Timing of HRT Influences Breast Cancer Risk

Uncertainty about estrogen alone

Nick Mulcahy

January 31, 2011

January 31, 2011 — Breast cancer risk associated with combination hormone replacement therapy (HRT) is greater if the therapy is started soon after menopause, according to the results of the observational Million Women Study conducted in the United Kingdom.

Among current users of estrogen–progestin formulations, the relative risks for breast cancer were greater if use began less than 5 years after menopause (relative risk [RR], 2.04; 95% confidence interval [CI], 1.95 to 2.14) than if it began 5 years or more after menopause (RR, 1.53; 95% CI, 1.38 to 1.70).

The findings, by Valerie Beral, MD, from the University of Oxford in the United Kingdom, and colleagues were published online January 28 in the Journal of the National Cancer Institute.

These results about the timing of combination HRT provide "substantial support" for the findings of the Women's Health Initiative (WHI) in the United States and the French E3N cohort, according to an editorial that accompanies the study.

"Many other findings" from the Million Women Study also parallel those of the WHI, according to the editorialists, Rowan T. Chlebowski, MD, PhD, from Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, in California, and Garnet Anderson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.

"In both [studies], the use of an estrogen–progestin formulation for a moderate duration was associated with increased breast cancer incidence. An increased risk of breast cancer was also associated with increased hormone use duration, increased risks of node-positive disease, and breast cancer mortality. Both studies also observed that breast cancer incidence rates declined rapidly after cessation of estrogen–progestin formulation use," they write.

Overall, for women who used combination HRT, compared with control subjects, there was a 39% increase in the relative risk of developing breast cancer in the Million Women Study and a 26% increase in the WHI trial, which the editorialists call "consistent" findings.

The similarity in the various results is "remarkable" and "increases confidence in the validity of the conclusions," say Dr. Chlebowski and Dr. Anderson. This is especially so because of "considerable methodological differences," they add.

The WHI was a randomized controlled trial that compared placebo with conjugated equine estrogen plus progestin (Prempro, Wyeth) and with conjugated equine estrogen alone (Premarin, Wyeth). The Million Women Study was an observational study of current HRT users (a variety of formulations), past users, and nonusers in 1.13 million women. The Million Women Study investigators estimated the adjusted relative risks of breast cancer in the different study groups and compared women receiving different types of HRT.

The WHI and Million Women Study had different findings in 1 major subgroup — women who used estrogen-only HRT.

In the Million Women Study, among current users of estrogen-only formulations, risk was statistically significantly increased if use began before or less than 5 years after menopause (RR,1.43; 95% CI, 1.35 to 1.51); there was little or no increase if use began 5 years or more after menopause.

However, in the WHI, no effect was seen in women initiating estrogen-only HRT closer to menopause (hazard ratio [HR],1.06, 95% CI, 0.74 to 1.51; P interaction = .07]. Furthermore, breast cancer risk was actually reduced a bit among estrogen-only users who first used hormones 5 years or more after menopause (HR, 0.63; 95% CI, 0.42 to 0.93).

"The question of the effect of estrogen-only formulation use on breast cancer risk in postmenopausal women, even with longer-term hormone use, still stands unanswered," write the editorialists.

The authors and editorialists have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online January 28, 2011. Full text, Editorial

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