Assessing HER2 testing quality in breast cancer: variables that influence HER2 positivity rate from a large, multicenter, observational study in Germany

Abstract

Despite 410 years of routine human epidermal growth factor receptor 2 (HER2) testing in breast cancer, testing quality is still an issue. Guidelines recommend assessing HER2 positivity rates as a quality indicator; however, the extent to which patient-or tumor-related factors influence HER2 positivity is still unknown. The present study analyzed these influences to identify pathology centers with HER2 positivity rates unexplained by patient-or tumor-related factors. This observational, prospective study monitored routine HER2 testing at 57 institutes of pathology in Germany (January 2013-August 2014). Data collected included HER2 test result, patient-and tumorrelated factors, sample source, and method of sample retrieval. Factors influencing HER2 positivity rates were identified by multiple logistic regression. Individual center effects were assessed in an extended multiple logistic regression model by their statistical significance after adjusting for the combined effect of patient-or tumorrelated covariates and multiple testing. Analyses included 15 332 invasive breast cancer samples. Histologic grade showed the strongest influence on HER2 positivity, followed by hormone receptor status, histologic subtype, age, and nodal status (all Po 0.0001). The overall HER2 positivity rate across centers was 14.4% (range 7.1-27.3%). A statistically significant center effect on the HER2 positivity rate was identified for three centers (Po 0.05), with a trend toward a center effect for a further three (P o0.2). This study, the first of its kind, highlights that assessing HER2 testing quality with HER2 positivity rates should include standardized assessment of patient-or tumor-related characteristics to identify centers with HER2 testing quality issues more effectively. As treatment options for HER2-positive breast cancer continue to evolve, identifying the right patients is key. Overexpression of the human epidermal growth factor receptor 2 (HER2) protein or amplification of the HER2 gene occurs in~15-20% of all breast cancers. 1 HER2-positive breast cancer has a worse prognosis than HER2-negative disease, having an increased risk of recurrence and a more aggressive disease course. 2-4 HER2 is a prognostic biomarker predictive for the response to HER2-targeted therapies including the recombinant monoclonal antibodies trastuzumab and pertuzumab, and the antibody-drug conjugate ado-trastuzumab emtansine, all of which specifically target HER2 and are effective treatments for HER2-positive breast Correspondence: Professor J

Hormone- and HER2-receptor assessment in 33,046 breast cancer patients: a nationwide comparison of positivity rates between pathology laboratories in the Netherlands

“…Overall positivity rates were 87.2% for ER, 71.3% for PR and 9.9% for HER2, which, for ER and PR, is in line with previous studies [ 48 – 50 ], whereas for HER2 this is somewhat lower than the percentages of 15%–25% that are often referred to [ 7 , 14 , 16 , 26 , 51 – 53 ]. Although we only included synoptic pathology reports, there is no reason to assume that our synoptic dataset may have been selective, since data from the Dutch Breast Cancer Audit (NBCA), which also holds data from narrative pathology reports, show similar receptor positivity rates [ 49 ].…”

“…We believe that creating insight and awareness in variation of clinically relevant biomarkers through annual individual pathology “mirror” reports is an important step toward improvement in breast cancer care. Monitoring the receptor positivity rates may help to identify laboratories with a high number of false-positive or false-negative results [ 7 , 14 , 16 , 37 , 38 ] that are not picked up by the external audits, since crucial steps like tissue fixation and processing are not covered by these tests [ 36 ]. Furthermore, pathologists and their laboratories may feel best addressed by their own, case-mix adjusted, “mirror” data visualized against other national laboratories.…”

“…For case-mix correction, all available clinicopathological risk factors were selected a priori based on literature [ 14 , 38 , 45 – 47 ] and on pathologists’ experience. These factors included age, sex, tumor size, type of surgery, histologic subtype, tumor grade and either the combined hormone-receptor status (for HER2-analysis) or HER2-receptor status (for ER- and PR-analysis).…”

“…Recently, surveillance of positivity rates has been suggested as a tool to identify laboratories with insufficient testing assays and a high yield of false-positive or false-negative results [ 7 , 14 , 16 , 37 ]. However, as test accuracy is not the only potential factor in receptor positivity rates, it is important to also take patient and tumor characteristics into account [ 14 , 38 ]. Such a study design would enable laboratories and pathologists to compare their receptor positivity rates with other laboratories, while controlling for differences in population characteristics (“case-mix”) [ 38 ].…”

“…This may be crucial to create awareness, as pathologists and their laboratories may feel addressed by their own case-mix adjusted “mirror” data. Previous studies using such a design found significant variation between pathology laboratories in Germany with a range of HER2 positivity rates varying from 7.6 to 31.6% [ 7 , 14 ] with significant outliers even after case-mix correction [ 14 ]. To the best of our knowledge, such studies have not been performed for ER- and PR-receptor positivity rates.…”