Women with estrogen receptor–positive (ER+) breast cancer who carry cardiovascular risk factors may face different heart-related outcomes depending on which endocrine therapy they receive, according to a retrospective cohort study published in the journal Cardio-Oncology. The research, based on deidentified electronic health records from the TriNetX Research Network covering 2013 to 2024, compared aromatase inhibitors (AIs) with tamoxifen, a selective estrogen receptor modulator (SERM), across two distinct patient groups: premenopausal women aged 18 to 51 and postmenopausal women aged 52 to 80. The findings suggest that in postmenopausal patients, AI therapy was associated with significantly higher odds of several cardiovascular disease (CVD) outcomes compared with tamoxifen, while in premenopausal women receiving ovarian function suppression (OFS), the differences were narrower.
ER+ breast cancer accounts for approximately 70 to 84 percent of all breast cancer diagnoses, making endocrine therapy a cornerstone of treatment for the vast majority of patients. Aromatase inhibitors, which include anastrozole, letrozole, and exemestane, work by blocking the enzyme responsible for estrogen production in postmenopausal women and are increasingly used in premenopausal women when combined with OFS. Tamoxifen, by contrast, acts as a selective estrogen receptor modulator, blocking estrogen receptors in breast tissue. While both approaches substantially improve cancer outcomes, cardiovascular disease has emerged as a leading cause of non-cancer mortality among breast cancer survivors, raising questions about the comparative cardiovascular safety of these agents, particularly in patients who already have pre-existing cardiovascular risk.
The study focused specifically on women with cardiovascular risk factors, including obesity, dyslipidemia, hypertension, diabetes, tobacco use, or established atherosclerotic heart disease, creating a population enriched for baseline cardiovascular vulnerability. Researchers used propensity score matching in a 1:1 ratio within each cohort to balance confounding variables between the AI and tamoxifen groups. Primary outcomes included clinically diagnosed hypertensive disorders, encompassing essential hypertension and secondary hypertensive conditions, as well as ischemic heart disease, pulmonary heart disease and pulmonary circulation disorders, atrial fibrillation or flutter, heart failure, atherosclerosis, and aortic aneurysm or dissection. Pulmonary heart disease and pulmonary circulation disorders were included due to documented overlap with thrombotic and vascular cardiovascular events. Associations were quantified using odds ratios (ORs) with 95 percent confidence intervals.
In postmenopausal women, the results showed that AI therapy was associated with significantly higher odds of multiple CVD outcomes compared with tamoxifen. Specifically, hypertensive diseases showed an odds ratio of 1.246 (p < 0.0001), ischemic heart disease an odds ratio of 1.196 (p < 0.0001), pulmonary heart disease an odds ratio of 1.245 (p = 0.0011), atrial fibrillation or flutter an odds ratio of 1.399 (p < 0.0001), heart failure an odds ratio of 1.265 (p < 0.0001), and atherosclerosis an odds ratio of 1.330 (p < 0.0001). The only outcome that did not reach statistical significance was aortic aneurysm or dissection, which showed an odds ratio of 1.056 with a p-value of 0.6856. These findings indicate that across nearly every measured cardiovascular domain, postmenopausal women receiving aromatase inhibitors in this risk-enriched population had modestly but consistently higher odds of adverse cardiac outcomes than those receiving tamoxifen.
In premenopausal women receiving OFS treatment alongside their endocrine therapy, the picture was different. AI use was associated with higher odds of hypertensive diseases compared with tamoxifen, with an odds ratio of 1.985 and a p-value of 0.0105. However, no significant difference was observed for heart failure, which showed an odds ratio of 1.179 with a p-value of 0.6777. This narrower pattern of associations in the premenopausal group suggests that the cardiovascular signal may be more pronounced in postmenopausal patients, though the study was not designed to establish causation and the retrospective design limits the strength of any causal inference.
Beyond the class-level comparison, the researchers also conducted agent-specific analyses to determine whether individual aromatase inhibitors carried different cardiovascular risk profiles. These analyses demonstrated that exemestane, a steroidal AI, was generally associated with higher odds of several CVD outcomes compared with both anastrozole and letrozole, the two non-steroidal AIs, in both pre- and postmenopausal populations. Additionally, 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 agents. This granularity within the AI class suggests that the choice of specific aromatase inhibitor may matter for cardiovascular outcomes, not just the choice between AI and tamoxifen.
The authors concluded that 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. They emphasized that these findings highlight the importance of incorporating baseline cardiovascular risk and AI selection into endocrine treatment decisions for breast cancer survivors. The study does not establish that aromatase inhibitors cause cardiovascular disease; rather, it identifies associations within a large, real-world dataset of patients already carrying cardiovascular risk factors. As a retrospective cohort study using electronic health records, it is subject to the limitations inherent in observational designs, including potential residual confounding and reliance on clinically diagnosed rather than prospectively adjudicated outcomes.
These results arrive at a moment when the growing population of breast cancer survivors is living longer, and non-cancer mortality, particularly from cardiovascular disease, is becoming an increasingly prominent concern in cardio-oncology. The study’s focus on a population enriched for baseline cardiovascular risk provides clinically relevant data for oncologists and cardiologists who must weigh the oncologic benefits of endocrine therapy against potential cardiovascular consequences in vulnerable patients. The findings do not suggest that aromatase inhibitors should be avoided, but they do underscore that treatment selection may benefit from a more nuanced consideration of each patient’s cardiovascular profile and the specific agent being prescribed.
The research adds to a broader conversation in cardio-oncology about how cancer therapies interact with cardiovascular health over time. With ER+ breast cancer representing the majority of diagnoses and endocrine therapy typically spanning five to ten years, even modest differences in cardiovascular odds across treatment options could translate into meaningful population-level effects. The study’s use of propensity score matching within a large real-world dataset strengthens the comparability of the treatment groups, though the authors note that further research would be needed to confirm these associations prospectively and to determine whether the observed differences reflect biological mechanisms, patient selection patterns, or other factors not captured in the electronic health record data.
Subject of Research: Cardiovascular outcomes associated with aromatase inhibitor versus tamoxifen endocrine therapy in women with ER-positive breast cancer and baseline cardiovascular risk
Article Title: Association of endocrine therapy and cardiovascular disease outcomes in patients with estrogen receptor positive breast cancer
Article References: Kovilakath, A., Harrell, J. C., Hundley, W. G., Cassel, B., & Salloum, F. N. (2026). Association of endocrine therapy and cardiovascular disease outcomes in patients with estrogen receptor positive breast cancer. Cardio-Oncology. https://doi.org/10.1186/s40959-026-00600-0
Image Credits: AI Generated
DOI: 10.1186/s40959-026-00600-0
Keywords: breast cancer, estrogen receptor positive, aromatase inhibitors, tamoxifen, cardiovascular disease, cardio-oncology, endocrine therapy, ovarian function suppression, hypertension, heart failure, atherosclerosis, TriNetX
News Source: Nathaniel Bowman. (November 6, 2026). Aromatase inhibitors linked to higher cardiovascular risk than tamoxifen in women with ER-positive breast cancer. Scienmag.
