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 )

<< Collection summaryDescription and technical characteristics of technology >>

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?"

View full card
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"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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)?"

View full card
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)?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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?"

View full card
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.
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