Obomanu, Elvis

e16449 Background: Pancreatic cancer (PC) carries a dismal 5-year survival of < 12%, and no FDA-approved agents exist for primary prevention. PC risk is strongly linked to obesity, diabetes, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) directly target obesity-driven inflammatory pathways, reduce metabolic stress, and modulate signaling pathways (PI3K/AKT/mTOR) that drive cancer apoptosis. Based on this biological rationale, we conducted the first large-scale real-world study to evaluate the safety and efficacy of GLP-1RA for primary prevention of PC in high-risk patients. Methods: Leveraging a large real-world database (TriNetX), we identified patients aged 18-90 years with ≥1 PC risk factor (tobacco use, obesity, type 2 diabetes, alcohol use disorder, chronic pancreatitis, first-degree relative with PC, genetic susceptibility to PC) based on ICD-10 codes. Patients were stratified by GLP-1RA exposure into two cohorts: Cohort A (GLP-1RA users with ≥ 2 months of prescriptions) and Cohort B (controls). The primary endpoint was incident PC, and the secondary endpoints were adverse events related to GLP-1RAs. Patients with outcomes before the study window were excluded. Propensity score matching adjusted for confounders. Multivariate logistic regression was used to estimate odds ratios for categorical outcomes, and the Cox proportional hazards model was used to estimate hazard ratios for time-to-event outcomes. Subgroup and sensitivity analyses were employed to validate the strength of our results. Results: Median follow-up was 3,397 days for GLP-1RA users and 2,531 days for controls. Demographics were balanced between cohorts (mean age 42 years; 74% White, 15% Black; 72% female). Among 572,330 high-risk patients (286,165 per cohort), PC incidence was significantly lower among GLP-1RA users (0.05%; 134/286,165) than among non-users (0.13%; 362/286,097), with a 2.6-fold reduction in the absolute incidence of PC among high-risk patients (NNT of 1,255). GLP-1RA use was associated with a 71% reduction in PC incidence (HR 0.289; 95% CI 0.237–0.352). GLP-1RA use was associated with an increased risk of gastrointestinal adverse events, including nausea/vomiting (HR 1.108; 95% CI 1.096–1.121), abdominal pain (HR 1.081; 95% CI 1.066–1.097), diarrhea (HR 1.199; 95% CI 1.182–1.217), and constipation (HR 1.159; 95% CI 1.143–1.176). Conclusions: GLP-1RA use significantly reduced PC incidence by 71% in high-risk patients, the strongest real-world signal yet for a pharmacologic prevention of this lethal malignancy. Although the absolute incidence remained low, the magnitude of the risk reduction underscores the transformative potential of GLP-1RA in preventive oncology. These findings address a critical unmet need in pancreatic oncology. Prospective mechanistic and randomized studies are warranted to validate these associations.

10522 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. While antiviral and metabolic therapies have reduced incidence, scalable pharmacologic strategies for primary prevention (PP) remain a critical unmet need. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated preclinical antitumor activity and the potential to mitigate hepatic lipotoxicity while promoting metabolic reprogramming to stabilize cirrhosis. However, while chemoprevention signals are observed in metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, the efficacy of GLP-1RAs for PP across diverse liver disease etiologies remains underexplored. To address this gap, we conducted a global, multicenter analysis on the efficacy and safety of GLP-1RAs for the PP of HCC in a pan-etiology high-risk cohort. Methods: A retrospective cohort study was conducted using the TriNetX database (150M patients across 108 health organizations). Adults 18–90 years at elevated HCC risk with ≥ 1 risk factor (chronic viral hepatitis, cirrhosis, MASLD, alcohol use disorder, or hereditary liver disorders) were identified. Cohort A (≥3 months of GLP-1RA) was propensity score-matched 1:1 with Cohort B (non-users) on demographics, HbA1c, BMI, and MELD-Na scores. The primary endpoint was incident HCC, and secondary endpoints were incidence of gastrointestinal (GI) side effects. We employed a 3-month lag period to mitigate immortal time bias. Time-to-event outcomes were assessed via Kaplan-Meier analysis and Cox proportional hazards models. Sensitivity & subgroup analyses were performed to confirm robustness across non-metabolic etiologies. Results: After matching, 592,718 patients were analyzed (296,359 per cohort). Median follow-up was 2,450 days for GLP-1RA users vs 2,114 days for non-users. GLP-1RA use was associated with a 73% reduction in incident HCC (140/296,345 events vs 432/296,198) [HR 0.271 (0.224-0.328)], (NNT=1,015). Notably, the protective effect was most pronounced in non-diabetics [HR 0.179 (0.140-0.229)] and lean patients (BMI < 29) [HR 0.161 (0.103-0.252)]. Risk reductions were sustained across all etiologies, including alcohol liver disease (HR 0.379), cirrhosis (HR 0.456), chronic viral hepatitis (HR 0.477), and MASLD (HR 0.605). GLP-1RA use was associated with a significant increase in GI adverse events. Conclusions: GLP-1RA use was associated with a 73% reduction in incident HCC, consistent across subgroups. The enhanced benefit in non-diabetic and lean cohorts suggests a direct anti-neoplastic mechanism independent of weight loss or glycemic control. The NNT of 1,015 highlights the substantial public health impact of GLP-1RA therapy in preventing a high-mortality malignancy. These findings warrant prospective validation.

