Closing the Personalized Medicine Information Gap: HER2 Test Documentation Practice

Breast cancer (BC) is the most frequently diagnosed cancer among Canadian women, with a projected incidence of 23,400 in 2011.¹ Early diagnosis and adjuvant treatment provide significant gains in life expectancy for women diagnosed with early-stage disease.² Recent advances in treatment focus on using genetic information to target treatments to patients who are likely to respond. One example is the human epidermal growth factor receptor-2 (HER2) oncogene and protein, first noted as predictors of overall survival and time to relapse in BC.3 Amplification of the HER2 oncogene in 20% of cancers is associated with poor prognosis, aggressive tumor proliferation, and poorer response to chemotherapy.^3,4 Trastuzumab therapy has demonstrated significant improvements in disease-free survival and mortality in patients whose tumors overexpress HER2.^5,6 Testing for HER2 to identify treatment candidates is typically conducted by immunohistochemistry (IHC) or in situ hybridization techniques, most commonly fluorescence (FISH).^7,8 Differences in test accuracy and cost prompted the development of testing guidelines⁷ to ensure efficient and accurate diagnosis of HER2-positive patients. Although less expensive, IHC is also less accurate.⁷ Quantification of HER2 gene overexpression by FISH is more accurate, but also more expensive and difficult to conduct. Guidelines recommend the use of either IHC or FISH to detect HER2 overexpression and promote reflex FISH testing to clarify the HER2 status of IHC-equivocal tumors.^7,8

Accurate identification of HER2-positive patients is crucial given the high cost of adjuvant trastuzumab therapy and the potential exposure of false-positive patients to cardiotoxic side effects. Adjuvant treatment guidelines recommend that all incident patients with invasive disease receive a HER2 workup.⁹ Economic evaluations of HER2 testing and treatment demonstrate the clinical and economic costs of failure to accurately classify IHC-equivocal patients.^10-12 Studies of HER2 testing in the early days of metastatic therapy in the United States suggested an information gap¹³ in HER2 documentation for 48% of eligible patients. More information is needed to gauge the quality of current practice and to establish a foundation for assessing the optimal use of personalized medicine in the real world. Without this information, it is difficult for administrators or researchers to understand issues related to access to testing, appropriateness of treatment, and cost-effective care. HER2 testing practice in Canada remains largely unreported in the literature, particularly with respect to how testing is documented, what tests were performed, test results, and whether reflex testing is conducted. A sample of early-stage patients in Nova Scotia suggests that 81% of patients received a HER2 test, but provides no insight into the type of test(s) used.¹⁴

We aimed to describe centralized HER2 test documentation and testing patterns in Ontario and to gain insight into how to use and interpret these data. Our specific objectives were to (1) assess the availability of data to evaluate HER2 testing practices from a centralized source in a real-world setting; (2) describe reporting system, clinical, or sociodemographic factors associated with HER2 documentation in Ontario; and (3) describe HER2 test utilization with respect to test type and test sequencing.

Methods

Study Design and Setting

A retrospective cohort design was used to study patients diagnosed with early-stage BC between 2006 and 2007 in the Canadian province of Ontario. This time frame allowed 6 months of lag time subsequent to the approval of adjuvant trastuzumab therapy in mid-2005.¹⁵ The associated treatment guideline and relevant policies were implemented provincewide under the auspices of Cancer Care Ontario (CCO). As the provincial cancer agency, CCO is involved in screening, diagnostic, treatment, recovery, and palliative services to all patients diagnosed with cancer in the publicly funded Ontario healthcare system. The New Drug Funding Program of CCO administers the reimbursement of new, expensive systemic therapies, including trastuzumab. At the time of this study, adjuvant trastuzumab treatment was available to patients with HER2-positive tumors larger than 1 cm that were previously treated with chemotherapy.^9,15 Ontario’s policy is to follow Canadian testing guidelines “…to test all patients with invasive breast cancer for HER2/neu at the time of diagnosis.” ^7,8 Testing was funded by the Ontario Ministry of Health and Long-term Care and routinely performed by pathologists irrespective of other clinical or pathologic factors. Tumor pathology should be reported centrally to the provincial cancer agency for maintenance of the cancer registry. Reimbursement for trastuzumab requires evidence of a positive HER2 test, but this is provided separately from registry reporting. Research ethics board approval was obtained from St. Joseph’s Healthcare Hamilton. The protocol was also approved by the privacy committees of CCO and the Institute for Clinical Evaluative Sciences. These agencies provided access to provincial and national administrative health data, and facilitated record linkage across data sources using anonymous patient identifiers. This manuscript was reviewed by CCO, the Institute for Clinical Evaluative Sciences, and the Ministry of Health and Long-term Care.

Participants