Hormone therapy’s protection against endometrial cancer persists in Women’s Health Initiative follow-up study



AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Rowan T. Chlebowski

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

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