ECC 2013: Continuous Combined Hormone Replacement Therapy Protects Against Endometrial Cancer


Key Points

  • Continuous combined estrogen/progestin use reduced the incidence of endometrial cancer by 35%.
  • Estrogen/progestin use may have a protective effect in women in the highest BMI categories, who have a substantially increased risk of endometrial cancer.
  • Although estrogen/progestin reduces endometrial cancer incidence, it increases breast cancer incidence and breast cancer–related deaths. Interventions that reduce the incidence of both cancers are needed.

According to an analysis of the Women’s Health Initiative, continuous combined use of estrogen plus progestin reduces the risk of endometrial cancer among postmenopausal women. The study was reported at the European Cancer Congress 2013 in Amsterdam (Abstract LBA13) by Rowan Chlebowski, MD, PhD, of the David Geffen School of Medicine at UCLA and Harbor-UCLA Medical Center.

“In postmenopausal women with a uterus and nonproliferative endometrial histology [at baseline], continuous combined estrogen/progestin use reduced endometrial cancer incidence by 35%,” Dr. Chlebowski said. “To our review, this is the first randomized clinical trial evidence that shows this.”

A second important finding of the trial was the association between obesity and endometrial cancer risk. Women with a body mass index (BMI) > 35 had approximately a sevenfold increased risk, the study found, and the combined therapy may have protective effect in obese women.

“BMI > 35 could be a unique target for a cancer prevention intervention in the future,” Dr. Chlebowski suggested.

Study Details

The Women’s Health Initiative enrolled 16,608 postmenopausal women from 40 U.S. clinical centers into a randomized, double-blind, placebo-controlled trial. Women aged 50 to 70 with an intact uterus and normal endometrial histology were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate or to placebo.

After 5.6 years of the intervention and 6.8 years of additional follow-up, 66 women in the combined hormone therapy group were diagnosed with endometrial cancer, compared with 95 in the placebo group, which translated to a 35% reduction in risk (P = .007). The analysis at 5.6 years had shown a 17% relative risk reduction that was not statistically significant.

Estrogen/Progestin Was Broadly Protective

In the current analysis, women in the estrogen/progestin group who did develop cancer tended to have fewer poorly differentiated/anaplastic tumors and less regional and distant disease, he added.

Although there were somewhat fewer endometrial cancers during the intervention period of the trial (25 vs 30), the difference between the arms largely emerged in the postintervention period, where there were 41 cases in the combined hormone group and 65 in the placebo group, a 41% reduction in risk (P = .008). “After about 5 years is when we see a separation of the curve,” Dr. Chlebowski noted.

In a sensitivity analysis that adjusted for adherence, the reduction in risk was 51% (P = .004). Adjusting for hysterectomy also did not change the results.

There was no difference in the effect according to age or time from menopause. Additionally, there was no significant interaction with race or ethnicity, smoking, physical activity, or prior estrogen alone or estrogen/progestin use.

The favorable effects of estrogen/progestin were broadly observed, including a protective effect in women in the highest BMI categories, who have a substantially increased risk of endometrial cancer.

“We saw a rapid and high-level rise of endometrial cancer in the obese women,” he said. Women with a BMI ≥ 40 had a relative risk of 7.40 and those with BMI 35-50 had a 6.66 relative risk (BMI < 25 served as the reference point). Women with BMI ≥ 40 had a 43% reduction in risk.

Deaths were also reduced in the estrogen/progestin group—5 vs 11—but this was not statistically significant.

Estrogen-Progestin Increases Breast Cancer Risk

Dr. Chlebowski noted that combined estrogen/progestin use has “opposite effects on breast and endometrial cancers.” Estrogen/progestin reduces endometrial cancer incidence but increases breast cancer incidence and breast cancer–related deaths, he noted.

The Women’s Health Initiative previously showed a 28% increased risk of breast cancer with combined hormone replacement therapy after 5.6 years of the intervention.

“Interventions that reduce both endometrial cancer and breast cancer are needed,” he said.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.