Abstract PS5-08-05: Predictive Role of the Gut Microbiome in Abemaciclib-Associated Diarrhea: A Prospective Translational Pilot Study

Abstract Background: Abemaciclib, a CDK4/6 inhibitor, is approved for the treatment of both early-stage and metastatic HR+/HER2− breast cancer. While it improves survival outcomes, diarrhea remains the most frequent and dose-limiting adverse event, often resulting in treatment interruption, dose reduction, or discontinuation. Maintaining full-dose intensity is particularly crucial in the metastatic setting, where drug exposure is directly correlated with efficacy. Preclinical studies suggest that abemaciclib-induced gastrointestinal (GI) toxicity may result from off-target inhibition of GSK3β, leading to activation of the Wnt/β-catenin pathway and epithelial hyperproliferation. Meanwhile, the gut microbiome has emerged as a key regulator of mucosal integrity, immune homeostasis, and drug response. Inter-individual variability in microbiome composition and function may modulate susceptibility to abemaciclib-related GI toxicity. We hypothesize that baseline gut microbiome characteristics are associated with the incidence, severity, and trajectory of abemaciclib-induced diarrhea. Identification of predictive microbial features may inform microbiome-modulating strategies to improve tolerability and maintain full-dose therapy. Methods: This is a prospective, double-arm pilot translational study enrolling 90 patients with HR+/HER2− breast cancer initiating CDK4/6 inhibitor therapy. Participants will be assigned to two cohorts: one receiving abemaciclib, and the other receiving a comparator CDK4/6 inhibitor with minimal GI toxicity (e.g., palbociclib or ribociclib). The primary objective is to evaluate the association between baseline gut microbiome composition and function with the severity of abemaciclib-induced diarrhea. Stool samples will be collected at baseline (pre-treatment) and one month after treatment initiation. Comprehensive multi-omic analyses will be performed, including shotgun metagenomics for microbial genome reconstruction and functional pathway annotation using tools such as KEGG, MetaCyc, and MAC. Stool metabolomic profiling will be conducted to elucidate potential mechanistic pathways. Systemic biomarkers such as circulating cytokines, intestinal fatty acid-binding protein (I-FABP), and lipopolysaccharide-binding protein (LBP) will also be assessed to evaluate epithelial damage and microbial translocation. The primary endpoint is the association between baseline microbiome features and diarrhea severity, graded using CTCAE v5.0. Secondary endpoints include longitudinal microbiome changes, treatment adherence, dose intensity, and patient-reported GI symptoms. Exploratory analyses will identify microbial taxa and metabolic pathways linked to susceptibility or resilience to GI toxicity. This pilot study aims to elucidate the role of the gut microbiome in modulating abemaciclib-associated diarrhea and to identify predictive biomarkers of toxicity. Findings may support the development of microbiome-informed strategies to enhance drug tolerability and maintain therapeutic intensity in HR+/HER2− breast cancer. Citation Format: S. Lee, H. Park, I. LEE, Y. Chae, J. Lee, B. Kang, H. Park, J. Moon. Predictive Role of the Gut Microbiome in Abemaciclib-Associated Diarrhea: A Prospective Translational Pilot Study [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 PS5-08-05.