A new study has found that women who used estrogen alone as hormone replacement therapy after menopause had a lower risk of developing breast cancer up to five years after they stopped taking it.
The report is a follow-up analysis of the landmark Women's Health Initiative, a clinical trial of tens of thousands of women begun in 1993 that sought to clarify the risks and benefits of two hormone replacement therapy regimens in postmenopausal women: estrogen plus progestin, which most women must take, and estrogen alone, taken by women who have had hysterectomies.
The double-hormone arm of the study was abruptly halted in 2002 after scientists found that it raised the risk of breast cancer without conferring hoped-for benefits on the heart. In 2004, the estrogen-alone arm of the study was also halted after researchers discovered an increased risk of stroke and blood clots.
After stopping the Estrogen only arm it was found that estrogen alone did not increase risk and maybe even lowered it. The new study, published in the journal Lancet Oncology, provides the strongest evidence yet that estrogen alone not only lowers breast cancer risk for a sustained time for some women but curbs the chances of dying from the disease.
Researchers followed 7,645 women from the original group of almost 11,000 participants for almost five years to see what happened to them after stopping estrogen therapy. The study found that women who took estrogen had a 23% reduced risk of breast cancer compared with those who took a placebo. Among the women who did develop breast cancer, those who took estrogen had a 63% reduced risk of dying from the disease compared with those who took a placebo.
“If women are suffering from serious menopause symptoms and have had a hysterectomy, then estrogen alone is a reasonable approach,” said Garnet Anderson, of the Fred Hutchinson Cancer Research Center in Seattle and the study's lead author.
“It's a very interesting finding,” said a coauthor of the study, Dr. Rowan T. Chlebowski, an investigator at the Los Angeles Biomedical Research Institute in Torrance and chief of medical oncology and hematology at Harbor-UCLA Medical Center. “It goes against a huge number of observational studies suggesting estrogen would increase the risk of breast cancer by itself. But this study points out that it's much more complex than we originally thought. Estrogen alone for the period we studied seems to be pretty safe and maybe even beneficial,” he said.
The lowered risk of breast cancer was striking among women who had a typical breast cancer risk. In women classified as at higher risk of breast cancer — either because of family history or a medical history of benign breast tumors — estrogen did not lower the risk.
Thus, while it's relatively safe for most women to take estrogen alone for several years for menopausal symptoms, these complexities mean estrogen alone can't be recommended as a strategy to prevent breast cancer, said Marcia L. Stefanick, a professor of medicine at Stanford University School of Medicine and an investigator on the Women's Health Initiative, who was not involved in the study. “This study is reassuring for women at low risk,” she said. “But for women at elevated risk of breast cancer, these data don't apply. That's an important distinction.” Estrogen-alone hormone replacement therapy still raises the risk of blood clots and stroke, she added.
What is puzzling is how estrogen, which is known to fuel the growth of breast cancer cells, would work to lower risk in some women. Some research suggests that when estrogen levels begin to decline during menopause, small tumors in the breast adapt and begin to grow at the lower concentration. When estrogen levels are boosted again through replacement therapy, the tumors may stop growing. “The idea is that normally, estrogen acts as a stimulant for breast cancer growth,” Chlebowski said, but after a period of deprivation, the effects of estrogen change.
“Estrogen on its own appears to be safe,” said Dr. Anthony Howell, professor of medical oncology at the University of Manchester, who co-authored a commentary in journal. Howell said altering the amount of estrogen in the body might help stop tumor growth, since fluctuating levels could interfere with tumor development.
It's also possible that the form of estrogen used in the Women's Health Initiative — pills containing conjugated equine estrogen made from the urine of pregnant mares — has properties that might reduce breast cancer risk by lowering the body's natural estrogen, said the authors of a commentary accompanying the study, Dr. Howell and Jack Cuzick of Queen Mary, University of London.
Other experts weren't convinced. “It's inconsistent with the totality of evidence that finds estrogen increases breast cancer risk,” said Valerie Beral, director of the cancer epidemiology unit at Oxford University. She said the analysis was a subset of a larger trial that wasn't designed to specifically look at breast cancer. “If you want to take hormone replacement therapy, estrogen-only has a much lesser effect on breast cancer than with progestin,” she said. “But to say it protects against breast cancer is wrong.”
Dr. Peter Bowen-Simpkins, medical director of the London Women's Clinic and a spokesman for Britain's Royal College of Obstetricians and Gynecologists, said the study was still reassuring news for women who had hysterectomies seeking relief from menopausal symptoms. “A lot of their suffering could be spared,” he said.
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