Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study

SIMPLE SUMMARY: Biomarkers that define breast cancer treatment recommendations include estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth-factor receptor 2 (HER2); histological grade; and in many countries, the Ki67 proliferation index. However, the subjective nature and degree of variability in breast cancer biomarker assessment might result in under- or overtreatment. We demonstrated that limited variability exists in ER, PR, and HER2 positivity rates among 29 departments in Sweden, including 43,261 patients. However, even a few outlier labs affect endocrine and anti-HER2 treatment rates in a clinically relevant proportion, indicating a need for improvement. Despite international guidelines, standardized protocols, and external quality control procedures, very high variability was found in Ki67 scoring and histological grading, indicating a need for new methods. Monitoring rates of biomarker expression and treatments among departments should be mandatory in order to detect variability issues affecting the clinical management of breast cancer. ABSTRACT: We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.