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 )

<< Ethical analysisSocial aspects >>

Organisational aspects

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

Summary

As far as can be judged from the literature and the survey results, introducing these tests into the clinical pathway of women with breast cancer does not have significant organisational impacts. However, the following must be kept in mind:

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

Introduction

Research in the Organisational Aspects domain seeks to find out what resources (equipment, running costs, human skills and knowledge, etc) must be mobilised and organised when implementing a new technology. It also looks at the consequences for an organisation and for stakeholders (other than patients and their carers) of introducing the technology. The focus is on how the technology is delivered. Organisational aspects are included in a health technology assessment (HTA) because they may reveal essential challenges and barriers in implementing health technologies.

In this Core HTA the new technologies are prognostic tests for breast cancer recurrence, and the objective is to assess the organisational effects of introducing them compared with the standard care pathway, which does not include such tests.

Methodology

Frame

The collection scope is used in this domain.

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

Urokinase plasminogen activator /plasminogen activator inhibitor 1 ELISA (uPA/PAI-1) is a registered enzyme-linked immunoassay (ELISA) kit (FEMTELLE) for the analysis of uPA/PAI-1 in fresh frozen tissue and is being provided by American Diagnostica Inc. It is CE marked in Europe but for research use only in the USA. Other commercial ELISA kits for separate in-house analysis of uPA and/or PAI-1 are available from different suppliers. These also use samples other than tissue and are also used for indications other than cancer {1}.

Technical details:

- Inspection of unfixed tissue

- Removal of a representative piece of tumour tissue (>50 mg)

- Freezing of the unfixed tissue (-20°C or colder)

- Storage of the frozen tissue (-20°C or colder) possible up to 3 weeks

Clinical Laboratory (Pathology, Hospital)

- Transport of frozen tumour tissue on dry ice

- Extraction of uPA and PAI-1

- Perform FEMTELLE uPA/PAI-1 ELISA

- Transfer of test results to physician

Costs for FEMTELLE including preparation, shipping and analysis of samples in a qualified laboratory amount to €400 (http://www.hkk.de/info/aktuelles/brustkrebs_tumorprognosetest). In house analysis with separate ELISA kits costs about €200.

Possible logistic issues to consider are {2}:

- Relatively large samples are needed. Given that the mean tumour size is <2 cm in many centres, this means that a substantial part of the tissue may be lacking for light microscopic investigation.

- Many centres no longer routinely freeze breast tissue and therefore lack the expensive equipment for this process.

Oncotype DX (Genomic Health) quantifies gene expression for 21 genes in breast cancer tissue by real-time reverse transcriptase-polymerase chain reaction (RT-PCR).

MammaPrint (Agendia) is a gene expression profiling platform based on microarray technology which uses a 70-gene expression profile {3}. The sample studied is fresh or frozen tissue. It has received 510(k) clearance from the FDA (premarket notification for medical devices), which also covers the use of Asuragen's RNARetain®, a room temperature, molecular fixative that supersedes freezing the tissue before shipment to the central US laboratory (www.agendia.com).

The test requires a fresh sample of tissue  composed of a minimum of 30% malignant cells and must be received by the company in their kit within 5 days of obtaining the material. The MammaPrint assay was developed on the basis of research initially conducted at the Netherlands Cancer Institute (Amsterdam) and collaborating institutions. Primary tumours from 117 patients with axillary lymph node-negative primary breast cancer were analysed on oligonucleotide microarrays. The data were subjected to supervised classification to establish a 70-gene RNA expression profile that correlated with a relatively short interval to distant metastases. [from NICE protocol and ASCO guideline]

Oncotype DX and MammaPrint have been evaluated and large-scale studies (TAILORx and MINDACT) are underway. The German Working Group for Gynecological Oncology1 (AGO) and the American Society of Clinical Oncology (ASCO) have recommended uPA/PAI-1 as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, alongside established clinical and histomorphological factors.

Oncotype DX is recommended for node negative, oestrogen receptor-positive women and MammaPrint is applied in all early breast cancers. The tests are expensive: MammaPrint costs €2675 and Oncotype DX, US $3400.

RT-PCR and microarray analysis usually cost US $3500 or more. Oncotype and MammaPrint are not routinely covered by German statutory health insurance. MammaPrint is covered by Medicare and Medicaid in the USA (Pharmacogenomics Reporter: 23 December 2009; www.genomeweb.com.)

MeSH Terms:

There are no MeSH-Terms for Oncotype DX and MammaPrint.

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

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy).

As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question.

Target population

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

Target population description

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

ComparisonStandard of care
Description

Standard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX).

Depending on manpower and time resources the three index tests may also be compared with each other.

