Description of Evidence
The WHI-combined HT trial was terminated early (in July 2002) because the overall health risks exceeded benefits.
The WHI investigated the effect of hormones and dietary interventions on breast cancer risk. Women aged 50 to 79 years who had intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with combined HT, with a hazard ratio (HR) of 1.24 (95% CI, 1.02-1.50), resulting in early termination of the combined HT arm of the trial. HT was also associated with a higher percentage of abnormal mammograms. The excess risk was observed in all subgroups of women for invasive breast cancer but not for in situ breast cancer. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu compared with those related to placebo, with a trend toward larger size and higher incidence of lymph node metastases. Extended follow-up of these women showed a larger difference in breast cancer incidence between HT and placebo-treated women and increased breast cancer specific mortality for the HT group at 14 years (25 vs. 12 deaths, 0.03% vs. 0.01% per year, HR = 1.95; 95% CI, 1.0-4.04; P = .049).
The WHI Estrogen-Alone Trial was a double-masked, placebo-controlled randomized clinical trial conducted among women who have had a hysterectomy. Women were randomly assigned to receive conjugated equine estrogens (CEE) or placebo. Estrogen-only preparations should only be considered among women who have had a hysterectomy since 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.[37,38] 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. Postintervention follow-up was conducted with an average follow-up of 10.7 years and CEE use for a median of 5.9 years. The decreased risk of invasive breast cancer persisted among those in the CEE group compared with the placebo group and was statistically significant over the entire follow-up period (HR = 0.77; 95% CI, 0.62-0.95; annualized rate of 0.27% vs. 0.35%, respectively). 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, colorectal cancer, or total mortality.