Utilization of HER2 Genetic Testing in a Multi-Institutional Observational Study

Published Online: November 20, 2012
Katrina A. B. Goddard, PhD; Erin J. Aiello Bowles, MPH; Heather Spencer Feigelson, PhD, MPH; Laurel A. Habel, PhD; Sharon Hensley Alford, PhD; Catherine A. McCarty, PhD, MPH; Larissa Nekhlyudov, MD, MPH; Adedayo A. Onitilo, MD, MSCR, FACP; Alanna K. Rahm, PhD, MS; and Jennifer A. Webster, MS
Introduction: Human epidermal growth factor receptor 2 (HER2) expression is amplified in about 20% of breast cancer tumors, and evaluation of HER2 status should influence therapy selection. A critical gap in our knowledge is the real-world implementation of HER2 testing and its impact on treatment decisions for women diagnosed with breast cancer.

Objectives: To assess use of HER2 testing, to describe characteristics of patients who do or do not receive HER2 testing, to describe which HER2 tests were used (fluorescence in situ hybridization or immunohistochemistry), and to evaluate trastuzumab use as a function of HER2 results.

Study Design: The population included 6460 women diagnosed with invasive breast cancer between 1999 and 2007 at 8 geographically distributed Cancer Research Network healthcare delivery systems in the United States.

Methods: Electronic records were used to identify patient and tumor characteristics and treatment with trastuzumab. Chart abstraction was performed for 400 women (50 per site) to identify receipt of HER2 testing and results.

Results: More than 90% of study participants received HER2 testing. Everyone who received trastuzumab had a HER2 test, and nearly all (>95%) who received trastuzumab had a positive HER2 test result recorded in their medical chart. Most (77%) eligible patients with a positive HER2 test result diagnosed after 2005 received trastuzumab. This study expands upon previous work in individual health plans.

Conclusions: HER2 status has been successfully incorporated into medical practice to guide treatment decisions for breast cancer patients in diverse integrated healthcare delivery settings.

(Am J Manag Care. 2012;18(11):704-712)
We evaluated real-world implementation of human epidermal growth factor receptor 2 (HER2) testing and its impact on treatment decisions for women diagnosed with breast cancer between 1999 and 2007 at 8 US integrated delivery systems. There was consistent success in implementation of HER2-guided treatment decisions for breast cancer patients in these settings.

  • More than 90% of study participants received HER2 testing.

  • Everyone who received trastuzumab had a HER2 test, and more than 95% of these women had a positive HER2 test result.

  • Most (77%) eligible patients with a positive HER2 test result diagnosed after 2005 received trastuzumab.
In 2011, about 230,000 women in the United States were newly diagnosed with invasive breast cancer.1 About 40,000 of these women are expected to die of this disease. Recent advances in medicine utilizing genetic-based technologies better predict cancer recurrence or response to various treatments and present an important opportunity for patients and their physicians to individualize therapy. However, there are limited reports in the literature about how such technologies are being incorporated into clinical practice and whether they are being used appropriately.2,3 As genetic-based technologies proliferate, understanding how and when these applications should be used in clinical practice becomes increasingly important.

One such genetic technology targets human epidermal growth factor receptor 2 (HER2). HER2 is a gene that influences cell growth, division, and repair. A normal cell has 2 copies of HER2. About 18% to 20% of breast cancers have HER2 gene amplification (more than 2 copies of this gene).4-6 HER2 amplification is associated with rapid tumor proliferation, shorter disease-free survival, and poorer overall survival.7-9 The drug trastuzumab (Herceptin, Genentech Inc, San Francisco, California) is indicated for individuals with breast cancer that either overexpresses the HER2 protein or amplifies the HER2 gene to prevent the growth of HER2-positive cancer cells.10-14 It was approved by the US Food and Drug Administration (FDA) for use in the treatment of metastatic breast cancer in 1998 based on the findings from 2 clinical trials, which showed improvement in the median time to progression of 3 to 5 months, and an increase in the overall response rate of 10% to 30%.15 Despite the fact that trastuzumab is also well established as a highly efficacious (adjuvant) antineoplastic agent for HER2-positive breast cancer, it is expensive ($44,000-$65,000 per year16,17) and may have serious cardiotoxic effects.18 Because of these factors, selecting patients for whom trastuzumab treatment is appropriate remains vital. Trastuzumab treatment should be cautiously used for patients with preexisting cardiac dysfunction or deteriorating cardiac function even if they have a positive HER2 test result, especially older women with prior cardiac history or prior cardiotoxic therapies.

Two types of tests are FDA approvedto select patients for treatment with trastuzumab. The first test is a based on immunohistochemistry (IHC) (eg, Dako HercepTest, Ventana PATHWAY), which measures membrane expression of HER2 receptor protein. The second type of test (eg, Vysis PathVysion, Ventana INFORM HER2 probe) is based on the fluorescence in situ hybridization (FISH) technology to measure the underlying gene amplification in tumor cells. In this approach, fluorescent probes are used to quantify the number of HER2 gene copies in a tumor cell. If there are 2 or more copies of the HER2 gene per chromosome 17, then a gene amplification has occurred, and the breast cancer is considered HER2 positive.

