Background: The three antibody-drug conjugates (ADCs) — sacituzumab govitecan (SG),trastuzumab deruxtecan (T-DXd), and trastuzumab emtansine (T-DM1) — that are FDA-approved for treatment of metastatic breast cancer (MBC) have markedly improved patient outcomes. However, most patients with MBC treated with ADCs ultimately have disease progression via either primary or acquired ADC resistance. Here, we characterized the transcriptomic profile of drug efflux genes in MBC prior to ADC treatment (tx) to elucidate biomarkers of response and resistance to SG, T-Dxd, and T-DM1.

Methods: We analyzed the transcriptomic tumor profile of six drug efflux pump genes (ABCB1,ABCC1–4, ABCG2) generated from pre-tx biopsies collected from patients with MBC (N = 453;36% TNBC, 26% HR+/HER2-, 20.5% HER2+, 19% NOS) 1 year prior to or up to 15 days post-tx with SG (n = 204), T-DXd (n = 178), or T-DM1 (n = 71). RNA-sequencing data were generated and processed with the Tempus xR assay. The correlation between duration of treatment (DoT) and gene expression was tested for all genes of interest using Pearson’s correlation coefficient. Cox proportional hazards models with risk set adjustment were used to test for associations between pre-tx gene expression and overall survival (OS), where gene expression was modeled as a continuous linear predictor. The proportional hazards assumption for OS was tested, and Cox modeling results were omitted when evidence of non-proportional hazards was detected. Given the exploratory nature of the analyses, all p-values are uncorrected and nominal statistical significance was set at p < 0.05.

Results: This diverse cohort had a median age of 52 and a range of races (55% White, 14%Black, 7.1% Other, 24% Unknown). Median DoT across all patients was 130 days. Higher expression of drug efflux pump genes was associated with shorter DoT for T-DXd (ABCB1:-0.290, p = 0.017; ABCC1: -0.274, p = 0.025). Additionally, higher expression of ABCB1 was associated with worse OS for T-DXd (HR: 1.30, 95% CI: 1.10 – 1.53, p = 0.002). In the SG cohort, no significant associations between efflux pump expression and DoT were found, but higher pre-tx ABCC1 and ABCC4 gene expression was associated with worse OS (HR: 1.34,95% CI: 1.02-1.75, p = 0.034; HR:1.19, 95%CI: 1.00-1.41, p = 0.042). In the T-DM1 cohort, no significant associations were found between efflux pump gene expression and DoT or OS.

Conclusions: Multi-modal analysis identified drug efflux pump gene expression as a potential biomarker of resistance, primarily to T-DXd. These findings should be further validated, and combinatorial clinical trial strategies may be explored.

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