Abstract Introduction: Endocrine therapy (ET) is central to treating hormone receptor-positive breast cancer (BC), but its side effects impact adherence and quality of life, especially in patients with metabolic dysfunction. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer cardiometabolic benefits, potentially improving inflammation, glycemic control, and physical well-being. However, data on SGLT-2 use in BC patients is scarce. This study is the first to evaluate the real-world effects of SGLT-2 inhibitors on all-cause mortality and ET tolerability in BC patients. Methodology: We conducted a real-world analysis using the TrinetX database, which includes data from 184 million patients in 156 healthcare organizations, to identify BC patients on ET (letrozole, anastrozole, exemestane, tamoxifen) who received SGLT-2 inhibitors vs. those who did not. Patients were grouped by age (≤50 and ≥51 years as a surrogate for menopausal status. Primary outcome: all-cause mortality from the start of the index event, defined as the first day meeting BC diagnosis and ET use, with or without SGLT-2. Secondary endpoint: ET tolerability. Propensity score matching completed by TriNetX adjusted for confounders. Multivariate analysis yielded odds ratios and risk differences with 95% CI. Results: Among 1,136 BC patients ≤50 years, 568 were assigned to each group (SGLT-2 vs non-SGLT-2). For patients ≥51 years (n=28,600), each group included 14,300. Demographics across cohorts were comparable. No mortality benefit was seen in premenopausal patients. In postmenopausal women, SGLT-2 use reduced all-cause mortality—647/13,676 events (SGLT-2) vs 953/13,517 (non-SGLT-2) [OR: 0.655 (0.591-0.726)]. In premenopausal patients, SGLT-2 reduced endometrial cancer risk [RD: -0.018 (-0.029, -0.007)] but increased diarrhea risk [OR: 2.305 (1.078, 4.930)]. No significant differences were found in hot flashes, PE, DVT, depression, osteoporosis, joint pain, fatigue, nausea/vomiting, abdominal pain, or dizziness. Among postmenopausal patients, SGLT-2 reduced PE [OR: 0.757 (0.605-0.948)] and osteoporosis [OR: 0.877 (0.784-0.981)], but increased risks of depression [OR: 1.153 (1.007-1.319)], nausea/vomiting [OR: 1.120 (1.001-1.253)], diarrhea [OR: 1.193 (1.058-1.345)], and dizziness [OR: 1.234 (1.103-1.380)]. No significant differences were found for hot flashes, DVT, EC, joint pain, fatigue, or abdominal pain. Conclusion: This analysis reveals novel evidence supporting the cardiometabolic potential of SGLT-2 inhibitors in hormone receptor-positive BC, particularly postmenopausal populations. These agents were linked to lower all-cause mortality and improved tolerance of specific ET-related effects. However, certain adverse risks require caution. Future prospective studies are essential to validate their role and safety in oncologic care. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Evaluating all-cause mortality and endocrine therapy tolerability with sodium glucose cotransporter-2 inhibitors in hormone receptor-positive breast cancer: A real-world analysis [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 PS1-05-28.

