Antibody-drug conjugates in breast cancer: Progress and future directions.

Abstract

Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer, enabling targeted delivery of potent cytotoxic payloads to antigen-expressing tumor cells. These agents have demonstrated efficacy across breast cancer subtypes, including chemotherapy-refractory disease and brain metastases, with manageable side-effect profiles. However, despite significant advances, identifying predictive biomarkers for response and understanding resistance mechanisms remain critical challenges that must be addressed to guide rational sequencing strategies and optimize combination approaches. The ADC platform offers remarkable versatility through diverse antigen targeting, variable linker chemistries enabling controlled payload release, multiple cytotoxic payload classes, and adjustable drug-to-antibody ratios. Next-generation platforms including bispecific targeting constructs, immune-stimulating antibody conjugates, and novel payloads such as PROTACs and RNA polymerase II inhibitors are being developed to further expand therapeutic applications. Realizing the full potential of these agents will require integrated biomarker development, a deeper understanding of resistance mechanisms, and optimized sequencing and combination strategies.