Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer
Zimmerman BS, Esteva FJ. Cancers 2024

Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in approximately 20% of breast cancer cases. This overexpression is correlated with a more aggressive form of the disease and predicts a less favorable prognosis. Historically, the standard treatment for patients with HER2-positive breast cancer has involved chemotherapy in combination with monoclonal antibodies that target the HER2 receptor, notably trastuzumab and pertuzumab. However, resistance to these drugs has been ubiquitous, presenting challenges in the management of the disease. Antibody–drug conjugates (ADCs) represent a promising therapeutic category for the treatment of breast cancer. Trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are currently approved ADCs. These molecules have been pivotal, demonstrating superior clinical outcomes over previous conventional treatments in HER2-positive breast cancer (T-DM1, T-DXd) and HER2-Low (T-DXd). However, drug resistance remains an unresolved problem, and there is interest in developing better-tolerated and more effective therapeutics for breast cancer. This review focuses on the emergence of innovative HER2-targeted ADCs, including those currently undergoing investigation in clinical trials.