Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to updated results of a multicenter, randomized trial.
These conclusions from an 11-year follow-up of 15,408 subjects in the Women's Health Initiative randomized clinical trial are the direct opposite of those reported by most observational studies of the issue, which linked combined hormone therapy with breast cancers that have more favorable characteristics and with longer patient survival.
The new findings likely foretell another substantial decline in the use of postmenopausal hormone therapy and a subsequent decrease in breast cancer incidence, much as the initial reports from the WHI study did, said Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif., and his colleagues.
They undertook the WHI update in part because “the influence of estrogen-plus-progestin on breast cancer mortality has not been addressed in a randomized trial setting.”
The WHI involved 16,608 postmenopausal women randomized to either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, most of the original study subjects consenting to participate in a median follow-up of 11 years.
In women on active hormone therapy, the rate of invasive breast cancer during the extended follow-up was 0.42% per year, compared with 0.34% for placebo.
Breast cancers in the hormone therapy group had a 24% rate of positive lymph nodes, vs. 16% for placebo. There were 2.6 and 1.3 deaths per 10,000 women per year due to breast cancer, respectively; and all-cause mortality was 5.3 and 3.4 deaths per 10,000 women per year, respectively (JAMA 2010;304:1684-92).
The Women's Health Initiative was funded by the National Heart, Lung, and Blood Institute. Dr. Chlebowski reported ties to AstraZeneca, Novartis, Pfizer, and Amgen. His associates reported ties to Procter & Gamble, Wyeth Laboratories (maker of Prempro used in the WHI), Upsher-Smith Laboratories, Meditrina Pharmaceuticals Merck, Boehringer Ingelheim, and Organon, and have served as legal consultants regarding hormone therapy.
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“It is probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study, and that with longer follow-up, the deleterious effect will appear larger,” said Dr. Peter B. Bach.
The mortality curves of the two study groups appear to be continuing to separate at the end of the current follow-up period. And the difference between the two study groups in cumulative breast cancer incidence also appears to be continuing to widen. Both trends indicate that the number of deaths associated with hormone therapy will continue to rise as time passes.
DR. PETER B. BACH is with the Health Outcomes Research Group at Memorial Sloan-Kettering Cancer Center, New York. He reported no financial disclosures. These comments are taken from his editorial accompanying the WHI report (JAMA 2010;304:1719-20).