Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival

Highlights

• Using menopausal hormone therapy prior to diagnosis extends ovarian cancer survival.

• Estrogen alone and estrogen+progestin are associated with better survival.

• Women who used hormone therapy have less residual disease after surgery.

Abstract

Purpose

Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival.

Methods

Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery.

Results

Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival.

Conclusions

Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

Introduction

Invasive epithelial ovarian cancers including ovarian, fallopian tube and primary peritoneal cancer (hereafter referred to as ovarian cancer) collectively account for more deaths than any other cancer of the female reproductive system in the United States, with a five-year survival rate of less than 50% [1]. There is clear evidence that menopausal estrogen-alone hormone therapy (ET) is associated with an increased risk of developing ovarian cancer [[2], [3], [4]], but the relationship between menopausal estrogen plus progestin therapy (EPT) and risk of ovarian cancer is less clear [3]. Further, the relationship between menopausal hormone therapy (MHT) use and survival may not be the same as the relationship with risk.

Pre-diagnosis MHT use and ovarian cancer survival has been examined in nine population-based studies [[5], [6], [7], [8], [9], [10], [11], [12], [13]]. Most observed a modestly inverse association, with hazard ratios ranging from 0.23 [11] to 1.1 [12] (Table S1), but protection was statistically significant in only one study (MHT use >5 years: HR, 0.79; 95% CI, 0.55 to 0.90) [5]. These studies were subject to one or more of the following important limitations: they (1) lacked information about duration of use; (2) did not distinguish between types of MHT use before diagnosis (i.e., ET and/or EPT); (3) had follow-up times of only a few years; (4) had an insufficient sample size to stratify by ovarian cancer histotype; and (5) lacked information about residual disease after debulking surgery. Many women use MHT for only a short period of time, thus missing duration information is an important weakness that may have masked effects in prior studies [14]. Rigorously evaluating the association between pre-diagnosis MHT use and ovarian cancer survival by hormone type, duration, survival time, residual disease and cancer histotype is essential to advance our understanding of disease prognosis.

In the present analysis from the Ovarian Cancer Association Consortium (OCAC), we followed 6419 women with ovarian cancer for up to 26 years and investigated the association between pre-diagnosis MHT use and survival. We investigated duration, type and timing of MHT use in each of the main histological subtypes. A particularly important prognostic factor in ovarian cancer survival is residual disease after initial debulking surgery. Therefore, we also considered the potential relationship of MHT use with residual disease after surgery.