GLP-1 therapy and hormone receptor–positive breast cancer risk and survival: A real-world analysis.

Abstract

10548 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management and cardiometabolic risk (CMR) reduction, yet their association with breast cancer (BC) incidence and survival in non-diabetic women with elevated BMI remains unclear. We evaluated the relationship between GLP-1 RA exposure and incident BC, as well as overall survival (OS), in a large real-world (RW) cohort of women without laboratory-defined diabetes. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network including female patients (pts) with BMI 25–35 kg/m². Age <50 vs ≥50 years served as proxies for pre- and postmenopausal status, with a ≥50 sensitivity analysis to assess age/menopause confounding. Pts with HbA1c ≥6.5% or prior BC were excluded. Cohorts were propensity score matched (PSM) on age at index, BMI, metformin and statin exposure, BRCA mutation status, hormonal contraceptive use, parity, breastfeeding history, and smoking status. The primary endpoint was incident HR+/HER2− BC, summarized as incidence proportion and risk reduction estimates; secondary analyses evaluated HR+/HER2+, HR−/HER2+, and triple-negative breast cancer (TNBC). OS was evaluated using Kaplan–Meier and Cox regression. Results: After PSM, 148,709 pts were included (mean age 45.8 ± 9.54 years in both cohorts). Over a median 36-month follow-up, incident HR+/HER2− BC was lower with GLP-1 RA vs controls (0.29% vs 0.33%), with an absolute difference −0.04% (95% CI −0.081 to −0.001%; P=0.046) and RR 0.88 (95% CI 0.77–0.99). OS was improved with GLP-1 RA vs controls (HR 0.75, 95% CI 0.65–0.86; P<0.0001). No difference in BC incidence was found for HR+/HER2+ (RR 0.98, 95% CI 0.86–1.12) or HR− subtypes, including HR−/HER2+ BC (RR 0.83, 95% CI 0.55–1.23) and TNBC (RR 0.68, 95% CI 0.41–1.12). Findings for HR+/HER2− were consistent across menopausal strata (Table). In the postmenopausal cohort (n=91,577; mean age 63.3 ± 6.88 vs 62.4 ± 6.52 years), GLP-1 RA exposure was also associated with lower incidence of HR+/HER2− BC (RR 0.93, 95% CI 0.86–0.99) and improved OS (HR 0.87, 95% CI 0.81–0.94; P=0.0003). Conclusions: In a large non-diabetic cohort of women with BMI 25–35 kg/m² and no prior BC, GLP-1 RA exposure was associated with a modest reduction in incident HR+/HER2− BC and improved OS. Despite limited follow-up and age-based menopausal proxies, these findings provide RW evidence supporting prospective validation with standardized exposure definitions and longer follow-up. Future studies should clarify whether GLP-1 RAs confer direct antitumor effects or indirect benefits mediated through weight loss and CMR reduction and identify pts most likely to derive BC risk and survival benefit. GLP-1 RA and HR+/HER2− BC outcomes. RR (Breast Cancer Incidence) HR (Overall Survival) Age <50 0.88 (0.77–0.99) 0.75 (0.65–0.86) Age ≥50 0.93 (0.86–0.99) 0.87 (0.81–0.94)