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New testing technologies – increasingly based on genomic information – are essential in the shift towards personalized medicine and molecular targeted therapies. Considering the rapid proliferation of new tests, healthcare insurers and policymakers are interested in assessing evidence about their use and value.
It is critical to build an evidence base to support effective decision-making related to testing technologies as they are used in clinical practice. The example of human epidermal growth factor receptor 2 (HER2) testing for breast cancer illustrates the challenges and opportunities. Many groups, including the Institute of Medicine; Agency for Healthcare Research and Quality; Secretary’s Advisory Committee on Genetics, Health, and Society; President’s Council of Advisors on Science and Technology; and Evaluation of Genomic Applications in Practice and Prevention Project have cited the need to improve the evidence base for genomic and testing technologies. This Commentary extends previous work, emphasizing the need for evidence to assess how technologies are actually used in clinical practice.
HER2 testing to target trastuzumab treatment for patients with breast cancer is perhaps the best known example of testing to target treatment. Gaps in knowledge about clinical practice for even this successful example portend an increasing need for evidence as new testing technologies enter clinical care. In addition, the high cost of many emerging therapies (e.g., trastuzumab therapy costs approximately $100,000/annually) also points to the need for evidence on how to most efficiently target therapies.
HER2 testing determines which patients overexpress the gene HER2; for those 20%–30% of patients, trastuzumab is highly effective. Trastuzumab and an accompanying test were approved in 1998 for metastatic breast cancer patients and its use was expanded to early-stage breast cancer patients after 2005. HER2 testing is now recommended for all patients with invasive breast cancer, and only patients with positive tests are recommended for trastuzumab treatment.
There is no consensus about optimal testing methods. Guidelines recommend using either immunohistochemistry (IHC); (with indeterminate results confirmed by fluorescence in situ hybridization FISH); or FISH to determine HER2 status.1 Although FISH is a better predictor of response to treatment, IHC costs substantially less and is more easily performed in community laboratories.1
Despite the clinical success of trastuzumab, there are concerns about the best methods for selecting patients for treatment. The accuracy and interpretation of HER2 tests have been highlighted in the media, with provocative headlines in some news stories. 2, 3 Even the company marketing trastuzumab publicly acknowledged the serious problem with test accuracy, noting that “about 5,000 patients in the US receive trastuzumab without any clinical benefit, and about 7,000 patients who could derive benefit are not being treated because of a false-negative test result.” (p. 168)4
Promising efforts are underway to address those gaps. Importantly, these findings do not challenge the efficacy of HER2 testing and trastuzumab treatment nor are they a reason to slow the pace of innovation or the diffusion of testing technologies into clinical practice. Rather, testing and treatment can be made more effective and efficient by gathering real-world data and incorporating these data into rigorous analyses of best-testing practices. The type and extent of evidence needed will vary by the specific situation as clinical trial data will never be able to address all of the questions. Approaches that facilitate both innovation and evidence must be developed, such as “coverage with evidence development” programs.
The example of HER2 highlights four potential solutions to the evidence gap:
Creative collaboration between academia, industry, and government is needed to build the evidence base; for example, the Aetna Foundation has funded the University of California at San Francisco and Brigham and Women’s Hospital to determine how physicians use HER2 tests to inform their treatment recommendations. This academia-industry collaboration takes advantage of rich health plan enrollee data and academic research expertise.
Greater use of testing to target treatments is inevitable and has the potential to improve both the quality and efficiency of care but evidence-based information is essential if these new technologies are to be used wisely.15 A comprehensive agenda for translational research is needed to move new discoveries into clinical care. This agenda will require attention to both translation of basic research findings into new therapeutic options and translation of research into practice.
This study was funded by two grants to Dr. Phillips from the National Cancer Institute (R01CA101849 and P01CA130818) and a grant from the Blue Shield Foundation of California (unrestricted). The funding organizations and sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and approval of the manuscript. Dr. Phillips has an unrestricted grant from the Aetna Foundation to examine the utilization of HER2 testing and gene expression profiling for breast cancer.
I am grateful to the following individuals for their invaluable contributions to this manuscript: Su-Ying Liang PhD (UCSF); Deborah A. Marshall, PhD (University of Calgary); Jennifer S. Haas, MD, MSPH (Brigham and Women’s Hospital); Elena B. Elkin, PhD (Memorial-Sloan Kettering Cancer Center); Michael J. Hassett, MD, MPH (Dana-Farber Cancer Institute); Ilia Ferrusi, B.Sc (McMaster University); Jane E. Brock, MBBS, PhD (Brigham and Women’s Hospital); and Stephanie L Van Bebber, M.Sc (UCSF). I also thank i3 innovus and Julia Trosman and the Center for Business Models in Healthcare for their commissioned reports developed for the Department of Clinical Pharmacy at the University of California, San Francisco. Lastly, I thank Mr. Kuo Tong, president and founder of Quorum Consulting in San Francisco, California, for the use of results from his poster presentation given at the 2007 Breast Cancer Symposium.