Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials

OncoTargets and Therapy
OncoTargets and Therapy

Background: Ovarian function suppression (OFS) significantly downregulates the concentration of plasma estrogens. However, it is unclear whether it offers any survival benefits if combined with adjuvant tamoxifen treatment in premenopausal women. This meta-analysis was designed to assess data from previous studies involving adjuvant tamoxifen treatment plus OFS in premenopausal breast cancer.
Methods: Electronic literature databases (PubMed, Embase, the Web of Science, and the Cochrane Library) were searched for relevant randomized controlled trials published prior to February 1, 2015. Only randomized controlled trials that compared tamoxifen alone with tamoxifen plus OFS for premenopausal women with breast cancer were selected. The evaluated endpoints were disease-free survival and overall survival.
Results: Four randomized controlled trials comprising 6,279 patients (OFS combination, n=3,133; tamoxifen alone, n=3,146) were included in the meta-analysis. There was no significant improvement in disease-free survival or overall survival with addition of OFS in either the whole population or the hormone receptor-positive subgroup. The risk of distant recurrence was not reduced with the addition of OFS in the whole population. A subgroup analysis showed that addition of OFS significantly improved overall survival in patients who were administered chemotherapy.
Conclusion: Based on the available studies, concurrent administration of OFS and adjuvant tamoxifen treatment for premenopausal women with breast cancer has no effect on prolonging disease-free survival and overall survival, excluding patients who were administered chemotherapy. It should not be widely recommended, except perhaps for women who were hormone-receptor positive and who were also administered adjuvant chemotherapy.


Keywords: tamoxifen, ovarian function suppression, breast cancer, premenopausal women, adjuvant treatment, meta-analysis  

INTRODUCTION

Breast cancer is still the leading cause of cancer-related death for women aged 20–59 years.1Approximately 25% of breast cancer patients are younger than 50 years of age.2 Sixty percent of premenopausal patients with breast cancer are estrogen receptor (ER)-positive.3 Estrogen can enhance the proliferation of ER-positive breast cancer cells. Estrogens are mainly secreted by the ovaries in premenopausal women. Tamoxifen, a selective ER modulator, acts as an antagonist of estrogen in breast cancer. Tamoxifen is now the standard adjuvant endocrine therapy for ER-positive breast cancer in premenopausal women. Since 1990, mortality related to breast cancer has decreased by over 25%, partly because of tamoxifen-based endocrine therapies.4

It has been reported that tamoxifen could increase plasma estradiol levels three to four times over pretreatment levels because of the stimulatory effects of tamoxifen on pituitary-ovarian function.5,6High plasma estradiol concentrations might partially weaken the effect of tamoxifen by competing for binding sites on ERs. Suppression of ovarian estrogen synthesis is a potential endocrine strategy. It is believed that ovarian function suppression (OFS) in combination with tamoxifen in premenopausal women is a more efficacious hormonal therapy for ER-positive breast cancer than tamoxifen alone. In advanced breast cancer, addition of OFS to tamoxifen prolongs progression-free survival and overall survival (OS).6 The question of whether there are any advantages to combining OFS with tamoxifen as an adjuvant treatment for premenopausal women has garnered a great deal of interest but has not yet been answered. Several studies have attempted to answer this question,7–9 but the results have been inconsistent. Sequential meta-analyses have reviewed adjuvant endocrine strategies for breast cancer, but none have focused on addition of ovarian suppression to adjuvant tamoxifen treatment for premenopausal women.10–13

Recently, the E-3193 and SOFT (Suppression of Ovarian Function Trial) trials have provided additional data.14,15 However, these studies were limited because of their sample size and were not definitive enough to generate guidelines for oncologists. As such, we believe a meta-analysis is necessary to help guide therapeutic decisions. To address these issues, we performed a meta-analysis to compare OFS plus tamoxifen with tamoxifen alone as an adjuvant treatment for premenopausal women. 

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