Abstract PD8-10: Glp-1 receptor agonist in combination with radiotherapy significantly delays tumor growth and improves overall survival in a murine model of triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a subtype of breast cancer that accounts for approximately 15-20% of all breast cancers and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. TNBC has the poorest prognosis among all breast cancer subtypes due to its molecular heterogeneity, high proliferation rate, and ability to undergo clonal evolution after treatment with chemotherapy. Despite remarkable improvement in the treatment of TNBC with chemoimmunotherapy (KEYNOTE-522, KEYNOTE-355), 37% of early-stage patients do not survive beyond the first 5 years following surgery. In the metastatic setting, the 5-year overall survival rate is a dismal 11%, highlighting the need for more effective therapies. A well-known significant risk factor for the development of TNBC is metabolic syndrome. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications approved for the treatment of type 2 diabetes mellitus and obesity that have garnered attention for their multifaceted roles beyond glycemic control, including in malignancy through modulating anti-tumor immunity and regulating signaling pathways involved in cancer cell growth and survival. Given their potential effect in breast cancer, we hypothesize that GLP-1RAs enhance the response to cytotoxic therapy, thereby delaying tumor growth and improving survival. Methods: Female C57BL/6 mice were inoculated with syngeneic EO771 TNBC cells, a murine model commonly used to mimic human TNBC, via intramammary injection in their lower mammary fat pads. Transplanted mice were treated when tumors achieved a minimum size of 300 mm3, at which time tumor-bearing mice were divided into the appropriate experimental cohorts with treatment groups receiving radiotherapy (RT) alone or radiotherapy combined with GLP-1 receptor agonist Exendin-4 (Ex-4). RT was given at a one-time dose of 16 Gy. Ex-4 was administered at a dosage of 30 nmol/kg body weight daily via IP injection. Tumor growth was quantitatively measured every 3 days throughout the studies using calipers until endpoint, defined as when the tumors reach a maximum size of 2000 mm3. Tumor size comparisons between experimental groups were analyzed using the 2-way ANOVA (Analysis of Variance) test. All end points were evaluated utilizing the Kaplan-Meier method. Hazard ratios (HR) were estimated using the Mantel-Haenszel method. All reported 95% confidence intervals (CI) are two-sided. Results: The results show that 14 days following RT, the combination of Ex-4 + RT (n = 6) significantly delayed tumor growth compared to RT alone (n = 7) (p = 0.0474). In addition, Ex-4 + RT significantly improved overall survival versus RT alone (HR 0.13, CI 0.03-0.59, p = 0.0081). The median survival of the RT cohort and Ex-4 + RT cohort were 18 days and 29 days, respectively, from the day of RT treatment. Additionally, we demonstrate that Ex-4-treated mice have altered immune cell composition compared to untreated mice, including changes in T cell subsets, B cells, and dendritic cells. Conclusion: Our results demonstrate that combination GLP-1RA and radiotherapy confers a significant delay in tumor growth and an improved overall survival benefit in a murine model of TNBC. Additional immunophenotypic and functional studies are ongoing to determine the mechanism by which combination treatment affects the anti-tumor immune response. Citation Format: L. Chen, E. Canseco, K. Asadipour, Y. Yuan, S. L. Stephen. Glp-1 receptor agonist in combination with radiotherapy significantly delays tumor growth and improves overall survival in a murine model of triple negative 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 PD8-10.