Evidence Report/Technology Assessment Number 160 Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-02-0018 Prepared by: The Johns Hopkins University Evidence-based Practice Center, Baltimore, MD Investigators Luigi Marchionni, M.D., Ph.D. Renee F. Wilson, M.Sc. Spyridon S. Marinopoulos, M.D., M.B.A. Antonio C. Wolff, M.D. Giovanni Parmigiani, M.D. Eric B. Bass, M.D., M.P.H. Steven N. Goodman, M.D., M.H.S., Ph.D. AHRQ Publication No. 08-E002 January 2008 This report is based on research conducted by the Johns Hopkins University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0018). The findings and conclusions in this document are those of the author(s), who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and 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. This report 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 of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. Suggested Citation: 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 Johns Hopkins University Evidence- based Practice Center under contract No. 290-02-0018). AHRQ Publication No. 08-E002. Rockville, MD: Agency for Healthcare Research and Quality. January 2008. The investigators have no relevant financial interests in the report. The investigators have no employment, consultancies, honoraria, or stock ownership or options, or royalties from any organization or entity with a financial interest or financial conflict with the subject matter discussed in the report. ii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The Centers for Disease Control and Prevention (CDC) requested and provided funding for this report. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments. To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release. AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality. We welcome comments on this evidence report. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by e-mail to [email protected]. Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. Director Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Julie Louise Gerberding, M.D., M.P.H. Gurvaneet Randhawa, M.D., M.P.H. Director EPC Program Task Order Officer Centers for Disease Control and Prevention Agency for Healthcare Research and Quality Beth Collins Sharp, Ph.D., R.N. Director, EPC Program Agency for Healthcare Research and Quality iii Acknowledgments The Evidence-based Practice Center thanks Michael Oladubu, D.D.S. and Allison Jonas, for their assistance with literature searching and database management, and project organization; Aly Shogan for her assistance in completing the sections on economics; Brenda Zacharko for her assistance with budget matters, and for her assistance with final preparations of the report. The Center also wishes to thank Gurvaneet Randhawa, M.D., M.P.H., AHRQ Task Order Officer, for his efforts in guiding this project and coordination with the CDC EGAPP group. iv Structured Abstract Objective: To assess the evidence that three marketed gene expression-based assays improve prognostic accuracy, treatment choice, and health outcomes in women diagnosed with early stage breast cancer. Data Sources: MEDLINE®, EMBASE, the Cochrane databases, test manufacturer Web sites, and information provided by manufacturers. Review Methods: We evaluated the evidence for three gene expression assays on the market; Oncotype DX™, MammaPrint® and the Breast Cancer Profiling (BCP or H/I ratio) test, and for gene expression signatures underlying the assays. We sought evidence on: (a) analytic performance of tests; (b) clinical validity (i.e., prognostic accuracy and discrimination); (c) clinical utility (i.e., prediction of treatment benefit); (d) harms; and (e) impact on clinical decision making and health care costs. Results: Few papers were found on the analytic validity of the Oncotype DX and MammaPrint tests, but these showed reasonable within-laboratory replicability. Pre-analytic issues related to sample storage and preparation may play a larger role than within-laboratory variation. For clinical validity, studies differed according to whether they examined the actual test that is currently being offered to patients or the underlying gene signature. Almost all of the Oncotype DX evidence was for the marketed test, the strongest validation study being from one arm of a randomized controlled trial (NSABP-14) with a clinically homogeneous population. This study showed that the test, added in a clinically meaningful manner to standard prognostic indices. The MammaPrint signature and test itself was examined in studies with clinically heterogeneous populations (e.g., mix of ER positivity and tamoxifen treatment) and showed a clinically relevant separation of patients into risk categories, but it was not clear exactly how many predictions would be shifted across decision thresholds if this were used in combination with traditional indices. The BCP test itself was examined in one study, and the signature was tested in a variety of formulations in several studies. One randomized controlled trial provided high quality retrospective evidence of the clinical utility of Oncotype DX to predict chemotherapy treatment benefit, but evidence for clinical utility was not found for MammaPrint or the H/I ratio. Three decision analyses examined the cost-effectiveness of breast cancer gene expression assays, and overall were inconclusive. Conclusions: Oncotype DX is furthest along the validation pathway, with strong retrospective evidence that it predicts distant spread and chemotherapy benefit to a clinically relevant extent over standard predictors, in a well-defined clinical subgroup with clear treatment implications. The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies. v Contents Executive Summary.........................................................................................................................1 Evidence Report………………………………………………………………………………….9 Chapter 1. Introduction ................................................................................................................11 Breast Cancer...........................................................................................................................11 Gene expression profiling..................................................................................................12 Breast Cancer Assays on the Market .......................................................................................13 RT-PCR..............................................................................................................................14