Closing the Personalized Medicine Information Gap: HER2 Test Documentation Practice

Despite universal access to HER2 testing in Ontario, variability in reporting by region and disease severity presents challenges for program evaluation and quality improvement initiatives.
Published Online: January 21, 2013
Ilia L. Ferrusi, PhD; Craig C. Earle, MD; Maureen Trudeau, MD; Natasha B. Leighl, MD; Eleanor Pullenayegum, PhD; Hoa Khong, MD; Jeffrey S. Hoch, PhD; and Deborah A. Marshall, PhD
Background: Uncertainty about human epidermal growth factor receptor-2 (HER2) testing practice in Canada continues to hinder efforts to improve personalized medicine. Pathologists routinely perform HER2 assessment for all tumors > 1 cm, and pathology is reported centrally to the provincial cancer registry.

Objectives: To understand patterns of HER2 test documentation for early-stage breast cancer (BC) patients in Ontario’s centralized pathology reporting system.

Study Design: Retrospective cohort study of central HER2 test documentation in early-stage BC patients diagnosed in 2006-2007.

Methods: Cohort and staging information was derived from cancer registry and admissions data. Linkage across administrative databases provided data on surgical and radiologic treatment, sociodemographic factors, diagnosis setting, and comorbidities. Pathology reports from the provincial cancer registry were reviewed for HER2 testing, hormone receptor, and grade. Unadjusted and adjusted odds ratios were calculated to determine factors related to HER2 documentation.

Results: A HER2 test was documented for 66% of 13,396 patients. HER2 documentation was associated with stage, hormone receptor, and tumor grade documentation. Higher stage and grade at diagnosis were also associated with HER2 documentation. All models suggested variable regional documentation patterns. Documentation did not differ by sociodemographic factors, presence of comorbidities, or surgical procedure.

Conclusions: Despite a universal testing policy, the rate of centralized HER2 test documentation was lower than expected and related to disease severity. Differences in regional reporting likely reflect ascertainment bias inherent to centralized pathology reporting rather than testing access. Improved HER2 reporting is encouraged for cancer registration, quality-of-care measurement, and program evaluation.

(Am J Manag Care. 2013;19(1):17-26)
Population-based analysis indicated that tumor pathology for human epidermal growth factor receptor-2 (HER2) testing was not consistently reported to the central registry, despite universal access to HER2 testing in the Ontario public healthcare system.

  • Locally performed HER2 tests were documented for 66% of patients at the centralized registry.

  • Although HER2 test documentation was unrelated to income or urban residence, it was related to documentation of other pathology factors and disease severity measured by stage and tumor grade.

  • Without improved or mandatory HER2 reporting to the central registry, program evaluation and health quality improvement studies are limited.
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.


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.


All female patients who were diagnosed with early-stage, invasive BC between January 1, 2006, and December 31, 2007, and were treated with surgery (modified radical or partial mastectomy, lumpectomy) within 6 months of diagnosis were eligible for the study. Patients with BC (International Classification of Diseases, Ninth Revision code 174) were identified from the Ontario Cancer Registry (OCR). The early-stage cohort was identified by eliminating metastatic and miscoded noninvasive carcinoma (stage 0) patients per clinical staging data.16 Patients with metastatic disease were additionally eliminated if either of the following were identified: (1) metastatic treatment protocols in New Drug Funding Program records or (2) advanced cancer diagnosis on inpatient admission records within 4 months of incident diagnosis. Finally, the cohort was limited to patients who received surgical treatment within 6 months of diagnosis per inpatient, ambulatory care, and health insurance billing records. Surgery was defined as modified radical mastectomy, partial mastectomy, or lumpectomy with the exclusion of needle biopsies or lymph node excision alone. Surgical treatment was limited to 6 months following diagnosis to allow for sufficient access to HER2 testing in patients who were diagnosed in late 2007. These exclusions isolated a patient population indicated for HER2 testing and potentially eligible for adjuvant trastuzumab treatment in Ontario (Figure 1). All follow-up was captured through administrative health data or medical records.

Variables, Sources, and Measurement

We collected variables measuring clinical, demographic, and healthcare system factors likely to influence HER2 test documentation or test usage. Administrative data were derived from several sources: (1) inpatient and outpatient procedures and diagnoses from Canadian Institute for Health Information Same Day Surgery,17 National Ambulatory Care Reporting System,17 and Discharge Abstract Databases18; (2) professional and procedure billing codes from the Ontario Health Insurance Program database; and (3) demographic information from the Institute for Clinical Evaluative Sciences Physician and Registered Persons databases.19 Incident diagnosis, institution of diagnosis, staging, laterality, and vital status were obtained from the OCR. Pathology reports submitted to CCO for OCR purposes were reviewed for HER2 testing, estrogen or progesterone receptor status, tumor grade, and testing laboratory. Whenever possible, we derived exclusion variables from multiple data sources to reduce the impact of nonreporting biases associated with a single data source. For example, surgical procedures were derived from Same Day Surgery, National Ambulatory Care Reporting System, and Ontario Health Insurance Program databases.

Data on the primary outcome, HER2 test documentation, were collected from pathology reports. We considered a patient to have HER2 test documentation when there was evidence in the pathology report that a HER2 test was requested or conducted. Detailed information was collected to document the type of test provided and sequencing. Testing was documented as IHC or FISH when any prespecified keyword (Table 1) was found in the report. A HER2 test was recorded as unknown when evidence of a HER2 test was present but the type was not distinguishable. The date of each HER2 test was recorded.

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