A new look at old problems: Ovarian function suppression in the real world

Breast cancer mortality has significantly declined over the past 4 decades in developed countries, including the United States, with recent evidence suggesting that among women younger than 70 years, improved treatment accounts for most of the progress. The development of HER2-directed therapies, the use of taxanes and dose-dense chemotherapy regimens, and the emergence of aromatase inhibitors (AIs) for postmenopausal women have all contributed. Despite demonstrated improvements for women of all ages, young women (40 years old or younger at diagnosis) appear to remain at increased risk for breast cancer mortality in comparison with older women. Recent well-controlled analyses have shown that the independent prognostic effect of young age is breast cancer subtype–specific and most evident in luminal-type breast cancers. Luminal breast cancers express hormone receptors and thus are particularly susceptible to endocrine manipulations: adjuvant endocrine therapy or the chemo-endocrine effect of chemotherapy in premenopausal women. Although the prognostic value of chemotherapy-induced amenorrhea was acknowledged for many years, the role of ovarian ablation as a part of modern endocrine therapy for early breast cancers developing in premenopausal women has been long debated. Initially published in 2014 and 2015, the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) trials, respectively, provided clear evidence supporting the benefit of adding pharmacological ovarian function suppression (OFS) to tamoxifen therapy and the incremental benefits of treatment with OFS and exemestane, an AI. In the 2018 update of SOFT, the combination treatment resulted in higher rates of both disease-free survival and overall survival than tamoxifen alone, particularly among women retaining a premenopausal estradiol status after chemotherapy. These practice-changing findings were rapidly implemented into professional guidelines; however, little real-world data detailing the use of OFS by providers and patients have been available to date. In this issue of Cancer, Reeder-Hayes et al present an analysis using a commercial insurance claims database (IBM MarketScan) and describing trends in the use of OFS as part of adjuvant endocrine treatment for early breast cancer from 2001 to 2016 and its effect on adherence to the oral agent. To approximate a premenopausal population, only women younger than 50 years at drug initiation were included, and anyone starting an AI without concomitant OFS was excluded. In this large population of 21,948 women, use of OFS rose steeply in the last 2 years of the study period from an average annual prevalence of <4% to 7.2% in 2015 and 11.3% in 2016. This finding is consistent with the trend reported for a similarly defined cohort from 5 large centers in Portugal, although the absolute rates were higher: an average of 15.5% in 2006-2013 rising to 25% in 2014-2015. Potential explanations for the lower rates reported by Reeder-Hayes et al include later adoption of OFS in the United States in a general population in comparison with specialized centers in Europe, where a higher risk population may be referred and for which OFS may have been more clearly indicated. Because the SOFT/TEXT results were first published in 2014, both analyses offer only an early glimpse at OFS uptake, and future studies will be needed to determine when and where a plateau is reached. Nevertheless, now that it is clear that OFS improves survival for select premenopausal women with hormone receptor–positive early breast cancer, implementation of this strategy for higher risk young survivors should mitigate, at least in part, disparities in this population. However, there are barriers to the potential widespread adoption of OFS. The addition of OFS to tamoxifen increases the risk of menopausal symptoms and hinders sexual activity, with some women reporting a decrease in quality of life. An AI versus tamoxifen in this situation does not seem to significantly affect quality of life, although it is associated with a distinct toxicity profile: more vaginal dryness, greater loss of sexual interest and difficulties in