Putting the Cardiovascular Safety of Aromatase Inhibitors in Patients with Early Breast Cancer into Perspective

Abstract

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.

A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer

“…As reported in a recent systematic review, treatment with AIs did not correlate with any definitive change or unfavorable effect on plasma lipoproteins [30], and in a sub-study of Japanese women from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial, exemestane or anastrozole treatment had no clinically significant effect on serum lipids in postmenopausal women with hormone-receptor-positive breast cancer [31]. Musculoskeletal symptoms and decreased bone mineral density are anticipated effects of hormonal therapies, such as AIs, that produce menopause-like effects [32].…”

“…Although results from two meta-analyses reported a higher risk of cardiovascular AEs associated with AIs compared with tamoxifen, these data have not been confirmed in a placebo-controlled trial, and available data do not support a substantial risk of ischemic cardiovascular events associated with AI treatment or differences in the risk of cardiovascular events for the different AIs [29, 30, 36–39]. Studies with longer follow-up time are needed to further define the cardiovascular safety profile of AI therapy.…”

Exemestane Use in Postmenopausal Women at High Risk for Invasive Breast Cancer: Evaluating Biomarkers of Efficacy and Safety

“…The strength of HDL as a cardioprotective factor is not as strong as previously thought, (44) but there are still concerns about the potential increase in cardiovascular risk in this healthy population. Younus et al (45) evaluated 22 papers that reported data regarding cardiovascular event incidence in women taking AIs from 8 randomized control trials. To date, no studies have shown that AIs increase cardiovascular risk but follow-up has been limited.…”

Role of aromatase in sex-specific cerebrovascular endothelial function in mice

“…Aromatase inhibitors (AIs), which are used clinically for treatment of breast cancer, carry the potential risk of increased cardiovascular events (5,22,28), in part mediated by the favorable effects of estrogen on plasma lipids (61) and vascular endothelial function (28). Although the link between the use of AIs and cardiovascular disease risk is still under investigation (33), aromatase gene polymorphisms in the human population have been shown to influence stroke and cardiovascular disease risk in a sexually dimorphic manner.…”