Breast Cancer Risk Tied To Hormone Replacement Therapy

Hormone replacement increases the risk of breast cancer in postmenopausal women, according to results of a study by University of Southern California researchers published in the Feb. 16 issue of the Journal of the National Cancer Institute. The study found that although estrogen has long been considered the primary hormonal risk, progestin may be a more important factor.

Ronald K. Ross, M.D., professor of preventive medicine at the USC Keck School of Medicine, and colleagues at the USC/Norris Comprehensive Cancer Center found that for every five years a woman uses estrogen, the risk of breast cancer increases six percent. But for every five years a woman takes both estrogen and progestin, called combined therapy-today's standard hormone replacement therapy to ease the symptoms of menopause-the risk of breast cancer rises 24 percent, the researchers showed.

Researchers often study hormone replacement therapy's effects, but this is by far the largest study to examine the effects of estrogen and progestin as well as estrogen alone on breast cancer. The study has more data than the combined world literature on this subject, including the recent National Cancer Institute study showing a link between hormone replacement therapy and breast cancer.

The USC researchers conducted a study of 1,897 postmenopausal women in Los Angeles County who were diagnosed with breast cancer in the late 1980s and mid-1990s, and compared them to 1,637 similar women with no breast cancer. The women, identified through the county's population-based cancer registry (the Cancer Surveillance Program, which Ross directs), were asked about their history of hormone replacement therapy and oral contraceptive use. The study included significant numbers of long-term hormone replacement therapy users who were found to have breast cancer. (The study found that for women who used combination therapy for 10 years or more, the risk of breast cancer was 50 percent greater compared to non-users of hormone replacement therapy). Doctors have prescribed estrogen to postmenopausal women to prevent osteoporosis, and the hormone markedly decreases the incidence of cardiovascular disease, the No. 1 cause of death in the United States, a finding first reported by this group of USC investigators. But using estrogen alone has been shown to substantially increase a woman's risk of endometrial cancer (also known as uterine cancer), the most common gynecological cancer. In response, medical scientists in the mid-1970s introduced the combined therapy of estrogen and progestin to reduce that danger-but no one was sure how combined therapy would affect the risk of breast cancer.

A woman can take combined therapy in two ways. One is called continuous combined therapy, in which she takes both estrogen and progestin every day of the month. The other is called sequential estrogen and estrogen plus progestin therapy, in which she takes estrogen alone during part of a month and then both estrogen and progestin during the rest of the month.

The researchers found that risks were higher for women who were on the sequential therapy than the continuous therapy (with breast cancer risk increasing 38 percent every five years for the sequential therapy users, far higher than the 9 percent risk increase every five years for the continuous therapy users). Although the differences were not statistically significant in the study, Ross says, the differences in risk were consistent among all segments of women studied and have implications for how hormone replacement therapy is best administered.

"Continuous combined therapy may be better overall, since you tend to see lower doses of progestin in that therapy," says Ross, who holds the Catherine and Joseph Aresty Chair in Urologic Research at the Keck School of Medicine of USC. Over time, he says, the doses of hormone administered to postmenopausal women might be lowered to decrease disease risk, much like the trend toward lower-dose birth control pills.