Canola, Marcela Mazo

10520 Background: Therapeutic options for breast cancer (BC) prevention for high-risk women remain limited, and not all eligible patients opt for endocrine therapy due to concerns related to adverse events (AEs). GLP1RAs are widely used for obesity and type 2 diabetes mellitus; their role in BC primary prevention (PP) in high-risk women with obesity has not been evaluated. Methods: Using the TriNetX Global Network (150 million patients, 108 organizations), we analyzed de-identified records of high-risk women aged 18–90 years with a BMI ≥ 30 who had health care encounters between January 1, 2000, and January 1, 2025, identified via ICD-10 codes. High risk was defined as at least one of the following: genetic predisposition to BC, family history of BC, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or dense breasts. Patients were grouped as having GLP1-RA use or no GLP-1RA use. Patients with a prior history of BC or use of endocrine therapy were excluded. GLP-1RA users were propensity score-matched 1:1 with non-users based on demographics, comorbidities, social determinants of health, lifestyle factors, BMI, HbA1c, and prior breast imaging. Incident BC served as the primary endpoint, with key AEs as secondary measures. Kaplan–Meier analysis and Cox proportional hazards models were utilized to assess outcomes, which were further validated through subgroup and sensitivity analyses. Results: Among 80,480 high-risk women with a BMI ≥ 30, 46,581 were assigned to each cohort. Baseline demographics were balanced between cohorts (mean age: 46 years, 70% White, 21% Black). Median follow-up was 2,790 vs 2,630 days for GLP-1RA users and non-users, respectively. BC incidence was 2.95% in GLP-1RA users (1,164/39,495 cases) vs 3.01% in non-users (1,200/39,057 cases) (3.27 vs. 3.57 cases per 1,000 person-years; HR 0.844; 95% CI, 0.779–0.915). GLP-1RA users exhibited an increased risk of endometrial cancer (HR 1.273; 95% CI, 1.088–1.491) and osteoporosis (HR 1.124; 95% CI, 1.054–1.199). No significant association was observed for venous thromboembolism. Gastrointestinal AEs were significantly higher in the GLP-1RA cohort. Conclusions: GLP-1RA use was associated with a modest reduction in BC incidence among high-risk women with obesity in this real-world study. Prospective randomized trials are needed to validate these associations.

Abstract Background: Latin Americans are more likely to be diagnosed with aggressive early-stage breast cancer compared to Non-Hispanic White. Multiple factors may contribute to this, including metabolic factors and ancestry. In a previous study, we identified upregulated immune pathway genes in Luminal B tumors from obese Black patients compared to matched White patients. In this study, we report clinical and transcriptomic profiles of breast tumors from Latin and White patients to enhance understanding of factors contributing to aggressive tumor biology in Latin patients. Methods: We matched 311 Latin and 311 White breast cancer patients enrolled in FLEX by age, T stage, N stage and clinical subtype (ER/PR and HER2 status). FLEX (NCT03053193) is a prospective, observational trial that includes stage I-III breast cancer patients who receive MammaPrint (with or without BluePrint) as standard of care and consent to whole transcriptome and clinical data collection. MammaPrint is a 70-gene risk of distant recurrence signature that classifies patients as Low Risk or High Risk. BluePrint is an 80-gene molecular subtyping signature, categorizes tumors as Luminal-, HER2- or Basal-Type. MammaPrint further groups Luminal into A (Low Risk) and B (High Risk). ImPrint is a 53-gene signature that has been shown to predict the likelihood of achieving pCR with PD1-PDL1 immune checkpoint inhibitors. Statistical analyses on groups were conducted using arsenal R package and p-value < 0.05 was considered significant. Whole transcriptome comparisons were made, using limma R package, between Latin and White patients stratified by BluePrint subtype Luminal and weight categories normal (body-mass-index (BMI) 18.5 to < 25) and obese (BMI ≥30). Significant differentially expressed genes had an adjusted p-value < 0.05. Gene set enrichment analysis (GSEA) was conducted using fgsea R package. Results: Latin patients had significantly higher percentage of type 2 diabetes (23.3% vs 8.5%), BMI obese (49.0% vs 39.4%), BluePrint Basal (14.8% vs 9.3%) and ImPrint Immune Sensitive (12.0% vs 5.1%) compared to matched White patients. When comparing whole transcriptome of tumors from Latin and White patients, only tumors stratified by Luminal B and obesity resulted in differentially expressed genes: Latin patients had higher expression (>2-fold change) of 42 immunoglobulin genes compared to White, with only IGKV6-21 being statistically significant. Additional immune related genes such as IKZF1 and AGER, as well as UTS2 (gene encoding a vasoconstrictor agent and contributor of angiogenesis) were significantly upregulated in Latin patients. Upregulation of immune related pathways such as inflammatory response, interferon alpha/gamma response and downregulation of adipogenesis, oxidative phosphorylation and MYC targets were identified in Latin patients compared to White using GSEA Hallmarks gene sets. Conclusion: There were additional clinical and genomic differences between tumors from Latin and White patients, even when controlling for age, T stage, N stage and clinical subtype. Particularly, there were more type 2 diabetes, BMI obese, BluePrint Basal, and ImPrint Immune Sensitive among Latin patients. In addition, transcriptomic differences between obese Latin and matched White patients were found in Luminal B subgroup that may contribute to the aggressive tumor biology; immunoglobulin genes and immune related pathways were associated with higher expression in Latin patients. This study suggests that biological differences in breast tumors, particularly from obese patients, may result from shared background and reflects the need for inclusion of diverse patient groups in clinical trials. Citation Format: Marcela Mazo-Canola, Virginia Kaklamani, Pooja Advani, Sailaja Kamaraju, Alfredo A. Santillan-Gomez, Robert Maganini, Julie Barone, Sahra Uygun, Lavanya Samraj, William Audeh, Joyce O'Shaughnessy, FLEX Investigators' Group. Racial disparities in breast cancer and effect of obesity: MammaPrint, BluePrint and whole transcriptome analyses of tumors in Latin American patients in FLEX trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS18-04.