Abstract 3888: TOP1 mutations mediate cross resistance to ADCs in metastatic breast cancer

Abstract Background: Antibody-drug conjugates (ADCs) have improved survival for patients with metastatic breast cancer (MBC). In patients with HER2 negative MBC, two ADCs have FDA approval: sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd), both with topoisomerase-I (topo-I) inhibitor payloads. Given the many other ADCs in development, there is great interest in using ADC after ADC to maximize treatment benefit for patients. However, there is limited understanding regarding resistance mechanisms to ADCs and impact on ADC sequencing. We conducted a translational study to address this, and here we report the incidence of TOP1 mutations and clinical impact on ADC sequencing. Methods: All patients with MBC treated with ADCs at a large academic medical institution (Massachusetts General Hospital) who had comprehensive plasma-based genotyping (500 gene GuardantOMNI panel) were included. Since both SG and T-DXd have topo-I inhibitor-based payloads, we particularly focused on TOP1 mutations, variant allele frequency (VAF), and germline/somatic characterization. Incidence of TOP1 mutations in the ADC cohort was compared to The Cancer Genome Atlas (TCGA). Clinical “cross-resistance” was defined as progressive disease (PD) as best response to second ADC (ADC2) or treatment time on ADC2 of less than 60 days. Results: Based on comprehensive plasma-based genotyping we identified 4 distinct TOP1 mutations: S57C, R364H, W401C, G359E, at a frequency of 6.0% (4/67) at the time of disease progression on ADC compared to a frequency of 0.5% described in primary breast cancer in TCGA. Two of the amino acids found to be mutated are known to form direct interactions with the DNA backbone (G359) or the topoisomerase inhibitor itself (R364). For clinical resistance, one patient was briefly on ADC2 but stopped after 1 dose for toxicity; among the other 3 patients, two had cross-resistance to ADC after ADC, with both ADCs containing topo-I inhibitor payloads. Median duration on first ADC was 455 days compared to a median of 52 days for ADC2. Finally, one patient treated sequentially with 3 ADCs (all with topo-I inhibitor payloads) was found to have rising TOP1 VAF with progressive ADC treatments. Conclusion: This is the first report describing emergence of TOP1 mutations under selective pressure from ADCs and the impact on mediating cross-resistance to ADC after ADC with topo-I inhibitor payloads. Novel ADCs with alternative payloads may potentially be more effective when used sequentially after an ADC with a topo-I inhibitor. Further biomarker research is needed to optimize ADC sequencing for patients with TOP1 mutant MBC. Citation Format: Rachel Occhiogrosso Abelman, Haley Barnes, Arielle J. Medford, Annika Putur, Bogang Wu, Caroline Weipert, Geoffrey Fell, Laura M. Spring, Seth A. Wander, Beverly Moy, Andreas Varkaris, Dejan Juric, Leif Ellisen, Ryan Corcoran, Aditya Bardia. TOP1 mutations mediate cross resistance to ADCs in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3888.