Toxicities of Antibody–Drug Conjugates in Breast Cancer: From Mechanistic Insights to Clinical Management

Background/Objectives: Antibody–drug conjugates (ADCs) have transformed the therapeutic landscape of breast cancer, expanding treatment opportunities across multiple disease settings. However, their increasing clinical use has revealed a heterogeneous spectrum of toxicities that extends beyond conventional chemotherapy-related adverse events. Emerging evidence suggests that ADC-associated toxicities are driven by a complex interplay between ADC structural characteristics, including target antigen expression, payload properties, linker stability, drug-to-antibody ratio, and patient-related susceptibility factors. This review aims to provide a comprehensive overview of ADC-related toxicities in breast cancer, integrating mechanistic insights with clinical management strategies and risk-adapted approaches. Methods: A narrative review of the literature was conducted focusing on clinical trials, real-world studies, translational investigations, and mechanistic evidence related to ADC-associated toxicities in breast cancer. Particular attention was given to the relationship between ADC design, toxicity mechanisms, patient-specific risk factors, and clinical management. Results: ADC-related toxicities encompass a broad range of adverse events, including hematologic toxicity, interstitial lung disease, gastrointestinal complications, hepatotoxicity, peripheral neuropathy, stomatitis, ocular toxicity, dermatologic adverse events, and cardiovascular manifestations. Current evidence indicates that toxicity profiles differ substantially across ADCs and are influenced by multiple factors, including payload class, linker chemistry, target biology, intracellular trafficking, bystander effects, systemic payload exposure, and host-related characteristics. While several toxicities can be anticipated through careful monitoring and early intervention, clinically significant variability remains, and validated predictive biomarkers are largely lacking. Emerging real-world evidence further highlights the importance of individualized toxicity assessment and multidisciplinary management. Conclusions: ADC-related toxicity should be viewed as a multifactorial biological process resulting from the interaction between ADC design and host susceptibility rather than as a uniform class effect. A mechanistic understanding of toxicity pathways may improve risk stratification, toxicity monitoring, and personalized management strategies. Future research should focus on the development of predictive biomarkers, pharmacologic risk models, and next-generation ADC platforms with improved therapeutic indices. This review proposes an integrated framework linking ADC structural determinants, toxicity mechanisms, and clinical management to support safer and more individualized use of ADCs in breast cancer.