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 24 October 2021]. Available from: http://corehta.info/ViewCover.aspx?id=113

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

<< Costs and economic evaluationOrganisational aspects >>

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?"

View full card
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.

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