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 )

<< Health Problem and Current Use of the TechnologySafety >>

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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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™?"

View full card
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?"

View full card
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™?"

View full card
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?"

View full card
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.

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