Abstract 4629: Plasma exosomal miRNA and disease progression in metastatic breast cancer on CDK4/6 inhibitors: A feasibility study

Abstract Background: Treatment resistance is common among metastatic breast cancer patients receiving CDK4/6 inhibitors (CDKi). Exosomal miRNA play a key role in intercellular communication and gene regulation that may predict treatment outcomes. We hypothesize that patient’s blood exosomal miRNA can uncover biological pathways critical for CDKi response and resistance. Methods: Plasma samples from metastatic breast cancer patients were prospectively collected every 12 weeks during CDKi treatment until discontinuation. Next generation sequencing was performed on isolated plasma exosomes for miRNA profiling. MiRNA independently associated with treatment response (hazard ratio [HR] < 1) and resistance (HR > 1) after Bonferroni correction were identified with mixed-effects Cox regression with time-to-disease progression as the outcome. We generated a miRNA-gene network using miRNet and performed pathway enrichment analysis of target genes using hypergeometric test. Results: Eleven patients provided 26 samples during CDKi treatment. Five (45%) progressed; they were more likely to be hormone receptor negative (40% vs 0%) and a race-ethnic minority (80% vs 17%). After adjustment, 54 and 18 miRNAs were associated with treatment response and resistance, respectively. A total of 48 pathways (false discovery rate [FDR] < 0.05) were identified in relation to treatment outcomes (Table 1). Of these, 25 pathways (52%, e.g. TGF-β, insulin, Jak-STAT) were associated exclusively with response, 2 (4%, long-term depression and oocyte meiosis) were associated with resistance, and 21 (44%, e.g. cell cycle, p53, neurotrophin) were shared by both. The study’s feasibility is demonstrated by the identification of numerous cell-cycle and cancer-specific pathways. Conclusion: This study highlighted the potential of exosomal miRNA as gene expression modulators to uncover key pathways underlying CDKi treatment outcomes. Findings warrant validation in independent studies. Citation Format: Ding Quan Ng, Julia Trudeau, Casey Hudson, Khai Kober, Kord M. Kober, Munjal M. Acharya, Alexandre Chan, Ritesh Parajuli. Plasma exosomal miRNA and disease progression in metastatic breast cancer on CDK4/6 inhibitors: A feasibility 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 4629.