HER2-Low Breast Cancer: Biological Framework and Determinants of HER2 Instability

Human epidermal growth factor receptor 2 (HER2)-low breast cancer is a clinically relevant subgroup defined by low but detectable HER2 protein expression, immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization findings, positioned at the interface between traditional HER2-positive and HER2-negative disease. The recent introduction of antibody-drug conjugates (ADCs) has increased the clinical significance of borderline HER2 expression and exposed important diagnostic challenges, particularly in cases with very low levels of membrane staining, including the emerging HER2-ultralow category. Background and Objectives: This review summarizes the pathological and biological framework of HER2-low and HER2-ultralow breast cancer and critically appraises the magnitude, direction, and determinants of HER2 variability under systemic therapy. Particular focus is placed on treatment-associated shifts after chemotherapy, intratumoral heterogeneity, and pre-analytical and analytical factors that can influence HER2 assessment, with direct implications for therapeutic stratification and biomarker reassessment. Materials and Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science, focusing on studies published within the last five years. Eligible publications included clinical trials, retrospective cohorts, and translational or molecular studies that reported paired HER2 assessment in breast cancer and were interpreted according to American Society of Clinical Oncology/College of American Pathologists-aligned criteria. Results: Across major cohorts, HER2-low appeared to be the most dynamic category, with variability frequently observed following systemic therapy. Beyond treatment-related effects, shifts in HER2 status may be attributable to intratumoral heterogeneity and technical variability, with the greatest impact observed at the IHC 0-1+ interface. Conclusions: Given the clinical relevance of low-level HER2 expression, standardized testing and transparent reporting are essential, and HER2 reassessment may be justified in selected clinical scenarios to optimize access to HER2-directed therapies.