The American Society of Clinical Oncology and College of American Pathologists HER2 testing guidelines currently recommend initial testing by IHC testing and reflex testing of equivocal result (2+) by FISH testing.19 Although some reports have suggested that the FISH technology more accurately predicts response to trastuzumab than IHC technology,20 a recent summary report indicates that both technologies perform equally well if carefully validated testing is performed.19 Cost may also be a factor in the selection of test modality, because the FISH test is generally more expensive to perform than the IHC test. For both testing methods, underlying quantitative measures can be translated into a dichotomous positive/negative finding. Both tests are considered equivocal when the quantitative measures are near the threshold for a positive result. Retesting might resolve these equivocal findings.19 Increased error rates and inconsistent results are also introduced by decentralized testing, particularly for centers with a low volume of testing. Thus, Wolff and colleagues19 recommend a quality assurance program for HER2 testing, and suggest various accreditation, proficiency, and competency measures for laboratories conducting HER2 testing.

Trastuzumab was initially approved by the FDA in 1998 for use in breast cancer patients with metastatic cancer. In November 2006, the FDA approved the use of trastuzumab in the adjuvant setting for women with lymph node–positive and HER2-positive breast cancer, following several major trials.11-13 Professional organizations, including a joint guideline from the American Society of Clinical Oncologists and College of American Pathologists, currently recommend that HER2 testing should be performed for all invasive breast cancers regardless of lymph node disease status.19 The National Comprehensive Cancer Network has also issued physician practice guidelines endorsing HER2 testing.21-24 Despite these evidence-based practice guidelines, there are few reports on how HER2 testing has been utilized in realworld settings. In particular, Phillips and colleagues3 highlighted the fact that little is known about how many patients are tested for HER2, which testing methods are used, whether patients are retested to confirm indeterminate results, and how many patients with negative or equivocal results receive trastuzumab. Additionally, it is not clear how trastuzumab is utilized across important subgroups such as patient age, race, and cancer stage.

To answer these questions, we conducted a large, multiinstitutional study in 8 Cancer Research Network (CRN) integrated healthcare delivery systems across the United States. The organizations participating in this study provide a unique resource to address this research question by providing access to longitudinal and comprehensive electronic medical record data for populations totaling more than 6 million covered lives. We describe the real-world implementation of HER2 testing and trastuzumab prescribing in this setting.


Study Population

The study population included 6460 women who were diagnosed with an invasive breast cancer that was 2+ cm in size or who had positive nodes at diagnosis from January 1, 1999, to December 31, 2007, and who were enrolled at one of the 8 participating CRN study sites for at least 12 months prior to diagnosis. These tumor size and lymph node status criteria were used to restrict the population to women similar to those in the adjuvant trastuzumab clinical trials. Subjects were followed for up to 12 months following diagnosis. Follow-up periods of less than 12 months were due to death or disenrollment during that period. The 8 participating study sites are geographically distributed within the United States and represent diverse populations: Group Health Cooperative (Washington), Kaiser Permanente Northwest (Oregon and Washington), Kaiser Permanente Northern California, Kaiser Permanente Colorado, Kaiser Permanente Georgia, Marshfield Clinic (Wisconsin), Henry Ford Health System (Michigan), and Harvard Pilgrim Health Care Institute with clinical data from Harvard Vanguard Medical Associates (Massachusetts). The study population included all eligible subjects at each site except for Kaiser Permanente Northern California, which contributed data on a 10% random sample of their eligible population.

A subset of 400 cases (50 from each site) was sampled from the original cohort for detailed chart review using stratified sampling (eAppendix, available at www.ajmc.com) to ensure adequate numbers of subjects with chemotherapy exposure and the outcome of heart failure. Weights were used for some analyses, and were calculated as 1 over the probability of being sampled (ie, 1/(1/N), where N is the number of subjects in that stratum; N >1, since at minimum the sampled subject belongs to the stratum). The primary purpose of the chart review was to validate electronic administrative data for chemotherapy exposure to anthracyclines or trastuzumab and the outcome of heart failure, as measured by clinical criteria and measurement of left ventricular ejection fraction, which was previously reported in a separate publication.25 However, the availability of data on HER2 genetic testing from the chart abstraction allowed us to conduct this secondary analysis. This study was approved by the institutional review boards (IRBs) at Group Health Cooperative, Marshfield Clinic Research Foundation, and Henry Ford Health System, and did not require written informed consent. The IRBs for the remaining sites ceded authority to the Group Health Cooperative IRB. A small number of health system members at each site have elected not to participate in anonymous or unconsented research protocols, and these subjects were excluded from this research study.

HER2 Genetic Testing

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