In a study reported in The Lancet, the Collaborative Group on Epidemiological Studies of Ovarian Cancer found that use of menopausal hormone therapy was associated with increased risk of ovarian cancer, with risk being highest among current users.¹

The study consisted of meta-analyses of individual participant datasets from 52 epidemiologic studies, including 17 prospective and 35 retrospective studies. The principal analyses involved prospective studies, with last hormone therapy use extrapolated forward for up to 4 years.

Risk in Current and Past Users

During prospective follow-up in the principal analysis, 12,110 postmenopausal women developed ovarian cancer, including 6,601 (55%) who had used hormone therapy. Compared with never-users, current users had a similar significantly increased risk of ovarian cancer with < 5 years of use (relative risk [RR] = 1.43, P < .00001) and ≥ 5 years of use (RR = 1.41, P < .0001).

Among past users with < 5 years since last use, risk was significantly increased among those with ≥ 5 years of use (RR = 1.29, P = .0008) and nonsignificantly increased in those with < 5 years of use (RR = 1.17, P = .08). Among past users with ≥ 5 years since last use, risk was significantly increased among those with ≥ 5 years of use (RR = 1.10, P = .02) but not among those with < 5 years of use (RR = 0.94, P = .1).

In an analysis including all studies (9,378 cases in 35 retrospective studies), compared with never-users, current users had an increased risk with < 5 years of use (RR = 1.27, P = .00001) or ≥ 5 years of use (RR = 1.34, P < .00001). Risk was nonsignificantly increased in past users with < 5 years since last use who had < 5 years of use (RR = 1.11, P = .07) and significantly increased in those with ≥ 5 years of use (RR = 1.25, P = .00002). Among past users with ≥ 5 years since last use, risk was not increased among those with < 5 years of use (RR = 0.97, P = .3) and was significantly increased in those with ≥ 5 years of use (RR = 1.11, P = .008).

Risk With Current/Recent Use

Compared with nonuse, current or recent use (defined as use of any duration stopped < 5 years before diagnosis) was associated with a significantly increased risk (RR = 1.37, P < .0001). This risk was similar in European (RR = 1.37, 99% confidence interval [CI] = 1.26–1.50) and American (RR = 1.35, 99% CI = 1.11–1.65) prospective studies and for prospective studies involving estrogen-only (RR = 1.37, 95% CI = 1.26–1.50) and estrogen-­progestogen hormone preparations (RR = 1.37, 95% CI = 1.26–1.48). Analysis in only retrospective studies did not show an increased risk (RR = 1.04, 99% CI = 0.93–1.16).

In prospective studies, risk differed across the four main tumor types (P < .0001 for heterogeneity), with a significantly increased risk with hormone therapy use being observed for serous tumors (RR = 1.53, P < .0001) and endometrioid tumors (RR = 1.42, P < .0001) but not for mucinous tumors (RR = 0.93, 95% CI = 0.77–1.12). Hormone therapy use was associated with a reduced risk of clear cell tumors (RR = 0.75, 95% CI = 0.57–0.98).

Persistence of Risk

Although risk declined with greater duration since last use, women who had used hormone therapy for at least 5 years (median duration = 9 years) and then stopped still had a significantly increased risk of ovarian cancer more than 5 years later (median time since last use = 10 years; RR = 1.10, P = .02). Risk of serous or endometrioid tumors was higher at 10 years since last use (RR = 1.25, P = .005).

Estimates of Excess Incidence and Death

Application of the relative risks identified in the prospective studies to age-specific ovarian cancer incidence and death rates in England yielded the following excess incidence and excess death estimates: for 5 years while they are taking hormone therapy (from age 50 to 54), their excess risk is 0.52; after they stop their excess risk is still elevated at age 55 to age 59, estimated to be 0.37 per 1,000; and at age 60 to age 64, there remains an excess incidence, estimated to be 0.1 per 1,000. The total for women who started hormone therapy at age 50 and used hormone therapy for 5 years is 1 per 1,000. The excess is greater the longer women take hormone therapy and the older they are when taking hormone therapy.

In total, there would be 1 additional ovarian cancer per 1,000 users and 1 additional death per 1,700 users. For 10 years of hormone therapy use, the absolute excess in incidence would be 0.52, 0.67, and 0.61 for the three age groups. There would be 1 additional case of ovarian cancer per 600 users and 1 additional death per 800 users.

The investigators concluded: “The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1,000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1,700 users.” ■

Disclosure: The study was funded by the Medical Research Council, Cancer Research UK. The study authors reported no potential conflicts of interest.

Reference

1. Collaborative Group on Epidemiological Studies of Ovarian Cancer: Menopausal hormone use and ovarian cancer risk: Individual participant meta-analysis of 52 epidemiological studies. Lancet 385:1835-1842, 2015.

Ana I. Tergas, MD, MPH, of Columbia University Medical Center, offers further commentary on hormonal therapy and risk of ovarian cancer.