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Breast Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI] - Description of Evidence


The WHI observational study was conducted in parallel with the WHI RCT, recruiting postmenopausal women aged 50 to 79 years. An analysis was conducted in the observational study of the WHI to further examine the prognosis of women taking combination HT who were diagnosed with breast cancer and the risks based on time between menopause and initiation of HT. After a mean follow-up of 11.3 years, the annualized incidence of breast cancer among women using estrogen plus progestin was 0.60% compared with 0.42% among nonusers (HR = 1.55; 95% CI, 1.41–1.70). Survival after the diagnosis of breast cancer was similar for combined HT users and nonusers. Death from breast cancer was higher among combined HT users than among nonusers, but the difference was not statistically significant (HR = 1.3; 94% CI, 0.90–1.93). Risks were highest among women initiating HT at the time of menopause, and risks diminished, but persisted with increasing time between menopause and starting combination HT. All-cause mortality after the diagnosis of breast cancer was statistically significantly higher among combined HT than among nonusers (HR = 1.87; 95% CI, 1.37–2.54.) Overall, these findings were consistent with results from the RCT.[37]

The WHI Estrogen-Alone Trial was a double-masked, placebo-controlled randomized clinical trial conducted among women who have had a hysterectomy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive either conjugated equine estrogen (CEE) or placebo. Estrogen-only preparations should only be considered among women who have had a hysterectomy because unopposed estrogen increases the risk of uterine cancer. Like the WHI combined-HT trial, this trial was stopped early because of an increased risk of stroke and no evidence of benefit as measured by a global index of risks and benefits.[38,39] After an average of 6.8 years of follow-up, the incidence of breast cancer was lower in the group receiving CEE compared with placebo but the difference was not statistically significant (HR = 0.77; 95% CI, 0.59–1.01; 26 vs. 33 cases of invasive breast cancer per 10,000 person-years [annualized rate of 0.26% vs. 0.33%], respectively). For the global index of risks and benefits (based on outcomes of stroke, pulmonary embolus, breast cancer, colorectal cancer, hip fractures, and death), there was a nonstatistically significant excess of two events per 10,000 person-years.[38] An extended follow-up for a median of 11.8 years was conducted with 78% of the trial participants consenting to take part.[39,40] Characteristics among those in the extended follow-up who were randomly assigned to receive active intervention with CEE or placebo were similar, except for slight imbalances in history of prior breast biopsy (19.8% among the CEE group and 22.3% among the placebo group) and prior hormone use (48.9% among the CEE group and 50.4% among the placebo group). At the end of the follow-up period, 151 cases of breast cancer occurred among the CEE group (0.27% per year) compared with 199 cases of breast cancer among the placebo group (0.35% per year) (HR = 0.77; 95% CI, 0.62–0.95).[39,40] Breast cancer mortality was statistically significantly lower in the CEE group (six deaths, 0.009% per year) than in the placebo group (16 deaths, 0.024% per year) (HR = 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% per year) than in the placebo group (0.076% per year) (HR = 0.62; 95% CI 0.39–0.97). Following discontinuation of CEE, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no increased or decreased risk of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer.[39] Among the subset of women in the WHI trial who initiated estrogen-only therapy within the first 5 years of onset of menopause, neither an excess nor decreased risk of developing breast cancer was observed (HR = 1.06; 95% CI, 0.74–1.51).

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