Antibody-drug conjugates in breast cancer: the first-line and curative setting

Antibody-drug conjugates (ADCs) have rapidly advanced from later-line salvage therapy into first-line metastatic and curative perioperative settings. This review appraises recent practice-changing data that collectively redefined treatment standards across Human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, and hormone receptor-positive/HER2-negative breast cancer.

Three trials, DESTINY-Breast09, DESTINY-Breast05, and DESTINY-Breast11, established the role of T-DXd across first-line metastatic and perioperative HER2-positive settings, with both early breast cancer indications receiving FDA approval in May 2026. In triple-negative disease, ASCENT-04/KEYNOTE-D19 established sacituzumab govitecan plus pembrolizumab as new first-line option for Programmed cell death ligand 1 (PD-L1)-positive metastatic TNBC. Meanwhile, TROPION-Breast02 had led to the approval of Datopotamab deruxtecan (Dato-DXd) for the first-line treatment of immunotherapy-ineligible patients with metastatic TNBC, whereas ASCENT-03 led to the NCCN incorporation of first-line sacituzumab govitecan for the same population. Multiple further neoadjuvant and adjuvant ADC trials are expected to further reshape treatment algorithms over the coming years.

ADCs now hold regulatory and guideline approval as preferred first-line options across all major breast cancer subtypes, in both the metastatic and curative perioperative settings. Proactive ILD surveillance is essential across all approved agents. Remaining challenges include sequencing among topoisomerase I inhibitor-payload ADCs and awaiting mature survival readouts from perioperative trials.