Estrogen-Only Therapy for Menopausal Symptoms Increases Ovarian Cancer Risk

CHICAGO — Use of conventional hormonal therapy for menopausal symptoms doubled the long-term risk of ovarian cancer and the risk of dying of the disease, according to an analysis of Women’s Health Initiative (WHI) clinical trial data.

Among 10,739 women with prior hysterectomy, treatment with conjugated equine estrogen (CEE) resulted in an ovarian cancer hazard ratio of 2.04 versus placebo during 20 years of follow-up (35 vs 17 cases). Ovarian cancer mortality almost tripled in the CEE group.

Women with an intact uterus received CEE plus medroxyprogesterone acetate (MPA), which did not significantly increase ovarian cancer risk or mortality versus placebo and was associated with a significant reduction in the risk of endometrial cancer.

“The findings should inform decisions regarding hormone therapy use and suggest reconsideration of guideline recommendations of estrogen-alone use in ovarian cancer survivors,” said Rowan Chlebowski, MD, PhD, of City of Hope in Duarte, California, during a press briefing prior to the American Society of Clinical Oncology meeting.

The findings should be considered with the recognition that the absolute risk of ovarian cancer incidence and mortality was extremely low in women who received CEE with or without MPA, said invited discussant Eleonora Teplinsky, MD, of Valley Health System in Paramus, New Jersey.

“This new information is really an important part of patient counseling and education and discussing with patients what their ovarian cancer risk is, but it should not necessarily detract or take away from a woman’s decision to take menopausal hormone therapy for relief of symptoms,” said Teplinsky.

“Currently, conjugated equine estrogen is a less commonly used estrogen preparation, and so we must take that into context as we extrapolate to modern-day estrogen formulations,” she added.

Despite the fact that hormone therapy for menopausal symptoms has been approved in the U.S. since 1943, its influence on endometrial and ovarian cancer incidence and mortality remains unsettled after more than 50 years of follow-up, said Chlebowski. Observational studies have generally shown increased risk with CEE alone, but findings with CEE plus a progestin have been mixed.

In an effort to bring more clarity to the discussion, investigators turned to the database of the WHI, initiated in 1991 to study major health issues causing morbidity and mortality in postmenopausal women. The analysis included 10,739 women with prior hysterectomy and 16,608 with an intact uterus. Eligible participants were ages 50-79 and had no history of breast cancer or suggestion of it on mammogram.

In both groups (CEE or CEE/MPA vs placebo), planned treatment was for 8.5 years. The comparison of CEE/MPA and placebo ended after 5.2 years because of an increased risk of breast cancer with the hormonal therapy. The trial of CEE versus placebo ended for futility after a mean follow-up of 6.8 years. Endometrial cancer and ovarian cancer were specified secondary outcomes.

The trials were conducted at 40 U.S. centers, where investigators enrolled participants from 1993-1998. During 20 years of follow-up, 35 ovarian cancers occurred in the CEE-alone arm versus 17 in the placebo group (HR 2.04, 95% CI 1.14-3.65, P=0.014). The CEE group had 25 ovarian cancer deaths versus nine in the placebo group (HR 2.79, 95% CI 1.30-5.99, P=0.006). All-cause mortality also was significantly higher in the CEE group (30 vs 12; HR 2.47, 95% CI 1.26-4.84, P=0.006).

In the trial of CEE/MPA, active hormonal treatment was associated with hazard ratios of 1.14-1.37 for ovarian mortality, cancer-specific mortality, and all-cause mortality, respectively. None of the differences reached statistical significance.

CEE/MPA was associated with a significant reduction in endometrial cancer incidence (106 vs 140; HR 0.72, 95% CI 0.56-0.92, P=0.010) and all-cause mortality (51 vs 72; HR 0.68, 95% CI 0.47-0.97, P=0.034). The hormonal therapy resulted in numerically lower endometrial cancer mortality (13 vs 21; HR 0.58, 95% CI 0.29-1.16, P=0.12).

In a discussion that followed his presentation, Chlebowski said applicability of the findings to contemporary hormonal strategies for menopausal symptoms is complicated by the fact that “it’s very, very difficult to find out what’s the true penetrance of other therapies: transdermal estradiol, lower-dose CEE, and MPA.”

“Everybody says [hormonal therapy] has shifted, but at the time this study was done, this was 90% of what was being used as therapy,” he continued. “It’s unclear what gynecologists in clinical practice have been doing. It’s been almost impossible for us to find in the last 10 years what the shift has been. It’s really not clear whether there’s been a huge sea change in what therapy has been given.”

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