Abstract PS3-05-26: Triple incretin receptor agonist induced weight loss delays tumor latency in obesity-associated breast cancer

Abstract Objective: To evaluate the impact of GLP-1R/GIPR/GCGR agonist-associated weight loss on breast cancer (BC) risk and tumor progression. Background: BC is the second leading cause of cancer death among women in the US. Obesity increases the risk of multiple cancers, including BC. Previous pre-clinical studies demonstrated that GLP-1 receptor agonists promote weight loss, improve metabolic dysfunction, reduce cancer risk and blunt progression in pancreatic and lung cancer, but effects on spontaneous BC were unknown. Hypothesis: To assess the impact of a novel triple incretin receptor agonist (TIRA) on BC risk and tumor progression in mice with obesity-associated metabolic dysfunction. Methods and Approach: Female FVB C3(1)-T antigen (“C3Tag”) mice, a genetically engineered mouse model (GEMM), which develop BC spontaneously, were utilized to evaluate effects of medical weight loss on tumor risk and outcomes. Overweight mice were subjected to: 1) vehicle (VEH) control to maintain body weight; 2) TIRA as weight loss intervention; or 3) caloric restriction to allow for weight matched (WM) controls. Mice were fed a high-fat diet from 8 weeks of age. After gaining weight, they received subcutaneous TIRA (15 nmol/kg) or vehicle every other day. One group was sacrificed at 15 weeks to investigate preneoplastic lesions in the mammary gland. The second group was allowed to proceed to endpoint to examine tumor latency, progression, and survival. N=10-12 per group. Gut microbiome and circulating mediators were quantified by proteomics and metabolomics. One way ANOVA was used. Results: TIRA and WM induced significant body weight loss (∼15-20%) within 2-3 weeks, followed by weight stabilization, with reduced circulating leptin concentration compared to VEH. TIRA and WM also reduced 4-hour fasting blood glucose, decreased gonadal white adipose tissue, and mammary fat pad mass. Moderately reduced muscle mass was observed in TIRA and WM mice in the preneoplasia group but not in the long-term survival group. TIRA delayed gastric emptying revealed by higher cecal contents compared to VEH and WM in the preneoplasia group. TIRA-induced ceramide, metabolite, and microbiome changes were evident. In the survival group, TIRA significantly delayed tumor latency compared to VEH. Conclusion: TIRA and WM effectively induced weight loss and improved metabolic dysfunction with both interventions demonstrating significantly reduced adiposity, hyperglycemia, and tumor-promoting adipokines. TIRA-associated weight loss significantly delayed tumor onset whereas WM did not, suggesting a TIRA-specific anti-tumor effect. Results demonstrate that pharmacological weight loss suppressed early tumor progression - despite being in a transgenically driven GEMM - and improved outcomes in obesity-associated BC. Citation Format: N. Pervaiz, S. J. Marathe, Z. Powell, L. G. McGrath, Z. T. Mustafa, L. Wang, M. C. Playdon, S. A. Summers, J. Hao, B. Li, J. F. Pierre, L. Makowski. Triple incretin receptor agonist induced weight loss delays tumor latency in obesity-associated breast cancer [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 PS3-05-26.