Assessment elements

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

Methodology description

Domain frame

The project scope applies to this domain and in addition all uPA/PAI-1 (urokinase plasminogen activator/plasminogen activator inhibitor 1) tests were included, not just FEMTELLE®. Where FEMTELLE-specific information was available this has been included; otherwise the data are about generic uPA/PAI-1 tests.

Information sources

Organisational aspects are rarely covered in clinical studies or HTA reports. Such information as there is tends to be sparse and anecdotal. We therefore undertook several activities:

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

1.  Literature search and review

The literature search was carried out in two stages:

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

This review identified 84 articles that were potentially relevant to the Organisational Aspects domain. The full text for 82 of the 84 references was retrieved. Two articles were not available within the resource constraints of this project. Data extraction was divided between the five authors: each of the 82 articles was reviewed by one author for relevant data. Data from 27 articles were used.

2.  Survey of clinicians and administrators

To complement the low level of data available in the literature, two electronic surveys covering areas in the Organisational Aspects and the Current Use domains of this HTA were developed. One survey was for clinicians and one for lead administrators. Both surveys consisted mainly of multiple choice questions with the option of selecting more than one answer per question. There were 17 questions in the clinician survey and 10 in the administrator survey. The surveys were developed mainly by NICE, with additional input from members of the two domain teams and Agenas. A link to the surveys, and a request to identify clinicians and administrators to complete it, was sent by Agenas to the national EUnetHTA agency in all 26 EUnetHTA countries on 14 February 2012. The deadline for completing the surveys was 5 March 2012. Due to low response rates the survey was made live again on 3 April with a deadline of 27 April 2012, and individuals from EUnetHTA agencies undertook to identify clinicians and administrators who could respond. Response rates were still low: eight responses were received in total from clinicians: three from the UK, two from Spain, two from Italy and one from Slovenia. Two responses were received in total from administrators (one from Spain and one from Italy). The survey questions and the results are in {COL-3}.

3.  Grey literature searches

Grey literature was searched for the ORG3 and ORG9 assessment elements. Details of the searches are covered in those elements and the identified literature is included in the domain references. Grey literature was not searched for any other assessment element.

Quality assessment tools or criteria

We are not aware of quality criteria for articles that consider the organisation of healthcare. Quality assessment criteria were therefore not applied to the studies that were identified for review.

Analysis and synthesis

Data from different studies were not synthesised as this was neither appropriate nor necessary for this domain.   A narrative synthesis was undertaken instead.

Result cards

Process

Result card for ORG1: "What work flow and patient flow processes are needed to use the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) on women with invasive breast cancer? "

View full card
ORG1: What work flow and patient flow processes are needed to use the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) on women with invasive breast cancer?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for ORG2: "What kind of staff, training and other human resources are required when the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) are used to support treatment choice? "

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ORG2: What kind of staff, training and other human resources are required when the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) are used to support treatment choice?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for ORG3: "What kind of co-operation and communication of activities have to be mobilised when the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) are introduced in the clinical pathways of women with invasive breast cancer?"

View full card
ORG3: What kind of co-operation and communication of activities have to be mobilised when the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) are introduced in the clinical pathways of women with invasive breast cancer?
Method
Result
Comment

Importance: Important

Transferability: Completely

Structure

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

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

Importance: Important

Transferability: Partially

Result card for ORG5: "What kind of investment is needed (equipment, premises, staffing costs, running costs) in order to introduce use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) for women with invasive breast cancer?"

View full card
ORG5: What kind of investment is needed (equipment, premises, staffing costs, running costs) in order to introduce use of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) for women with invasive breast cancer?
Method
Result

Importance: Important

Transferability: Partially

Management

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

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

Importance: Critical

Transferability: Partially

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

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

Importance: Important

Transferability: Partially

Culture

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

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

Importance: Important

Transferability: Partially

Result card for ORG10: "How should stakeholders (excluding patients/carers, their representative organisations and the public) be taken into account in planning the introduction of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)?"

View full card
ORG10: How should stakeholders (excluding patients/carers, their representative organisations and the public) be taken into account in planning the introduction of the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint)?
Method
Result
Comment

Importance: Important

Transferability: Partially

Discussion

As described in the section on domain methodology, quality criteria were not applied to the studies identified for review. The real impact of the points identified in the literature on organisational issues is therefore unknown.

The response to the electronic survey of clinicians was too low (eight responses) to be statistically representative. The low response rate is likely to be at least in part due to the low use of the tests in European countries. {RC-CUR11}

Further research on all of the domain assessment elements would generate more certainty about the interpretations in the results cards above. However, issues such as communication or eligibility for tests vary culturally and in different countries, so it is not certain that it would be cost effective to undertake such research.

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