The Women's Health Initiative (WHI) Estrogen-Alone trial, which randomized women with prior hysterectomy to conjugated equine estrogens (CEE) or placebo, was stopped earlier than planned because of increased stroke incidence and no reduction in risk of coronary heart disease. In contrast to substantial epidemiological evidence associating exogenous (originating externally) estrogens with increased breast cancer incidence, preliminary analyses found fewer breast cancers in women in the CEE group, prompting a detailed updated analysis of breast cancer incidence and mammographic reports.
Marcia L. Stefanick, Ph.D., of Stanford University, Stanford, Calif., and colleagues with the WHI study, analyzed the data from the CEE-alone group of the WHI study to determine the effects of CEE on breast cancers and mammographic findings. The study included 10,739 postmenopausal women aged 50 to 79 years with prior hysterectomy who were randomized to CEE or placebo at 40 U.S. clinical centers from 1993 through 1998. Mammography screenings and clinical breast examinations were performed at baseline and annually. All breast cancers diagnosed through February 29, 2004, are included. Participants received a dose of 0.625 mg/d of CEE or an identical-appearing placebo.
In an analyses of all events (n = 237 cases) occurring prior to intervention termination, after an average follow-up of 7.1 years, nonsignificant reductions were observed for invasive breast cancer (20 percent lower rate) and for total breast cancer (18 percent lower rate) in women randomized to CEE, when compared to the placebo group. The annualized rates were 0.28 (104 cases in the CEE group) and 0.34 (133 cases in the placebo group). In further analyses, fewer breast cancers with localized disease were diagnosed in the CEE group than in the placebo group (31 percent lower rate), while the incidence of cancers of more advanced stage was comparable in the two groups. A similar reduction was found for ductal carcinomas, but not for lobular disease.
After the first year, the percentage of mammograms with abnormalities requiring follow-up was substantially higher in the CEE group compared with the placebo group (9.2 percent vs. 5.5 percent). Each year thereafter, the percentage of mammograms requiring follow-up was significantly higher in the CEE group resulting in a cumulative percentage of 36.2 percent in the CEE group and 28.1 percent in the placebo group over the course of the trial. However, this difference was primarily in assessments requiring short interval follow-up.
"In conclusion, CEE alone for seven years does not increase breast cancer incidence in postmenopausal women with hysterectomy, and may decrease the risk of early stage disease and ductal carcinomas. This result is in clear contrast to the WHI trial of CEE combined with medroxyprogesterone acetate in women with a uterus, which showed a significant increase in breast cancer incidence over a mean of 5.6 years of follow-up. Both trials showed a substantial increase in the frequency of mammograms requiring follow-up from the first year onward. However, this increase was seen only for recommended short-interval follow-up mammograms in the Estrogen-Alone trial, whereas it applied also to those with suspicious abnormality or highly suggestive of malignancy in the estrogen plus progestin (E + P) trial. Initiation of CEE alone in women after hysterectomy should continue to be based on careful consideration of potential risks and benefits for a given individual," the authors write.
(JAMA. 2006;295:1647-1657. Available pre-embargo to the media at www.jamamedia.org)
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