PI-047 - GENOME-WIDE ASSOCIATION STUDY IDENTIFIES GENETIC VARIANTS ASSOCIATED WITH CARDIOVASCULAR ADVERSE EVENTS IN BREAST CANCER PATIENTS TREATED WITH AROMATASE INHIBITORS: RESULTS FROM THE ALL OF US.

M. Tantawy¹, D. DeRemer², L. Ricks-Santi², D. Wang³, C. McDonough⁴, K. Daily², Y. Gong⁵; ¹University of Florida, University of Florida- Gainesville, FL, USA, ²University of Florida, University of Florida - Gainesville, FL, USA, ³University of Florida College of Pharmacy, University of Florida - Gainesville, FL, USA, ⁴Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida., Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida - Gainesville, Florida., USA, ⁵University of Florida, GNV, United States.

Background: Breast cancer (BC) is the most prevalent cancer among women in the United States. Globally, BC affects 2.1 million women annually, with hormone-dependent BC comprising approximately 70% of cases (75% in postmenopausal women). The use of therapies such as aromatase inhibitors (AIs) have improved survival rates, yet these treatments are associated with an increased risk of cardiovascular adverse events (CVAE), especially in patients with pre-existing cardiovascular disease (CVD). This study investigates the association between AI treatment and CVAE in BC patients and germline genetic variants and AI-related CVAE.

Methods: We included female BC patients (ICD-9 code 174; ICD-10 codes C50.0-C50.9) aged ≥18 years who received AIs (anastrozole, exemestane, or letrozole) after BC diagnosis. A total of 2,554 female BC patients treated with AIs and genotyped with the global diversity array in the All of Us (AoU) database was identified, comprising 73.9% non-Hispanic White (NHW,) 10.1% non-Hispanic African American (NHAA), and 16% Hispanic individuals. CVAE defined as patients with congestive heart failure, ischemic stroke, myocardial infarction, and cardiomyopathy were identified after BC diagnosis using validated ICD codes, patients with one of CVAE before AIs treatment were excluded. We conducted a genome-wide association analysis (GWAS) using HAIL in 2,144 female BC patients including1887 NHW), and 257 NHAA). The analysis was conducted using logistic regression and adjusted for age, hypertension, hyperlipidemia, and diabetes.

Results: Among 2144 BC patients, 180 (9.5%) NHW and 39 (15%) NHAA patients developed CVAE post-treatment, (p = 0.007) with an odds ratio (OR) of 1.77. In NHW, the SNP rs17178963 near the HMGA2 gene (p = 1.11 × 10^-7, OR=2.35, 95% confidence interval (CI) = 1.71–3.22 was associated with CVAE. This SNP was also identified as an eQTL in tibial artery in GTEx (p = 0.00014). In NHAA, SNP rs4567786 in the 3’ UTR of the H3-3B gene (p = 1.48 × 10^-6, OR=8.34 and 95% CI=3.52–19.8) was associated with CVAE.

Conclusion: This study identified SNPs in HMGA2 and H3-3B as being associated with CVAE in NHW and NHAA BC patients, respectively. Further research is required to elucidate the biological mechanisms underlying these associations.