Adjuvant endocrine therapy use in female breast cancer survivors and the risk of cardiovascular disease

BACKGROUND: Women diagnosed with oestrogen receptor positive breast cancer are prescribed endocrine therapies, tamoxifen or aromatase inhibitors (AI), to block the effects of oestrogen on the growth of tumour cells. Tamoxifen is known to be associated with an increased risk of venous thromboembolic events, but the long-term effect of both tamoxifen and AI use on the risk of a range of distinct cardiovascular diseases (CVD) remain unclear. METHODS: Two studies were carried out using prospectively collected data from the UK Clinical Practice Datalink linked with Hospital Episode Statistics, and data from the US SEER-Medicare database, to assemble cohorts of postmenopausal women diagnosed with breast cancer. Cox proportional hazards regression models were used to examine the associations between tamoxifen and AIs and a comprehensive range of CVDs in both the UK and US study populations. The UK study directly compared AI users with tamoxifen users; the US study included a third “unexposed” group of women with oestrogen receptor positive breast cancer prescribed no endocrine therapies. RESULTS: Results in the UK study suggested a pattern of an increased risk of non-venous CVDs in AI compared with tamoxifen users, with evidence of an increased risk of heart failure and arrhythmias in AI compared with tamoxifen users (adjusted HR: 1.70, 95% CI: 1.26-2.29; adjusted HR: 1.38, 95% CI 1.12-1.70 respectively). The US study then suggested that these associations may be driven by a decreased risk of non-venous CVD outcomes in tamoxifen users compared with those unexposed, with adjusted HRs ranging from 0.44 (95% CI: 0.30-0.63) in the myocardial infarction analysis to 0.91 (95% CI: 0.75-1.10) in the peripheral vascular disease analysis. Evidence of a modest reduced risk of several non-venous CVD outcomes among AI users compared with those unexposed was also observed, but results were suggestive of residual confounding. As expected there were more venous thromboembolic events in tamoxifen users compared with both AI users and those unexposed. There was a general consistency between comparable results in the two studies. CONCLUSIONS: Among postmenopausal women diagnosed with breast cancer, there was convincing evidence of a higher risk of several non-venous CVDs in those prescribed an AI compared with those prescribed tamoxifen, but this appeared to be driven by protective effects of tamoxifen on these outcomes, rather than any toxic effects of AIs. The known association between tamoxifen use and an increased risk of venous thromboembolism was also confirmed. As more postmenopausal women diagnosed with oestrogen receptor positive breast cancer are prescribed AIs rather than tamoxifen, additional large-scale population based studies are needed to better understand the risk-benefit balance of endocrine therapies with respect to both cancer and cardiovascular outcomes