Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing.

Antibody-drug conjugates (ADCs) are a transformative approach in breast cancer therapy, offering targeted treatment with reduced toxicity by selectively delivering cytotoxic agents to cancer cells. While ADCs like trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have shown significant efficacy, resistance mechanisms such as antigen loss, impaired internalization, and efflux of cytotoxic payloads challenge their effectiveness. This review discusses these resistance mechanisms and explores advanced strategies to overcome them, including innovations in linker chemistry, multi-antigen targeting, and biomarker-driven personalization. Additionally, therapeutic sequencing - determining the optimal order of ADCs with other treatments such as chemotherapy, endocrine therapy, and immunotherapy - is examined as a crucial approach to maximize ADC efficacy and manage resistance. Evidence-based sequencing strategies, particularly for human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC), are supported by clinical trials demonstrating the benefits of ADCs in both early-stage and metastatic settings. The potential of combination therapies, such as ADCs with immune checkpoint inhibitors (ICIs), further highlights the evolving landscape of breast cancer treatment. As ADC technology advances, personalized approaches integrating biomarkers and optimized sequencing protocols offer promising avenues to enhance treatment outcomes and combat resistance in breast cancer.