International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-low and Ultralow Categories.

Abstract

The concept of "HER2-negative" breast cancer is evolving, with the recognition of HER2-low and HER2-ultralow subsets. These subsets are clinically relevant regarding treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which has shown survival benefit in patients with metastatic carcinoma with minimal HER2 protein expression that lack HER2 gene amplification by in situ hybridisation (ISH). In clinical trials using T-DXd, HER2-low was defined as immunohistochemistry (IHC) score 1+ or IHC score 2+ without HER2 gene amplification. HER2-ultralow was defined as faint or barely perceptible, incomplete membrane staining in >0 to ≤10% of tumour cells (IHC score 0+/with membrane staining) and HER2-null as complete absence of staining (IHC score 0/absent membrane staining). These results now necessitate more detailed evaluation and reporting of traditional "HER2-negative" results to identify patients with metastatic breast cancer who may benefit from T-DXd therapy. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have extended regulatory approval of T-DXd to patients with metastatic breast cancer showing HER2-low or HER2-ultralow expression. Updated clinical management guidelines now, therefore, incorporate the spectrum of HER2 results into treatment selection algorithms in the metastatic setting. To align histopathologic practice with these developments, the College of American Pathologists (CAP) has issued a new biomarker-reporting template that recommends explicit distinction between IHC 0/absent membrane staining and IHC 0+/with membrane staining. Key concerns among pathologists include assay variability, scoring reproducibility and quality assurance standards for accurately detecting such low levels of HER2 expression. This manuscript provides expert consensus, evidence-based practical recommendations for identifying and reporting tumours with HER2-low and HER2-ultralow expression. We emphasise standardised testing protocols, validated assays, robust internal and external controls, and focused training for pathologists. A universal structured pathology report is proposed to highlight the accurate distinction between IHC 0 (null), IHC 0+ (ultralow), and HER2-low expression.