Genomic and Transcriptomic Mediators of Resistance to Antibody-Drug Conjugates (adcs) in Metastatic Breast Cancer (MBC): A Comprehensive Multi-Center Study

ADCs have revolutionized the therapeutic landscape in oncology. Three ADCs are US FDA-approved in MBC: sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), with many others in development. Despite these advances, ADC resistance mechanisms remain unknown. To discern biomarkers of therapeutic resistance, we evaluated genomic and transcriptomic differences in MBC before and after ADC treatment (tx). We analyzed next-generation sequencing (NGS) data from patients (pts) in the Tempus Database that received SG, T-DXd or T-DM1 pre or post biopsy (bx) (nSG=157, nT-Dxd=120, nT-DM1=84; 32.4% TNBC, 27.1% HR+/HER2-, 20.2% HER2+, 20.2% NOS). Pre-tx groups included pts with bx collected < 1 year before or < 15 days after the ADC start date. Post-tx groups included pts who had bx collected < 3 months (mo) after ADC end date. Acquired resistance (AcqRes) was analyzed by comparison of pre- and post-tx bx for pts treated with ADC for > 3 mo. Primary resistance (PrRes) was defined as pre- and post-tx bx for pts treated with ADC for < 3 mo. We evaluated resistance based on ADC mechanisms of action (MoA), including genes related to antigen expression, processing mechanism, payload effect and efflux pumps. Somatic differences were compared using Pearson’s Chi-squared test or Fisher’s exact test, as appropriate. In this exploratory analysis, all p-values are reported as uncorrected. The median log2(TPM) gene expression was compared between groups using the Wilcoxon rank sum exact test. In the AcqRes cohort, there were no significant differences in mutation frequency or expression of the target antigen for pre/post-SG or T-DXd bx, though in the pre- vs post-T-DM1 bx there was a decrease in ERBB2 alterations (69% vs 40%, p=0.047) and expression (10.9 vs. 8.4, p=0.024). A trend toward higher expression across efflux pump genes was seen in pts with AcqRes for SG (ABCB1: 2.7 vs 3.4, p=0.08; ABCC2: 2.4 vs 3.4, p=0.2) and T-DXd (ABCC1: 6.3 vs. 6.7, p=0.016; ABCB1: 2.77 vs. 3.44, p=0.4), with mixed changes in T-DM1 (ABCB1: 3.3 vs. 2.7, p=0.08; ABCC1: 6.3 vs. 6.8, p=0.05; ABCC2: 3.19 vs. 3.18, p=0.2). A trend of higher efflux pump gene expression was associated with PrRes to SG and T-DXd. Overall, there were no significant differences in expression of genes associated with ADC processing or DNA damage repair, though rare mutations in TOP1 and ATM were associated with PrRes to T-DXd. Genomic and transcriptomic analysis identified potential mechanisms of AcqRes and PrRes to SG and T-DXd, including higher drug efflux pump expression. This might be related to the ADC MoA, particularly the payload release and bystander effect. Additional research is needed to validate these novel findings and the molecular underpinnings mediating resistance to ADCs. Samer Alkassis, Marla Lipsyc-Sharf, Catherine Hegarty-Traverso, Jacob Mercer, Binyam Yilma, Stamatina Fragkogianni, Yuan Yuan, Funda Meric-Bernstam, Hope Rugo, Joyce O’Shaughnessy, Mothaffar Rimawi, Rachel Schiff, David Elashoff, John Glaspy, Martina McDermott, Amy Cummings, Calvin Chao, Aditya Bardia. Genomic and transcriptomic mediators of resistance to antibody-drug conjugates (ADCs) in metastatic breast cancer (MBC): A comprehensive multi-center study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1711.