Adjuvant Endocrine Therapy for Breast Cancer: Don't Ditch the Switch!

Abstract

The meta-analysis has been an invaluable tool in the evaluation of adjuvant therapy for breast cancer and has supported the use of tamoxifen, anthracyclines, and taxanes via the compilation of results from small trials that individually yielded less than dramatic results. Indeed, recent results of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis demonstrated the enduring benefit in 15-year recurrence-free and overall survival for 5 years of adjuvant tamoxifen for women of any age with earlystage steroid receptor–positive breast cancer (1). It also confirmed an age-related increase in the risks of thromboembolic events and endometrial cancer without an excess in non-breast cancer–related deaths. In recent years, the use of tamoxifen in postmenopausal women has been eclipsed by enthusiasm about aromatase inhibitors. Multiple studies have documented a greater reduction in breast cancer recurrence and a seemingly more favorable toxicity profile with aromatase inhibitors compared with tamoxifen, which has led to their widespread use over tamoxifen, despite the fact that an overall survival benefit with this approach has not been observed. These results have led to guidelines by entities such as the American Society of Clinical Oncology (2) and the National Comprehensive Cancer Network (3) stating that aromatase inhibitors should be considered in place of or in sequence with tamoxifen for most postmenopausal women with early-stage hormone receptor–positive breast cancer. The emergence of data from large trials of adjuvant aromatase inhibitors has enabled several meta-analyses to be performed, one of which is reported by Amir et al. (4) in this issue of the Journal. The authors hypothesized that the relative toxicity of aromatase inhibitors compared with tamoxifen could explain the discordant observation of their improved benefit in disease-free survival without enhanced overall survival benefit. Their meta-analysis was restricted to seven randomized controlled trials that enrolled 30 0 23 patients and compared 5 years of aromatase inhibitor, 5 years of tamoxifen, or a switch from one to the other as primary endocrine therapy. In addition to conventional breast cancer endpoints, they focused on six prespecified serious adverse events —cardiovascular disease, cerebrovascular disease, bone fracture, thromboembolic events, endometrial carcinoma, and other non-breast cancers. In large part, the analysis confirmed what we already know: Compared with tamoxifen, the use of aromatase inhibitors was associated with a statistically significant increase in bone fractures and decrease in endometrial cancer and thromboembolic events and no difference in the risks of second cancers. What we learned, however, was that there was no difference in the risk of cerebrovascular disease with tamoxifen compared with aromatase inhibitors, and the risk of cardiovascular disease was statistically significantly higher with aro matase inhibitors compared with tamoxifen, although the magnitude of the difference was small—an absolute difference in risk of 0.8% and a number needed to harm of 132. It is notable that use of up-front aromatase inhibitors was also associated with a nonstatistically significantly higher odds of death without breast cancer recurrence compared with the use of tamoxifen alone or switching from tamoxifen to aromatase inhibitors (odds ratio = 1.11, 95% confidence interval = 0.98 to 1.26, P = .09). Of particular interest was the finding that those treated with a switching strategy had a statistically significant reduction in the odds of death without breast cancer recurrence compared with those treated with 5 years of tamoxifen or 5 years of an aromatase inhibitor alone (odds ratio = 0.87, 95% 95% confidence interval = 0.77 to 0.99, P = .03). In absolute terms, the difference is exceedingly small—a 0.2% difference in absolute risk of death without breast cancer recurrence. From these findings, Amir et al. ( 4) concluded that the switching strategy allows patients to reap the positive benefits of the aromatase inhibitors while limiting potential toxicity.