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 )

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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


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