GLP-1 RA for primary prevention of post-mastectomy lymphedema in breast cancer patients: A multicenter real-world analysis.

628 Background: Post-mastectomy lymphedema (PML) remains a significant morbidity for breast cancer (BC) survivors, particularly following axillary lymph node dissection (ALND). Complications, including recurrent cellulitis, lymphangitis, and chronic pain, significantly impair quality of life. While weight optimization is a cornerstone of PML management, the specific role of Glucagon-like Peptide-1 Receptor Agonists for the primary prevention of PML is poorly characterized. Data is limited to single-center retrospective studies (1) and case reports. This is the first, large-scale, multi-center, real-world analysis to evaluate the efficacy of GLP-1 RA for the primary prevention of PML in BC patients. Methods: Utilizing the TriNetX Global Collaborative Network, a retrospective cohort study was conducted on a population of 150 million patients across 108 healthcare organizations (Jan 2000 – Jan 2025). We evaluated the impact of GLP-1 RAs on the incidence of PML in BC patients. Patients were stratified into two cohorts: those who underwent mastectomy and received GLP-1 RAs, and a control group of mastectomy patients without GLP-1 RA exposure. 1:1 Propensity Score Matching (PSM) was used to balance cohorts for demographics, BMI, comorbidities, concurrent medications, and laboratory values. Following a median 650-day follow-up, hazard ratios (HR) and 95% Confidence Intervals (CI) were calculated using Kaplan-Meier survival analysis and Cox proportional hazards models to assess PML risk. Results: After 1:1 propensity score matching, 61,630 patients were included (n = 30,815 per cohort). The GLP-1 RA cohort had a mean age of 62.1 ± 10.8 years and was mainly female (99.2%). Racial distribution was 71.0% White, 18.0% Black or African American, and 2.9% Asian. Standardized mean differences for all matched covariates were <0.1, indicating excellent balance within the cohort. Kaplan-Meier survival analysis demonstrated a 63% significant reduction in incident PML among GLP-1 RA users compared to the control group (HR 0.373; 95% CI, 0.324–0.429; p < 0.0001). The absolute incidence of PML was 0.88% (258/29,259) in the GLP-1 RA cohort vs 2.58% (779/30,237) in the control group, yielding an absolute risk reduction of 1.7% and a number needed to treat (NNT) of 59. Conclusions: In this large-scale, real-world analysis, GLP-1 RA use was associated with a profound 63% reduction in the risk of PML. These findings suggest that GLP-1 RAs may serve as a potent primary preventive role in BC survivorship, potentially through mechanisms beyond weight loss, including systemic anti-inflammatory effects and a disease-modifying role in the lymphatic microenvironment. With a NNT of 59, incorporating GLP-1 RAs into the supportive care of high-risk BC patients could significantly reduce the burden of chronic lymphedema. Prospective randomized controlled trials are warranted to validate these results.