http://www.nytimes.com/2003/06/24/health/24CND-HORM.html?ei=5070&en=8ea57a1e5559977f&ex=1057464000&pagewanted=print&position=

Study Reinforces Hormones' Link to Breast Cancer

By DENISE GRADY

ne year after a major study linked postmenopausal hormone therapy to an increased risk of breast cancer, new findings from the same study paint an even more ominous picture of the hormones' role in the disease.

The new results pertain to a widely used type of hormone therapy that combines estrogen and progestin; the most popular brand is Prempro, made by Wyeth. The results do not apply to the use of estrogen alone.

In addition to stimulating the growth of breast cancer, the combined hormones may also make tumors harder to detect, leading to dangerous delays in diagnosis, researchers are to report on Wednesday in The Journal of the American Medical Association.

Women on hormones are also more likely to have changes in their breast tissue that lead to abnormal mammograms, and those problems can show up quickly, during the first year of hormone use. Many of the abnormalities turn out to be harmless, but they can be nerve-racking and even risky, since they require further tests that may include biopsies. Of the three million women in the United States who now take combined hormones, about 120,000 a year may have abnormal mammograms solely because of hormone treatment, the researchers said.

Because breast abnormalities can develop so soon after a woman starts taking hormones, the new findings raise questions about the safety of even short-term use, which is commonly recommended to treat severe hot flashes and other menopausal symptoms.

A sharply worded editorial accompanying the report said it provided "further compelling evidence against the use of combination estrogen plus progestin hormone therapy."

The hormone combination is now approved in the United States for only two uses: to treat menopausal symptoms and to prevent the bone-thinning disease osteoporosis. Because the hormones have risks, women are advised to use the lowest dose for the shortest time possible, and to consult their doctors about safer ways to prevent osteoporosis.

Bad news has been piling up about hormones, which were once promoted as every woman's key to lasting youth, health and femininity. Recent studies have found that many of the expected benefits never materialized and, indeed, that hormones raise the risk of several serious diseases, including some they were supposed to prevent. The increased risks are small, but many doctors say even a small risk is not worth taking if there is no benefit to counterbalance it. And for hormone therapy, rigorous studies have demolished many claims of benefit.

For example, a study published last month found that combined hormones doubled the risk of Alzheimer's disease and other types of dementia in women who began the treatment at age 65 or older. That result was an especially hard blow, because many doctors and patients had hoped for the opposite result, that hormone therapy would prevent dementia.

The latest findings on breast cancer are from the Women's Health Initiative, a large federal study of the combination therapy that was stopped ahead of schedule a year ago because the hormones caused a small but significant increase in the risk of breast cancer. The study also found that hormones increased the risks of heart attack and stroke, which they were once thought to prevent. Hormones also increased the odds of blood clots.

The study included 16,000 women and is widely considered to be the most reliable and scientifically rigorous of the many studies on hormone therapy, because it is the largest experiment to compare women on hormones with a group taking placebos.

The new report is based on a further analysis of the data from the Women's Health Initiative. The first report last July found a 26 percent increase in the risk of breast cancer, which translates into eight extra cases per 10,000 women. In other words, if 10,000 women take hormones, 41 will develop breast cancer, as opposed to only 33 breast cancers in 10,000 women not on hormones. The latest report found a similar small increase in risk, 24 percent after 5.6 years of follow-up.

What is new in the latest report is the finding that compared to women not on hormones, those who take estrogen and progestin tend to develop tumors that are found at a more advanced stage and are harder to cure.

Of the 8,506 women on hormones, 199 developed invasive breast cancers, compared to 150 cases in the 8,102 women on placebos. In the women taking hormones, 25.4 percent had cancers that had begun to spread either to nearby tissue or distant parts of the body, compared with only 16 percent in the placebo group.

In addition, after one year of treatment 9.4 percent of women in the hormone group had abnormal mammograms, as opposed to only 5.4 percent in the placebo group. The increased odds of an abnormal mammogram translate into 1 in 25 treated women per year.

"This reinforces the breast cancer data and for the first time raises a new concern regarding the risk-benefit ratio of short term use," said Dr. Rowan T. Chlebowski, the lead investigator in the study and a medical oncologist at the Research and Education Institute at Harbor-U.C.L.A. Medical Center in Torrance, Calif.

"This will give women something to think about," he continued. "Do you want to take an intervention like estrogen plus progestin that will reduces hot flashes 90 percent, probably at the cost of having a 1 in 25 chance of having this abnormal mammogram, which might be more significant?

"I think a lot of women with modest symptoms will now say, `Wait a minute.' "