Abstract PD3-02: Personalized Acquired CDK4/6i Resistance: Associations with Baseline Characteristics Like Obesity in Real-World (RW) Clinical-Multiomics Data

Abstract Introduction: CDK4/6 inhibition has become a cornerstone in the treatment (tx) of patients (pts) with HR+/HER2- advanced breast cancer (advBC) but resistance remains a major challenge. Understanding acquired resistance mechanisms associated with pt clinical and demographic characteristics is needed to more precisely optimize tx. Historically, a lack of robust RW clinical-multiomic data, including baseline details, limited research in this space. We leveraged a novel RW clinical-multiomics database with deep clinical data to assess differences in CDK4/6i resistance mechanisms based on baseline characteristics. Methods: This study used the US-based deidentified Flatiron Health (FH)-Caris Life Sciences Breast Cancer Clinical-Molecular Database, with clinical data from the FH Research Database linked to whole exome sequencing (WES), whole transcriptome sequencing (WTS), immunohistochemistry, and digital pathology data from Caris (data cutoff 12/31/2024). Study criteria included CDK4/6i (palbociclib, ribociclib, or abemaciclib) tx for advBC, ≥2 visits in the FH network, and either WES+WTS from a sample collected between -90d and +14d of CDK4/6i start (Cohort 1, pre-tx) or WES+WTS from a sample collected post CDK4/6i start and between -14d pre-progression and +21d post next tx start (Cohort 2, post-CDK4/6i progression). Characteristics were summarized with descriptive statistics. Differential expression, mutational prevalence, and gene ontology (GO) analyses were conducted for the full study population and by baseline obesity status (between -6m and +7d of CDK4/6i start). Results: A total of 1406 pts (Cohort 1, n = 1183; Cohort 2, n = 231) who received a CDK4/6i for advBC met study criteria (baseline characteristics summarized in Table 1). Post-CDK4/6i progression, ESR1 and RB1 alterations were enriched, and 232 genes were differentially expressed (FDR 0.01, log fold-change 0.5) including MUC5AC, ACAN, IGHV4-39, MEGF10, FAT3, and MMP9. GO analyses revealed distinct processes associated with CDK4/6i resistance depending on baseline obesity status. For pts with obesity, top distinct molecular processes with differential gene expression in post-progression samples included endopeptidase activity, FGF binding, and MHC class II receptor activity. Alternatively, for pts not obese at baseline, extracellular matrix, glycosaminoglycan binding, metabolic processes, collagen binding, and ERBB2 class receptor binding were the top unique GOs enriched in post-progression samples. Conclusion: Using a novel RW clinical-multiomics database, this study confirmed known biological associations related to CDK4/6i resistance and uncovered new ones. Critically, we identified distinctions in acquired resistance processes linked to baseline obesity, with potential implications for tx. These findings warrant further validation. Citation Format: K. M. Zimmerman Savill, L. Bouzit, N. Liao, C. Cho-Phan, S. Papillon-Cavanagh. Personalized Acquired CDK4/6i Resistance: Associations with Baseline Characteristics Like Obesity in Real-World (RW) Clinical-Multiomics Data abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD3-02.