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# Impact of Gene Expression Profiling Tests on Breast CancerOutcomes

*Evidence Reports/Technology Assessments, No. 160*

Investigators: Luigi Marchionni, MD, PhD, Renee F Wilson, MSc, Spyridon S Marinopoulos, MD, MBA, Antonio C Wolff, MD, Giovanni Parmigiani, MD, Eric B Bass, MD, MPH, and Steven N Goodman, MD, MHS, PhD.

Agency for Healthcare Research and Quality (US)2008 Jan

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## Structured Abstract

#### Objective:

To assess the evidence that three marketed gene expression-based assays improveprognostic accuracy, treatment choice, and health outcomes in women diagnosed withearly stage breast cancer.

#### Data Sources:

MEDLINE®, EMBASE, the Cochrane databases, test manufacturer Web sites, andinformation provided by manufacturers.

#### Review Methods:

We evaluated the evidence for three gene expression assays on the market;Onco*type* DX™, MammaPrint® and the Breast Cancer Profiling (BCP orH/I ratio) test, and for gene expression signatures underlying the assays. We soughtevidence on: (a) analytic performance of tests; (b) clinical validity (i.e.,prognostic accuracy and discrimination); (c) clinical utility (i.e., prediction oftreatment benefit); (d) harms; and (e) impact on clinical decision making and healthcare costs.

#### Results:

Few papers were found on the analytic validity of the Onco*type* DXand MammaPrint tests, but these showed reasonable within-laboratory replicability.Pre-analytic issues related to sample storage and preparation may play a larger rolethan within-laboratory variation. For clinical validity, studies differed accordingto whether they examined the actual test that is currently being offered to patientsor the underlying gene signature. Almost all of the Onco*type* DXevidence was for the marketed test, the strongest validation study being from one armof a randomized controlled trial (NSABP-14) with a clinically homogeneous population.This study showed that the test, added in a clinically meaningful manner to standardprognostic indices. The MammaPrint signature and test itself was examined in studieswith clinically heterogeneous populations (e.g., mix of ER positivity and tamoxifentreatment) and showed a clinically relevant separation of patients into riskcategories, but it was not clear exactly how many predictions would be shifted acrossdecision thresholds if this were used in combination with traditional indices. TheBCP test itself was examined in one study, and the signature was tested in a varietyof formulations in several studies. One randomized controlled trial provided highquality retrospective evidence of the clinical utility of Onco*type*DX to predict chemotherapy treatment benefit, but evidence for clinical utility wasnot found for MammaPrint or the H/I ratio. Three decision analyses examined thecost-effectiveness of breast cancer gene expression assays, and overall wereinconclusive.

#### Conclusions:

Onco*type* DX is furthest along the validation pathway, with strongretrospective evidence that it predicts distant spread and chemotherapy benefit to aclinically relevant extent over standard predictors, in a well-defined clinicalsubgroup with clear treatment implications. The evidence for clinical implications ofusing MammaPrint was not as clear as with Onco*type* DX, and theability to predict chemotherapy benefit does not yet exist. The H/I ratio testrequires further validation. For all tests, the relationship of predicted to observedrisk in different populations still needs further study, as does their incrementalcontribution, optimal implementation, and relevance to patients on currenttherapies.

## Contents

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                        - Preface
                        - Acknowledgments
                        - Executive Summary
                        - 1. Introduction                           - Breast Cancer
                          - Breast Cancer Assays on the Market
                          - Sources of Variability in Gene Expression Analysis
                          - Objectives of the Evidence Report
                          - Structured Approach to Assessment of the Questions
                        - 2. Methods                           - Recruitment of Technical Experts and Peer Reviewers
                          - Key Questions
                          - Literature Search Methods
                          - Title Review
                          - Abstract Review
                          - Article Inclusion/Exclusion
                          - Data Abstraction
                          - Quality Assessment
                          - Data Synthesis
                          - Data Entry and Quality Control
                          - Grading of the Evidence
                          - Peer Review
                        - 3. Results                           - Key question 1. What is the direct evidence that gene expression profiling tests in women diagnosed with breast cancer, or any specific subset of this population, lead to improvement in outcomes?
                          - Key question 2. What are the sources of and contributions to analytic validity in these gene expression-based prognostic estimators for women diagnosed with breast cancer?
                          - Key Question 3. What is the clinical validity of gene expression profiling tests in women diagnosed with breast cancer?
                          - Key Question 4. What is the clinical utility of these tests?
                          - Ongoing Studies
                          - Other Relevant Studies
                          - Studies Excluded Upon Complete Review
                        - 4. Discussion                           - Onco*type* DX
                          - MammaPrint
                          - H/I Ratio Signature and Breast Cancer Profiling (BCP)
                          - General Comments on Analytic Validity and Laboratory Quality Control
                          - Overall Implications and Recommendations
                          - Conclusion
                          - References and Included Studies
                        - Appendixes                           - Appendix A: List of Acronyms
                          - Appendix B: Glossary
                          - Appendix C: Description of Genes
                          - Appendix D: Technologies
                          - Appendix E: Technical Experts and Peer Reviewers
                          - Appendix F: Detailed Electronic Database Search Strategies
                          - Appendix G: Title Review Forms
                          - Appendix H: Excluded Articles
                          - Appendix I: Evidence Tables

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1

#### Suggested citation:

Marchionni L, Wilson RF, Marinopoulos SS, WolffAC, Parmigiani G, Bass EB, Goodman SN. Impact of Gene Expression Profiling Tests onBreast Cancer Outcomes. Evidence Report/Technology Assessment No. 160. (Prepared byThe Johns Hopkins University Evidence-based Practice Center under contract No.290-02-0018). AHRQ Publication No. 08-E002. Rockville, MD: Agency for HealthcareResearch and Quality. January 2008. DOI: https://doi.org/10.23970/AHRQEPCERTA160.

This report is based on research conducted by the Johns Hopkins UniversityEvidence-based Practice Center (EPC) under contract to the Agency for HealthcareResearch and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0018). The findings andconclusions in this document are those of the author(s), who are responsible for itscontent, and do not necessarily represent the views of AHRQ. No statement in this reportshould be construed as an official position of AHRQ or of the U.S. Department of Healthand Human Services.

The information in this report is intended to help clinicians, employers, policymakers,and others make informed decisions about the provision of health care services. Thisreport is intended as a reference and not as a substitute for clinical judgment.

This report may be used, in whole or in part, as the basis for the development ofclinical practice guidelines and other quality enhancement tools, or as a basis forreimbursement and coverage policies. AHRQ or U.S. Department of Health and HumanServices endorsement of such derivative products may not be stated or implied.

**The investigators have no relevant financial interests in the report. Theinvestigators have no employment, consultancies, honoraria, or stock ownership oroptions, or royalties from any organization or entity with a financial interest orfinancial conflict with the subject matter discussed in the report.**

                        - 1
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540 Gaither Road, Rockville, MD 20850. www​.ahrq.gov

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Bookshelf ID: NBK38448

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                    - Cite this Page Marchionni L, Wilson RF, Marinopoulos SS, et al. Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Jan. (Evidence Reports/Technology Assessments, No. 160.)

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