Antibody-Drug Conjugate Sequencing in Metastatic Breast Cancer

Antibody-drug conjugates (ADCs) have redefined the therapeutic paradigm of metastatic breast cancer by combining targeted antibody specificity with potent cytotoxic payloads. The regulatory approvals of sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd) and datopotamab deruxtecan (Dato-DXd) have expanded treatment options for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative and triple-negative breast cancer. However, as more patients become exposed to multiple ADCs during their disease course, optimal sequencing strategies remain undefined. This review discusses the evolving role of ADCs in the management of metastatic breast cancer and examines emerging evidence on their sequential use across different molecular subtypes. It summarizes findings from real-world studies and retrospective analyses that evaluate clinical outcomes, safety profiles and potential mechanisms of cross-resistance when ADCs are used sequentially. The biological determinants of response and resistance mechanisms are explored. Furthermore, this article outlines current guideline recommendations and highlights ongoing clinical and translational studies investigating sequencing approaches and biomarker-driven strategies. Collectively, these studies support the development of an individualized framework for ADC sequencing in metastatic breast cancer, bridging the current clinical practice with the emerging precision oncology paradigm. PEER REVIEWED ARTICLE **Peer reviewers:** Dr Jose Luis Sandoval, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland One anonymous peer reviewer Received on January 05, 2026; accepted after peer review on February 09, 2026; published online on February 16, 2026.