Association of endocrine therapy and cardiovascular disease outcomes in patients with estrogen receptor positive breast cancer

Estrogen receptor–positive (ER+) breast cancer accounts for approximately 70–84% of all breast cancer diagnoses, with aromatase inhibitors (AIs) and tamoxifen (a selective estrogen receptor modulator, SERM) serving as cornerstone endocrine therapies. While these treatments substantially improve cancer outcomes, cardiovascular disease (CVD) has emerged as a leading cause of non-cancer mortality among survivors. Although AIs are preferentially prescribed in postmenopausal women and increasingly in premenopausal women with ovarian function suppression (OFS) treatment, their comparative cardiovascular safety relative to tamoxifen remains incompletely defined, particularly in patients with pre-existing cardiovascular risk. We evaluated CVD outcomes associated with AI versus tamoxifen therapy across menopausal groups within a population enriched for baseline cardiovascular risk. We conducted a retrospective cohort study using deidentified electronic health records from the TriNetX Research Network (2013–2024). Women with cardiovascular risk factors (including obesity, dyslipidemia, hypertension, diabetes, tobacco use, or established atherosclerotic heart disease) and ER+ breast cancer were included. Two cohorts were analyzed: (1) premenopausal women (18–51 years) treated with AIs or tamoxifen in combination with OFS and (2) postmenopausal women (52–80 years) treated with AIs or tamoxifen. Primary outcomes included clinically diagnosed hypertensive disorders, encompassing essential hypertension and secondary hypertensive conditions, ischemic heart disease, pulmonary heart disease and pulmonary circulation disorders, included due to documented overlap with thrombotic and vascular cardiovascular events, atrial fibrillation/flutter, heart failure, atherosclerosis, and aortic aneurysm/dissection. Propensity score matching (1:1) was performed within each cohort. Associations were quantified using odds ratios (ORs) with 95% confidence intervals (CIs). In postmenopausal women, AI therapy was associated with significantly higher odds of multiple CVD outcomes compared with tamoxifen, including hypertensive diseases (OR 1.246, p < 0.0001), ischemic heart disease (OR 1.196, p < 0.0001), pulmonary heart disease (OR 1.245, p = 0.0011), atrial fibrillation/flutter (OR 1.399, p < 0.0001), heart failure (OR 1.265, p < 0.0001), and atherosclerosis (OR 1.330, p < 0.0001), while no significant difference was observed for aortic aneurysm/dissection (OR 1.056, p = 0.6856). In premenopausal women receiving OFS treatment, AI use was associated with higher odds of hypertensive diseases compared with tamoxifen (OR 1.985, p = 0.0105), while no significant difference was observed for heart failure (OR 1.179, p = 0.6777). Agent-specific analyses demonstrated that exemestane was generally associated with higher odds of several CVD outcomes compared with anastrozole and letrozole in both pre- and postmenopausal populations. In postmenopausal women, anastrozole was associated with lower odds of atherosclerosis compared with letrozole, while other cardiovascular outcomes did not significantly differ between these two non-steroidal AIs. Among women with ER+ breast cancer and baseline cardiovascular risk, AI therapy was associated with increased CVD outcomes compared with tamoxifen, particularly in postmenopausal patients. Among individual AIs, exemestane was generally associated with higher odds of several CVD outcomes relative to the non-steroidal agents. These findings highlight the importance of incorporating baseline cardiovascular risk and AI selection into endocrine treatment decisions for breast cancer survivors.