Relatively short-term use of combined estrogen plus progestin hormone replacement therapy is associated with an increased risk of breast cancer, diagnosis at a more advanced stage of breast cancer, and more abnormal mammograms, according to an article in the June 25th issue of The Journal of the American Medical Association.

The current study follows the Women’s Health Initiative, the major clinical trial of longer-term hormone replacement therapy use, which was stopped early because of observed increases in health risks (including breast cancer) that outweighed benefits. Overall results from the trial, which involved 16,608 postmenopausal women, were reported in 2002.

In the current study, Rowan T. Chlebowski, M.D., Ph.D., and his American colleagues analyzed data collected during the Initiative to determine any relationships between shorter-term use of combined hormone replacement therapy, breast cancer characteristics, and mammography results.

The researchers found that use of combined hormone therapy was associated with an increase in the total number of cases of breast cancer (245 cases versus 185 cases) and cases of invasive breast cancer (199 cases versus 150 cases) compared with placebo.

Invasive breast cancers among women in the hormone therapy group were larger and were diagnosed at a more advanced stage compared with those diagnosed in the placebo group. The researchers also found that after 1 year of hormone use, the percentage of women with abnormal mammograms was substantially greater in the hormone therapy group (716 [9.4 percent] of 7,656) compared with the placebo group (398 [5.4 percent] of 7,310), a pattern that continued throughout the duration of the study.

"The breast cancers diagnosed in women in the hormone therapy group had similar histology and grade but were more likely to have advanced stage versus those in women in the placebo group," the researchers wrote. "These results suggest that invasive breast cancers developing in women receiving estrogen plus progestin therapy may have an unfavorable prognosis."

"The absolute increase in abnormal mammograms of about 4 percent per year in women receiving estrogen plus progestin translates into approximately 120,000 otherwise avoidable abnormal mammograms annually for the estimated 3 million U.S. postmenopausal women currently using this hormone regimen," the authors said.

"Consideration for use of estrogen plus progestin for any duration by postmenopausal women should incorporate the current findings into established and emerging risks and benefits of these agents," they concluded.

In an accompanying editorial, Peter H. Gann, M.D., Sc.D., and Monica Morrow, M.D., commented on the additional findings regarding combined hormone replacement therapy and association with breast cancer: "The study [Women’s Health Initiative] demonstrates that alteration of a woman's basic hormonal physiology over decades in the interest of long-term disease prevention is fraught with hazard."

They added, "The ability of combined hormone therapy to decrease mammographic sensitivity creates an almost unique situation in which an agent increases the risk of developing a disease while simultaneously delaying its detection."

According to the editorialists, "Experienced observers hesitate to label any biomedical research study as 'definitive,' especially in an area as historically controversial as the study of menopausal hormone therapy. Nevertheless, the Women’s Health Initiative trial of estrogen plus progestin therapy is as close to definitive as can be expected. The effort and commitment of the investigators, funding agency, and participants were prodigious. Although the results are clear enough to discourage any future attempt at replication, further research certainly is necessary."

"In the meantime, the message for physicians caring for menopausal patients is clear. The increased risk of breast cancer and the mammographic abnormalities among women in the Women’s Health Initiative study provide further compelling evidence against the use of combination estrogen plus progestin hormone therapy," they concluded.