Extended adjuvant endocrine therapy in hormone-receptor positive breast cancer

Abstract

A high ongoing recurrence rate in patients with endocrine responsive breast cancer provides the rationale for offering endocrine treatment for more than five years. The MA.17 study, comparing the aromatase inhibitor (AI) letrozole for five years after an initial five years of tamoxifen to no further treatment, provided the proof-of-principle for extended endocrine treatment. These results have meanwhile been confirmed by several other studies and an EBCTCG meta-analysis. More recently, data from the ATLAS trial, comparing 10 to five years of tamoxifen, have been published, similarly showing a benefit for longer endocrine treatment with tamoxifen. In postmenopausal women -including those who had been premenopausal at initial diagnosis - a cross-trial comparison of ATLAS and the AI studies indicates superiority of switching to letrozole versus ongoing tamoxifen, similar to superiority of the AIs over tamoxifen in the metastatic and early breast cancer settings.

Extended adjuvant endocrine therapy in hormone-receptor positive early breast cancer: Current and future evidence

“…In a review published in 2013, Strasser-Weippl et al performed an unofficial analysis comparing extended therapy using AIs with tamoxifen after 5 years of tamoxifen. Comparing hazard ratios of two separate studies, they state that switching to an AI after 5 years of tamoxifen appears beneficial over continuing with tamoxifen, and that it would lead to a larger recurrence rate reduction and a better overall survival [44]. Although comparing hazard ratios of different studies is controversial, this would be in accordance with the findings in 'regular' adjuvant treatment that AI-containing regimes have better outcomes compared to tamoxifen monotherapy.…”

HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo

“…Aromatase inhibitors are already in clinical use and are frequently used for example as adjuvant treatment for breast cancer together with selective estrogen receptor modulators, such as tamoxifen [79][80][81], while HSD17B1 inhibitors are currently under development [82]. However, aromatase inhibitors may cause serious adverse effects [83], due to the almost complete suppression of the estrogen action. Suggested by animal experiments, the modulation of the concentration of active estrogens in the target tissues by HSD17B1 inhibition is expected to induce less severe side effects than the total estrogen ablation [67].…”

The changing role of ER in endocrine resistance

“…Tamoxifen, which has been used as an effective anti-estrogen therapy since the 1970s 6,7 , continues to represent the standard adjuvant treatment for many pre-menopausal women with ER+ tumors, though recent results also suggest a potential role for adding ovarian suppression to tamoxifen or using AIs instead for higher risk tumors in this setting 8,9 . Over the past decade AIs have been shown to be more effective than tamoxifen in postmenopausal women in both early and advanced stages of ER+ breast cancer 10 . A more potent inhibition of ER with SERDs, such as fulvestrant, preferably at high doses as suggested from recent studies (reviewed in 11 ), may improve patient outcome by preventing or delaying resistance in both early and metastatic settings.…”