Estrogen Use May Decrease Risk of Breast Cancer Death, Large ACS Study Suggests

ATLANTA—A study of more than 400,000 postmenopausal women has foundno increased risk of fatal breast cancer with use of estrogen replacementtherapy (ERT). In fact, women who reported ever having used estrogen actuallyhad a 16% decreased risk of dying of breast cancer, Dawn Willis, PhD, MPH,reported for the American Cancer Society (ACS) at a general session ofthe San Antonio Breast Cancer Symposium.

The Society's Cancer Prevention Study II (CPSII) is a large prospectivecohort study that began in 1982 to study risk factors for various cancers."We have, at present, analyzed ERT in relationship to breast, ovarian,and colon cancer," Dr. Willis said.

The cohort completed questionnaires in 1982; deaths were determinedfrom the National Death Index, and cause of death from death certificates.During nine years of follow-up, there were 884 deaths among never-usersof estrogen and 585 among ever-users. For those using estrogen for oneyear or less, the relative risk of breast cancer death was .85; for twoto 10 years of use, .78; and for 11 years or more, .93.

One surprising finding was a trend toward a greater decreased risk amongthose who started estrogen at a younger age, Dr. Willis said. The relativerisk was .66 for those who began estrogen when less than 40 years of age;.84 for those who started estrogen at age 40 to 49; and .89 for those whostarted hormones at age 50 and above.

One possible explanation is that women who start to use estrogen earlyhave probably done so because their ovaries were removed. However, thetrend still held after adjusting for age at menopause and type of menopause(natural or surgical).

The researchers also looked for interactions with potential confounders,"to find out if estrogen acts differently in, say, women who havea family history or who have had breast cysts," Dr. Willis said. Thedata showed no interaction with family history and a possible interactionwith fibrocystic disease.

An unexpected finding, however, was a strong interaction with age ofmenarche. "Women who reported menarche at 14 or older had the highestdegree of association of estrogen use with decreased risk of fatal breastcancer," she said.

Some Caveats

Unfortunately, Dr. Willis said, "epidemiology never provides definitiveanswers; it only gives tantalizing clues." Thus, there are a numberof possible explanations for the findings.

She pointed out that there could be a selection bias. "Women whotake estrogen are well known to be generally healthier than women who don't;they're thinner; exercise more, and are less likely to smoke," Dr.Willis said. (Interestingly, she added, they are more likely to drink.)

A further selection bias may occur because physicians are perhaps notinclined to put women at high risk for breast cancer on ERT. However, shesaid, "in our population this was not true; women with family historiesand those with self-reported cysts, which might be considered high-riskgroups, were just as likely as others to have used estrogen."

Surveillance bias also might be present, since women who take hormonesare under a physician's care and generally receive yearly mammograms andclinical breast examinations. Thus, any breast tumors that these womenhad would be detected at an early stage with a better prognosis and lessrisk of death.

A possible molecular biological explanation for the result is that estrogenhas been reported to increase the expression of the tumor suppressor geneBRCA1, she added.

Overall, the researchers concluded from this study and other data thatsix to 10 years of estrogen use will reduce a woman's risk of fatal breastcancer by a small amount, increase her risk of ovarian cancer death bya very small amount, and decrease her risk of colon polyps and colon cancerfatality.

"All of these cancer increases and decreases pale in comparisonto the decreased risk of death from cardiovascular disease with use ofERT," she said, "and we cannot even factor in the improvementsin quality of life."

Dr. Willis called for more research into the pathology of tumors thatdevelop in women who are taking hormones, and for more basic science "toexplain this phenomenon so we'll know whether it really is a biologicaldifference in the tumors or a sociological difference in users."