Abstract P2-09-06: Addition of ovarian function suppression to endocrine therapy in premenopausal women with early breast cancer: A meta-analysis
Authors: Chlebowski R , Pan K , Col NF 
Published: March 2017

Abstract
Introduction
The Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and EXemestane Trial (TEXT), together with the Austrian Breast Cancer Study Group (ABCSG-12)and the Eastern Cooperative Oncology Group 3193 (E-3193 trials, have examined adding ovarian function suppression (OFS) using gonadotropin–releasing hormone (GnRH) agonists to endocrine therapy in premenopausal women with early stage breast cancer. However, OFS with GnRH agonist plus aromatase inhibitor has subsequently been found to not consistently reduce estradiol levels to optimal target in the SOFT-EST study (JCO 2016; 34:1584) and implications of these study findings for clinical practice are controversial. Therefore, to further examine this issue, we conducted a systematic literature review and meta-analysis of available evidence.
Methods
We updated a recently published literature review of randomized clinical trials (JCO 2016; 34:1689) through June 1, 2016 using the keywords “breast cancer,” “ovarian function suppression,” “tamoxifen,” and “aromatase inhibitor”. Of 683 of records identified through database searching, the 4 studies named above met inclusion criteria and were included in the quantitative synthesis. Information on disease-free survival (DFS) and overall survival was examined using hazard ratio (HR) and 95% confidence interval (CI). Because of significant heterogeneity in one performed meta-analyses, the random-effects (DerSimonian and Laird) method was used to estimate the combined RR for studies (Open MetaAnalyst).
Results
Combining ABCSG-12, SOFT and TEXT trial findings, OFS addition to aromatase inhibitor resulted in 65 fewer DFS events across the 3 trials compared to OFS addition to tamoxifen (350 DFS events vs. 415 DFS events, respectively, HR 0.89, 95% CI 0.57-1.39, P=0.62, Tau2 =0.09, heterogeneity P&lt;0.01). In contrast, 30 more deaths were seen with OFS plus aromatase inhibitor use (155 deaths vs. 125 deaths, respectively, HR 1.31, 95% CI 0.93 -1.84, P=0.12, Tau2 =0.03, heterogeneity P=0.18). Combining SOFT and E-3193 trials to compare OFS addition to tamoxifen to tamoxifen alone use, more concordance between DFS events and overall survival is seen. There were 24 fewer DFS events across the 2 trials with OFS addition to tamoxifen compared to tamoxifen alone (160 DFS events vs. 184 DFS events, respectively, HR 0.83, 95% CI 0.67-1.03, P=0.09, Tau2 =0, heterogeneity P=0.94) and there were 14 fewer deaths in the OFS plus tamoxifen compared to tamoxifen alone group (58 deaths vs. 72 deaths, respectively, HR 0.76 95% CI 0.53 -1.07, P=0.12, Tau2 =0, heterogeneity P=0.78).
Conclusion
In conclusion, the apparent discordance between DFS and overall survival in the aromatase inhibitor and OFS trials and the results suggesting incomplete and/or intermittent estrogen suppression with GNRH analogs in the SOFT-EST trial suggest that adoption of OFS plus aromatase inhibitor use as adjuvant therapy in premenopausal women with early stage breast cancer may be premature. Longer term survival analyses of the endocrine therapy trials are needed before reliable risks and benefits of aromatase inhibitor plus OFS and tamoxifen plus OFS use as adjuvant therapy can be determined.
Citation Format: Chlebowski R, Pan K, Col NF. Addition of ovarian function suppression to endocrine therapy in premenopausal women with early breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-06.