Abstract Introduction: Endocrine therapy (ET) improves survival in hormone receptor-positive breast cancer (BC) but has side effects that may affect compliance. GLP-1 receptor agonists (GLP-1 RA), used for diabetes and obesity, possess anti-inflammatory properties and may reduce cancer incidence. Their impact on all-cause mortality and ET tolerability remains underexplored. This real-world analysis is the first of its kind to examine the effects of GLP-1 RA on these outcomes. Methods: We used de-identified data across 130 million patients and 108 health systems from the TriNetX database to identify obese women (BMI ≥30) with BC receiving ET. Patients were grouped by GLP-1 RA exposure into age cohorts (≤50 and ≥51 years, as a surrogate for menopause). The primary endpoint was all-cause mortality; the secondary endpoint was ET tolerability. The index event was the first day meeting all criteria: BC and obesity diagnoses, and initiation of ET ± GLP-1 RA. Patients with outcomes before the study window were excluded. Propensity score matching performed by TriNetX adjusted for demographics, diabetes, comorbidities, cancer stage, and prior chemotherapy. Multivariate logistic regression assessed associations (risk ratios [RR], 95% CIs). Results: After matching, 2,574 patients were assigned to the age ≤50 group: Cohort A (GLP-1 RA exposure, n=1,287) and Cohort B (non-exposure, n=1,287). 13,012 patients were in the age ≥51 group: Cohort C (GLP-1 RA exposure, n=6,506) and Cohort D (non-exposure, n=6,506). In the ≤50 group, the mean age at index event was 42.3 ± 5.2, 99.5% female, 68.9% White, 16.9% Black, and a mean BMI of 37 in Cohort A, with similar demographics and BMI in Cohort B. In the ≥51 group, there was a mean age at index event of 61.8 ± 7.7, 99% female, 71.7% White, 17.4% Black, and a mean BMI of 37 in Cohort C with similar demographics and BMI in Cohort D. GLP-1 RA use significantly reduced all-cause mortality in all cohorts. In the age ≤50 group, there were 29/1,242 events in Cohort A and 71/1,258 in Cohort B [RR 0.414 (0.271-0.633)]. In the age ≥51 group, there were 240/6,287 events in Cohort C and 400/6,285 in Cohort D [RR 0.600 (0.513-0.701)]. GLP-1 RA use worsened ET side effects. In the age ≤50 group, GLP-1RA increased the risk of hot flashes [RR: 1.473 (1.235-1.756)], venous thromboembolism (VTE) [RR: 1.439 (1.090-1.902)], nausea/vomiting [RR: 1.460 (1.242-1.717)], abdominal pain [RR: 1.353 (1.184-1.545)], diarrhea [RR: 1.319 (1.096-1.589)], joint pain [RR: 1.382 (1.243-1.536)], and depression [RR:1.634 (1.382-1.932)]. No significant risk was found in endometrial cancer (EC) and osteoporosis. In the age ≥ 51 group, GLP-1 RA use increased hot flashes [RR: 0.1.239 (1.091-1.407)], [RR:0.591 (0.482-0.724)], nausea/vomiting [RR: 1.429 (1.324-1.542)], abdominal pain [RR: 1.310 (1.227—1.399)], diarrhea [RR: 1.446 (1.328-1.575)], joint pain [RR: 1.334 (1.270-1.400)], osteoporosis [RR: 1.110 (1.026-1.201)], and depression [RR: 1.536 (1.413-1.670)]. No significant differences were noted in VTE and EC risk. Conclusion: This real-world analysis demonstrates that GLP-1RA use is associated with a significant reduction in all-cause mortality among obese BC patients undergoing ET. However, GLP-1 RA exposure appears to exacerbate several ET-related adverse effects. Future prospective studies are needed to determine these associations as they may warrant clinical consideration. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Real-world Analysis on the Impact of GLP-1 Receptor Agonists on All-cause Mortality and Endocrine Therapy-Tolerability in Obese Breast Cancer Patients [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 PD8-06.