humans only.

[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)

  1. The papers (publications) did not involve women with breast cancer;  
  2. The papers (publications) did not involve at least one of the following tests: Oncotype DX , MammaPrint,  and uPA/PA1 tests;
  3. The papers (publications) published in a language other than English; 
  4. Duplicate of original publication.

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.

Core HTA on Prognostic Tests for Breast Cancer

Questions for the manufacturer of the technology: FEMTELLE®, uPA/PAI-1 ELISA (American Diagnostica GmbH)

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.

Core HTA on Prognostic Tests for Breast Cancer

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.

Core HTA on Prognostic Tests for Breast Cancer

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

pdf113.COL Appendix 3

Appendix COL-4 Abbreviations list

  • AE assessment element
  • AGO German Working Group for Gynecological Oncology
  • ASCO American Society of Clinical Oncology
  • BMI  body mass index
  • CHT chemotherapy plus hormonal therapy
  • CLIA Clinical Laboratory Improvement Amendments
  • COLMOD 1 collaborative model 1
  • CUR Health Problem and Current Use domain
  • DCIS ductal carcinoma in situ
  • DCS decisional conflict scale
  • DFS disease-free survival
  • ECO Costs and economic evaluation domain
  • EFF Effectiveness domain
  • EGAPP Evaluation of Genomic Applications in Practice and Prevention
  • ELISA enzyme-linked immunoassay
  • EMA European Medicines Agency
  • ER+, ER- oestrogen receptor positive, negative
  • ESIS European chemical Substances Information System
  • ETH Ethical domain
  • EU European Union
  • EU-OSHA European Agency for Safety and Health at Work
  • FDA US Food and Drug Administration
  • FFPE formalin fixed and paraffin embedded
  • HER2 human epidermal growth factor receptor 2
  • HRT hormone replacement therapy
  • HT hormonal therapy
  • HTA health technology assessment
  • IARC International Agency for Research on Cancer
  • IPCS International Programme on Chemical Safety
  • IVD in vitro diagnostic
  • JA1 First EUnetHTA Joint Action
  • LCIS lobular carcinoma in situ
  • LEG Legal aspects domain
  • LN+ LN- lymph node negative
  • MSDS Material Safety Data Sheets
  • NCCN National Comprehensive Cancer Network
  • NPI Nottingham Prognostic Index
  • OECD Organisation for Economic Co-operation and Development
  • OELs occupational exposure limits
  • ORG Organisational aspects domain
  • OS overall survival
  • PAI-1 plasminogen activator inhibitor 1
  • PET` positron emission tomography
  • PMA pre-market approval
  • PTBCR prognostic tests for breast cancer recurrence
  • RCT randomised controlled trials
  • REACH Registration, Evaluation, Authorisation and Restriction of Chemical substances
  • RS recurrence score
  • RT–PCR reverse transcriptase –polymerase chain reaction
  • SAF Safety domain
  • SAG Stakeholder Advisory Group
  • SOC Social aspects domain
  • STAI state or situational anxiety
  • TEC Description and technical characteristics domain
  • TNM tumour, node, metastasis
  • TWA time-weighted average
  • uPA urokinase plasminogen activator
  • WP4 Work Package 4