The “ADC-after-ADC” paradigm: navigating cross-resistance and sequencing in breast cancer therapy

Antibody–drug conjugates (ADCs) are entering earlier lines of breast cancer therapy, but evidence guiding treatment after a prior ADC remains limited. We performed a structured narrative synthesis of prospective post–prior-ADC studies, peer-reviewed retrospective cohorts, human translational analyses, functional preclinical studies, regulatory documents, and trial registries through July 23, 2026. No completed trial has randomized clinically comparable patients between alternative ADC sequence orders. DESTINY-Breast02 demonstrates trastuzumab deruxtecan activity after trastuzumab emtansine, whereas DESTINY-Breast03 is a head-to-head construct comparison and not a sequential-treatment study. Retrospective cohorts show that a second ADC can retain activity, but usually report shorter progression-free survival, real-world progression-free survival, or time to treatment failure than with the first ADC. These findings cannot isolate biological cross-resistance from later treatment line, disease evolution, intervening therapy, selection, changing fitness, toxicity, and non-equivalent endpoints. Longitudinal human studies support selected target-level and payload-level mechanisms, including decreased HER2 expression and acquired TOP1 alterations; generalized trafficking failure, efflux-mediated cross-resistance, and clinical rescue through linker or payload switching remain predominantly preclinical or hypothesis-generating. Sequential decisions should therefore be anchored to subtype-specific prospective evidence and current indications, then refined by the reason the prior ADC stopped, current target eligibility, central nervous system disease, prior toxicity, organ and marrow reserve, non-ADC alternatives, access, and patient goals. Current evidence supports individualized decision-making, not a validated universal sequence.