WHI Estrogen-Alone Data Indicate No Overall Benefit for Disease Prevention, No Apparent Increase in Cancer Risk
Data from the Women's Health Initiative (WHI) study to investigate the effect of estrogen-alone hormone replacement therapy (HRT) on the incidence of chronic disease indicate that there is no overall benefit for disease prevention. Specifically for cancer, it showed no effect on the risk of breast or colorectal cancer. Use of estrogen did, however, increase the risk of stroke by 39 percent, a finding that prompted the decision in February by the National Institutes of Health to bring the trial to a premature end. It was slated to run through March 2005. The trial's stoppage was initially announced in early March, but the complete data from the study were not published until this week in the Journal of the American Medical Association (JAMA).
Of particular interest to the cancer community is the finding that estrogen did not increase participants' risk of breast cancer during the study period. In fact, there was a trend, though not statistically significant, toward reduction in breast cancer incidence. Overall, 218 of the more than 10,000 postmenopausal women in the study - all of whom had undergone hysterectomy - developed breast cancer.
The finding of reduced incidence "was unanticipated," the WHI study authors wrote, and contrasts with the finding from several other HRT trials, including a separate WHI study of estrogen-progestin combination therapy that was stopped two years ago. In that study, which involved postmenopausal women who had not had a hysterectomy, participants on HRT were at increased risk of breast cancer and decreased risk of colorectal cancer. And in a large observational trial, the Million Women Study, published last August in The Lancet, women on either estrogen alone or an estrogen-progestin combination had a significantly increased risk of breast cancer, especially those in the latter group.
All women in the WHI estrogen-alone trial underwent annual clinical breast exams and mammograms, so screening differences between the placebo and treatment groups could not account for the discrepancy with the other trials, the authors wrote."
This is a complicated study with a number of variables," noted Dr. Leslie Ford, associate director for clinical research at NCI's Division of Cancer Prevention. "There are still unanswered questions related to the baseline breast cancer risk of the women, the stage and severity of breast cancer diagnosed, and the long-term follow-up of the women. Additionally, only one type of estrogen preparation was tested."
Postmenopausal women who have had a hysterectomy can find some peace of mind in the fact that short-term, low-dose HRT may provide effective relief of menopausal symptoms without an increase in breast cancer risk," Dr. Ford continued. "But it's important to remember that the increase in stroke in the study group was significant and that the morbidity associated with stroke can be quite severe."
Extended follow-up of study participants is planned, and "analyses of [participants'] breast cancer characteristics… may provide additional insight," the authors wrote.
Speaking about the WHI estrogen-alone trial as a whole, National Heart, Lung, and Blood Institute Acting Director Dr. Barbara Alving said, "These findings confirm that estrogen-alone therapy should not be used to prevent chronic disease. We believe the findings support current FDA recommendations that hormone therapy only be used to treat menopausal symptoms and that it be used at the smallest effective dose for the shortest possible time."
In an accompanying editorial in JAMA, Drs. Stephen B. Hulley and Deborah Grady, both from the University of California, San Francisco, agreed with Dr. Alving's assessment. "In the absence of evidence for an overall net benefit of postmenopausal treatment with estrogen alone, and with the evidence that estrogen plus progestin is harmful, neither therapy should be used for preventing disease."