Redefining breast cancer: therapeutic opportunities in HER2-low and emerging molecular subtypes

Breast cancer classification has undergone significant evolution; however, the long-standing binary model distinguishing HER2-positive from HER2-negative disease is now recognized as overly simplistic and clinically limiting. Emerging evidence supports the identification of HER2-low (IHC 1 + or 2 + /ISH -) as a biologically heterogeneous and therapeutically actionable subgroup within the continuum of HER2 expression. This review synthesizes current advances in the understanding of HER2-low disease, with particular emphasis on its molecular characteristics, diagnostic challenges, and therapeutic implications in the era of precision oncology. The clinical relevance of HER2-low tumors has been propelled by the development of next-generation antibody-drug conjugates (ADCs), most notably trastuzumab deruxtecan, which has demonstrated robust survival benefits in patients previously classified as HER2-negative. These agents leverage low antigen expression through improved linker stability, high drug-to-antibody ratios, and a potent bystander effect, thereby expanding the scope of HER2-targeted therapy. In parallel, accumulating data reveal substantial biological complexity in HER2-low tumors, including variable hormone receptor co-expression, distinct genomic and transcriptomic signatures, and dynamic tumor microenvironment interactions. Key limitations such as inter-observer variability in HER2 assessment, intratumoral heterogeneity, and emerging resistance mechanisms-driven by drug efflux transporters and clonal evolution-are also critically examined. Furthermore, advances in liquid biopsy, artificial intelligence-assisted pathology, and multi-omics integration are redefining tumor stratification beyond static HER2 categorization. Overall, this review highlights HER2-low as a paradigm-shifting entity and underscores the need to harmonize diagnostic precision with innovative therapeutic strategies to optimize clinical outcomes.