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20-year follow-up of WHI trials: lower breast cancer mortality with CEE alone, no difference with CEE plus progesterone
Clinical Question
Does hormone replacement therapy increase the risk of breast cancer incidence and mortality in postmenopausal women?
Bottom line
This cumulative 20-year follow-up report from the Women's Health Initiative hormone replacement therapy (HRT) trials found significantly lower breast cancer incidence and lower breast cancer mortality among postmenopausal women who previously took estrogen alone (with a prior hysterectomy) than among women who took a placebo. Women in the same age group who took estrogen plus progesterone have a significantly increased incidence of breast cancer compared with those who took a placebo, but no significant difference in breast cancer mortality. 1b
Reference
Study design: Randomized controlled trial (double-blinded)
Funding: Government
Setting: Outpatient (any)
Synopsis
This report is a 20+-year median cumulative follow-up of the Women's Health Initiative HRT trials that evaluated the outcomes from giving conjugated equine estrogens (CEE) plus progesterone to postmenopausal women, aged 50 years to 79 years, with an intact uterus, and giving CEE alone to women in the same age group with a previous hysterectomy. The original trials were stopped after 7.2 years because of an increased risk of stroke in the treatment groups. After the original trials were stopped, less than 4% of the women reported continued HRT use. We previously reported the cumulative 18-year follow-up report, which showed no significant differences in all-cause mortality, cardiovascular-related mortality, or cancer-related mortality in postmenopausal women who previously took CEE plus progesterone or CEE alone (with a prior hysterectomy) compared with women who took a placebo. This additional follow-up report focuses on breast cancer incidence and mortality. Using data obtained from regular surveillance of the National Death Index and cancer registries, as well as reports from next of kin, information was available for more than 98% of the 27,347 original participants. Compared with placebo, CEE alone was associated with a statistically significant lower breast cancer incidence (hazard ratio [HR] = 0.78; 95% CI 0.65 - 0.93) and breast cancer mortality (HR = 0.60; 0.37 - 0.97). CEE plus progesterone was associated with a statistically significant higher breast cancer incidence (HR = 1.28; 1.13 - 1.45), but no significant difference in breast cancer mortality.
Reviewer
David C. Slawson, MD
Professor and Vice Chair of Family Medicine for Education and Scholarship
Atrium Health
Professor of Family Medicine, UNC Chapel Hill
Charlotte, NC
Comments
Error in the POEM reporting of this paper
As do many physicians, the writer of this POEM does not seem to know that Provera and progesterone are two very different compounds. The WHI study used Provera in the combination arm, and demonstrated increased risk in women receiving Premarin and Provera. Women receiving Premarin alone had reduced risk of breast cancer and heart disease relative to women receiving placebo. This increased risk with Provera makes the distinction very relevant. Physicians need to know that progesterone is a vasodilator and is converted to a mood-regulating hormone in the brain. Provera is vasospastic, frequently causes mood agitation or dysphoria, is associated with birth defects, and increases cyclin in the breast. This information is nearly 20 years old, so it is long since time to understand the distinction.