Advances in Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Low Tumors: From Trastuzumab to Antibody-Drug Conjugates.

The assessment of human epidermal growth factor receptor 2 (HER2) expression status has evolved from the traditional binary classification of positive/negative to a continuum that includes HER2-low expression. This shift has redefined the treatment landscape for approximately half of breast cancer patients. Trastuzumab, the cornerstone monoclonal antibody targeting HER2, significantly improves outcomes in HER2-high patients by blocking downstream signaling pathways and mediating antibody-dependent cellular cytotoxicity. However, its efficacy remains limited in tumors with low HER2 expression. In recent years, the emergence of antibody-drug conjugates (ADCs) has overcome this limitation. Represented by trastuzumab deruxtecan (T-DXd), a new generation of ADCs has successfully extended therapeutic benefits to HER2-low tumors through high drug-to-antibody ratios, cleavable linkers, and potent bystander effects. T-DXd has been established as the new standard of care for previously treated patients. This review systematically outlines the evolution of HER2 expression profiles, the mechanism of action and limitations of trastuzumab, and focuses on analyzing the breakthrough role of ADCs centered on trastuzumab emtansine (T-DM1) and T-DXd in HER2-low tumors, key clinical evidence, and adverse reaction management. Additionally, it explores the application prospects of combination strategies involving ADCs with chemotherapy and immunotherapy. Finally, the article summarizes challenges facing the current treatment paradigm and outlines future directions for standardized testing and novel therapeutic development.