Application and Progress of Antibody-Drug Conjugates (ADCs) in the Treatment of Metastatic Triple-Negative Breast Cancer

Abstract

Metastatic triple-negative breast cancer (TNBC) lacks actionable targets, and chemotherapy yields median progression-free survival (mPFS) of 4.6-9.7 months and median overall survival (mOS) of 12.6-26.3 months. Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors only help subsets (objective response rate [ORR] of ~ 5% and ~ 12%, respectively). Antibody-drug conjugates (ADCs) have emerged as a leading therapeutic strategy: sacituzumab govitecan extended mPFS to 5.6 months (ASCENT trial), SKB264 to 6.7 months, and datopotamab deruxtecan achieved an ORR of 79%. In Human epidermal growth factor receptor 2 (HER2)-low TNBC, trastuzumab deruxtecan prolonged OS to 18.2 months, while disitamab vedotin and SHR-A1811 achieved ORRs of 26% and 60%, respectively. ADCs targeting Human epidermal growth factor receptor 3 (HER3)-, Nectin-4-, LIV-1- and folate receptor α (FRα) showed responses in 22%-54% of cases. Resistance can arise via antigen loss, endocytic defects, lysosomal failure, and efflux pumps. Bispecific ADCs, linker optimization, and combination regimens (ICI, PARPi) are under investigation. Future efforts will focus on targeting epidermal growth factor receptor (EGFR) and FRα and on developing multimodal immunovascular strategies to sustain clinical benefit.

Keywords: Antibody-drug conjugate; Human epidermal growth factor receptor 2; Metastatic triple-negative breast cancer; Trophoblast cell surface antigen 2.

Fig. 1

Mechanisms of ADCs resistance in TNBC therapy. The figure was created in BioRender.com. ADCs antibody-drug conjugates, TNBC triple-negative breast cancer