ATLANTAA study of more than 400,000 postmenopausal women has found no increased risk of fatal breast cancer with use of estrogen replacement therapy (ERT). In fact, women who reported ever having used estrogen actually had a 16% decreased risk of dying of breast cancer, Dawn Willis, PhD, MPH, reported for the American Cancer Society (ACS) at a general session of the San Antonio Breast Cancer Symposium.
The Society's Cancer Prevention Study II (CPSII) is a large prospective cohort 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 determined from the National Death Index, and cause of death from death certificates. During nine years of follow-up, there were 884 deaths among never-users of estrogen and 585 among ever-users. For those using estrogen for one year or less, the relative risk of breast cancer death was .85; for two to 10 years of use, .78; and for 11 years or more, .93.
One surprising finding was a trend toward a greater decreased risk among those who started estrogen at a younger age, Dr. Willis said. The relative risk 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 who started hormones at age 50 and above.
One possible explanation is that women who start to use estrogen early have probably done so because their ovaries were removed. However, the trend 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 have a family history or who have had breast cysts," Dr. Willis said. The data showed no interaction with family history and a possible interaction with fibrocystic disease.
An unexpected finding, however, was a strong interaction with age of menarche. "Women who reported menarche at 14 or older had the highest degree of association of estrogen use with decreased risk of fatal breast cancer," she said.
Unfortunately, Dr. Willis said, "epidemiology never provides definitive answers; it only gives tantalizing clues." Thus, there are a number of possible explanations for the findings.
She pointed out that there could be a selection bias. "Women who take 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 not inclined to put women at high risk for breast cancer on ERT. However, she said, "in our population this was not true; women with family histories and those with self-reported cysts, which might be considered high-risk groups, were just as likely as others to have used estrogen."
Surveillance bias also might be present, since women who take hormones are under a physician's care and generally receive yearly mammograms and clinical breast examinations. Thus, any breast tumors that these women had would be detected at an early stage with a better prognosis and less risk of death.
A possible molecular biological explanation for the result is that estrogen has been reported to increase the expression of the tumor suppressor gene BRCA1, she added.
Overall, the researchers concluded from this study and other data that six to 10 years of estrogen use will reduce a woman's risk of fatal breast cancer by a small amount, increase her risk of ovarian cancer death by a very small amount, and decrease her risk of colon polyps and colon cancer fatality.
"All of these cancer increases and decreases pale in comparison to the decreased risk of death from cardiovascular disease with use of ERT," she said, "and we cannot even factor in the improvements in quality of life."
Dr. Willis called for more research into the pathology of tumors that develop in women who are taking hormones, and for more basic science "to explain this phenomenon so we'll know whether it really is a biological difference in the tumors or a sociological difference in users."