Why Should HER2 Be Tested in Breast Cancer？
Worldwide, breast cancer is a common malignancy among women. Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2-directed monoclonal antibodies, HER2-positive breast cancer was associated with a relatively poor prognosis. With the advent of monoclonal HER2-targeting antibodies (e.g., trastuzumab and pertuzumab), clinical outcomes for HER2-positive breast cancer have improved dramatically, and a greater proportion of patients with nonmetastatic disease are now cured. Historically, however, HER2-negative tumors were not considered eligible for HER2-targeting agents because of the absence of oncogene addiction driven by HER2 gene amplification. The DESTINY-Breast04 (DB-04) and DESTINY-Breast06 (DB-06) clinical trials have since demonstrated the remarkable efficacy of T-DXd compared with physician's choice chemotherapy in patients with previously treated metastatic HER2-low and HER2-ultralow breast cancer.Both the US FDA and the European Medicines Agency have now extended the regulatory approval of T-DXd to patients with HER2-low tumors and, when hormone receptor-positive, to patients with HER2-ultralow unresectable or metastatic breast cancer, as defined in the DB-04 and DB-06 trials. Reflecting these approvals, the National Comprehensive Cancer Network and an expert consensus from the European Society for Medical Oncology have incorporated T-DXd into treatment pathways for metastatic breast cancer based on the specific details of HER2 IHC results.
Fig 1. Proposal for HER2 scoring algorithm
The Importance of Quality Control in Breast Cancer HER2 IHC Testing
HER2 exhibits membranous staining. However, a range of factors—including fixation, antigen retrieval, antibody clones, reaction time, temperature, and substrate concentration—can influence HER2 staining intensity. HER2 intratumoral heterogeneity, particularly in HER2-low breast cancer, together with the semi-quantitative and subjective nature of HER2 assessment, may lead to inter-observer variability and affect the accuracy of results.To ensure reproducibility and clinical utility, strategies for optimizing HER2 testing must include stringent quality control protocols and harmonized pathology reporting, thereby supporting informed and consistent clinical decision-making. These strategies include using validated HER2 IHC assays; employing appropriate internal and external quality controls with a range of expression (0, 1+, 2+, 3+); and participating in external quality assessment (EQA) programs for HER2 testing, among other measures.
References
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