In 2002, the federally funded Women’s Health Initiative—a randomized, placebo-controlled clinical trial investigating the effects of menopausal hormone therapy in healthy menopausal women—was abruptly halted when it was determined that taking estrogen and progestin hormones after menopause increased the risk of breast cancer, heart disease, and circulatory disorders.
Now, results from a 20-year follow-up to the Women’s Health Initiative investigating the long-term influence of menopausal hormone therapy on ovarian and endometrial cancer incidence and mortality are available. Researchers found that conjugated equine estrogen alone significantly increased ovarian cancer incidence and mortality in women who had a prior hysterectomy; in contrast, in women with an intact uterus, combination estrogen plus medroxyprogesterone acetate did not increase ovarian cancer incidence or mortality and actually reduced endometrial cancer incidence. The study will be presented at the 2024 ASCO Annual Meeting, by Rowan T. Chlebowski, MD, PhD, and colleagues (Abstract 10506).
Rowan T. Chlebowski, MD, PhD
Study Methodology
The researchers examined data from the Women’s Health Initiative (WHI), which was funded by the National Institutes of Health from 1993 to 1998. The WHI had recruited over 27,000 postmenopausal women aged 50 to 79 years without a prior history of breast cancer or invasive cancer within 10 years (and no baseline endometrial pathology in those receiving the combination hormone therapy) from 40 centers in the United States.
Of the 16,608 women in the study with a uterus, 8,506 were randomly assigned to receive daily doses of conjugated equine estrogen (CEE) at 0.625 mg plus 2.5 mg of medroxyprogesterone acetate (MPA), and 8,102 received placebo. In 10,739 women with a prior hysterectomy, 5,310 were randomly assigned to receive daily doses of CEE alone at 0.625 mg, and 5,429 received placebo. The intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE alone). The researchers verified cancer diagnoses by central pathology report review. Mortality findings were enhanced by serial National Death Index queries.
The primary outcomes of the analysis were ovarian cancer and endometrial cancer incidence and related mortality.
Results
The researchers’ 20-year follow-up included mortality information for more than 98% of WHI participants. In the initial WHI report on the influence of CEE alone on ovarian cancer, CEE alone significantly increased ovarian cancer incidence vs placebo (35 cases [0.041% annualized rate] vs 17 [0.020%]; hazard ratio [HR] = 2.04, 95% confidence interval [CI] = 1.14–3.65, P = .01); CEE alone also increased ovarian cancer mortality (HR = 2.79, 95% CI = 1.30–5.99, P = .006). Kaplan-Meier plot estimates and cumulative hazard ratios indicated a persistent CEE alone adverse effect on ovarian cancer incidence that emerged after 12 years of follow-up and did not diminish (P = .006).
In contrast, the researchers found that use of CEE plus MPA did not increase ovarian cancer incidence compared to placebo (75 cases [0.051%] vs 63 [0.045%], HR = 1.14, 95% CI = 0.82–1.59, P = .44); it also did not increase ovarian cancer mortality (HR = 1.21, 95% CI = 0.84–1.74). CEE plus MPA significantly lowered endometrial cancer incidence vs placebo (106 cases [0.073%] vs 140 [0.10%], HR = 0.72, 95% CI = 0.56–0.92, P = .01) without a statistically significant influence on endometrial mortality (HR = 0.58, 95% CI = 0.29–1.16).
Conclusions
The researchers concluded that in randomized placebo-controlled clinical trial settings, in women with a prior hysterectomy, CEE alone significantly increased ovarian cancer incidence and increased ovarian cancer mortality, whereas in women with a uterus, CEE plus MPA did not—in contrast to most observational studies. They also found that CEE plus MPA reduced endometrial cancer incidence.
“These findings [should] inform decisions regarding menopausal hormone therapy use,” concluded the study authors.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
