Breast Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI] - Description of Evidence
A smaller trial from Denmark supports the results of the WHI Estrogen-Alone Trial. Between 1990 and 1993, 1,006 healthy, recently postmenopausal women aged 45 to 58 years were randomly assigned to receive either HT or no treatment. Follow-up continued for up to 16 years. In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate; women who had undergone hysterectomy received 2 mg estradiol a day. The primary endpoints were cardiovascular, with incidence of breast cancer being secondary. The authors observed a nonsignificant reduction in the risk of breast cancer in the HT arm (HR = 0.58; 95% CI, 0.27–1.27) and a significant reduction in the risk of death or breast cancer (HR = 0.54; 95% CI, 0.32–0.91).
The evidence from randomized trials should be put into context with the evidence from observational studies that suggests that there is an increased risk of developing breast cancer associated with estrogen-only postmenopausal HT. The Million Women Study  observed no increased risk of breast cancer among women whose first use of estrogen-only therapy was 5 or more years after menopause, but the risk was statistically significantly higher among women initiating therapy within 5 years of menopause (RR = 1.43; 95% CI, 1.36–1.49). Among that group, the risk increased with duration of hormone use. Overall, risks associated with estrogen-only HT were lower than those observed for combined estrogen-progestin HT. Estrogen-only therapy, even for more than 25 years duration, was not associated with invasive breast cancer in a case-control study of women aged 65 years and older. The Collaborative Group on Hormonal Factors in Breast Cancer, a reanalysis of data from 52 observational studies of HT and breast cancer, had information on specific hormonal preparations for 39% of eligible women and most of these women reported use of estrogen-alone preparations. The combined analysis showed no marked variation between estrogen-only preparations and combined HT. However, the collaborative analysis, overall, provided limited information on estrogen-only versus combination estrogen-progestin therapy. Factors that may explain the disparate findings of the association between estrogen-only use and the risk of developing breast cancer, which were observed in the clinical trial and observational studies, include an imbalance in the prevalence of routine screening between users and nonusers of hormones, and gap time between the onset of menopause and the first use of postmenopausal hormone therapy.[44,45]