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Six years after a landmark federal study established that hormone-replacement therapy (HRT) increases the risk of breast cancer in postmenopausal women, researchers are still trying to tease out exactly how the hormones interfere with women's health. The assumption has always been that stopping hormone therapy would lead to a corresponding drop in breast-cancer risk, but now newly published data from the original trial — the multiyear Women's Health Initiative involving tens of thousands of women — suggest that the benefit occurs much more immediately than previously thought.

The finding is a contentious one. The authors of the new paper, which appears in the Feb. 5 issue of the New England Journal of Medicine, found that the rate of breast cancer in postmenopausal women fell just two years after they stopped hormone therapy and continued to decline yearly. In addition, researchers found that women taking supplemental estrogen and progestin had doubled their risk of breast cancer after five years, compared with women not taking HRT.

The question is why. The authors hypothesize that the decline in breast cancer rates was largely due to the sudden stoppage of hormone therapy. But this correlation, first presented at the San Antonio Breast Cancer Conference in December, has been met with skepticism by other researchers in the community. They raised concerns about drawing a cause-and-effect relationship, since the sharpest decline in women's breast cancer rates occurred in the year after the WHI was halted and its data released, between 2002 and 2003 — too soon to see such a dramatic change in a complex disease like breast cancer, which takes many years to develop.

Samuel Shapiro, a visiting professor of epidemiology at University of Capetown, notes that any cancers that might have existed in breast tissue when these women stopped hormone therapy would not have simply disappeared post-treatment. "Once the growth of a tumor has accelerated, it can't be decelerated," he says. "I'm not aware of any evidence to show that happens."

Dr. Roman Chelbowski, lead author of the current study and a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, disagrees. He says the rapid decline in cancer rates was due not only to an overall drop in breast-cancer risk, but also to the withdrawal of excess estrogen, which may actually have served as a treatment for tiny, preclinical breast cancers. "When you change from a high- to a low-estrogen environment, it's like giving breast cancer treatment," he says. "These are preclinical cancers that are below the level of detection, and that accounts for why biologically we can see such a quick effect in stopping hormone therapy." In the three-year WHI study alone, there were 20,000 preclinical breast cancer cases among the women who continued taking hormone therapy — cancers that may potentially have been avoided.

"That is a reasonable and biologically plausible explanation for why we might be seeing a more precipitous drop in breast cancer than we might expect from the normal lead time for reduction of malignancies," says Dr. Jonathan Berek, chair of obstetrics and gynecology at Stanford University School of Medicine, who was not involved in the study.

Berek notes that while breast cancers do generally grow for a decade or more before becoming detectable, cancer is a tricky disease that constantly tests our expectations. "Nobody understands this disease that well, and maybe what this study is telling us is that the biology of these estrogen-dependent cancers is not quite what people thought it was."

And although the academic back-and-forth over what caused an undeniably good health trend — a reduction in breast cancer — might seem superfluous, the study does reaffirm an important message for women: Hormone use at menopause does increase the risk of breast cancer, so estrogen and progestin should be used for the shortest possible time, only to relieve menopausal symptoms. "This study isn't an indictment of hormone use at menopause," says Berek. "It just means that like all medicines, hormones have their benefits and risks, so they have to be used very judiciously and for a short time."

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