TOP1 Mutations and Cross-Resistance to Antibody–Drug Conjugates in Patients with Metastatic Breast Cancer

作者：Rachel O. Abelman, Bogang Wu, Haley Barnes, Arielle J. Medford, Bryanna L. Norden, Annika Putur, Elena Bitman, Win Thant, Ting Liu, Caroline Weipert, Geoffrey Fell, Laura M. Spring, Seth A. Wander, Beverly Moy, Neelima Vidula, Steven J. Isakoff, Andreas Varkaris, Dejan Juric, Ryan B. Corcoran, Leif W. Ellisen, Aditya Bardia · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-24-2771 · 被引用次数：51 · 研究领域：HER2/EGFR in Cancer Research、Advanced Breast Cancer Therapies、Cancer Treatment and Pharmacology

PURPOSE: Antibody-drug conjugates (ADC) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer. However, knowledge of ADC resistance mechanisms and potential impact on the sequential use of ADCs is limited. In this study, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with metastatic breast cancer treated with ADCs with available posttreatment plasma-based genotyping were included. TOP1 mutation incidence, mutant allele frequency, and functional characterization were assessed, and incidence was compared with that in patients with metastatic breast cancer not receiving ADC treatment and in The Cancer Genome Atlas. RESULTS: Plasma-based genotyping identified distinct TOP1 mutations (S57C, R364H, W401C, and G359E) in 12.9% of patients (4/31) at the time of disease progression on ADC, compared with 0.7% (3/420) in non-ADC-treated patients with metastatic breast cancer and 0.5% in The Cancer Genome Atlas. The appearance of mutations was associated with clinical cross-resistance, as median duration on the first ADC was 455 versus 52 days for the second ADC. The functional characterization of three novel TOP1-mutant proteins demonstrated that all exhibited reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor ADC payloads SN38 and deruxtecan. CONCLUSIONS: We describe ...