What risk hormones? Conflicting studies reveal problems in pinning down breast cancer risks

Science News, August 5, 1995 by Lisa Seachrist

Women contemplating postmenopausal hormone therapy have a right to be confused. Scientists report one week that taking hormones raises the likelihood of developing breast cancer. A few weeks later, another study indicates that they don't.

The controversy surrounding whether hormone replacement therapy (HRT) makes women more susceptible to breast cancer leaves them trying to decide for themselves whether the benefits of therapy outweigh their individual risks--which may depend on factors such as reproductive and family history. Amid the current scientific uncertainty, it's like betting all your money on a horse without knowing the odds for the race.

Estrogen-only preparations of postmenopausal HRT undoubtedly offer substantial protection against heart disease and osteoporosis. In fact, comparing the use of estrogen-only HRT to no therapy shows that "HRT benefits outweigh the risks in terms of basic deaths from any disease," says Louise Brinton of the National Cancer Institute in Bethesda, Md.

But that protection may come at a price: Endometrial cancer is a side effect of estrogen-only therapy. What's more, estrogen-only HRT appears to increase the risk of breast cancer, especially with long-term use.

Results of a recent study indicate that adding progestin (synthetic progesterone) to estrogen protects against endometrial cancer without eliminating estrogen's beneficial cardiac effects. Scientists then wondered whether the addition of progestin would ameliorate or amplify estrogen's effect on the breast. Harvard University researchers led by Walter Willett seemed to have answered that question when they reported in the June 15 New England Journal of Medicine that long-term use of HRT increases the risk of developing breast cancer, regardless of formulation (SN: 6/17/95, p.375).

Yet just 4 weeks later, a team led by Janet L. Stanford at the Fred Hutchinson Cancer Research Center in Seattle reported in the Journal of the American Medical Association that women who took the estrogen-plus-progestin formulation did not face an increased risk of breast cancer.

These conflicting reports left women even more confused about the prudence of taking HRT, whether for the rest of their lives or just a short time. For the scientific community, the wide discrepancy between the reports illustrates the difficulty of assessing moderate risk factors associated with disease and the perils of comparing very different epidemiological studies.

Unlike the case of lung cancer, which strikes smokers 10 to 20 times more often than nonsmokers, pinning down risk factors for developing breast cancer hasn't been easy. With the exception of the rare and not able BRCA1 and BRCA2 genes, which lead to breast cancer for 85 out of every 100 carriers, no one risk factor proclaims dire consequences.

Brinton maintains that "at best we can only explain 50 percent of all cases of breast cancer with any [identifiable] risk factors." This fact has led Willett to note that "simply being a woman in America places you at risk."

Approximately one out of every eight women in the United States will develop breast cancer during her lifetime (SN: 7/31/93, p.77). The American Cancer Society estimates that in 1995, doctors will diagnose 182,000 U.S. women and 1,400 U.S. men with breast cancer. "Quite obviously there is something different about being a women . . . that puts you at risk for breast cancer," says Barbara Hulka of the University of North Carolina at Chapel Hill School of Public Health.

The most obvious difference between men and women is the sex hormones coursing through their bodies. Estrogen and progesterone, the primary female hormones, stimulate breast cells to grow and divide. Studies in animals show that the two hormones spur the growth of breast cancers. And studies have found that women whose ovaries were removed early in life have markedly reduced rates of breast cancer, presumably because they lack ovarian estrogen and progesterone.

Further evidence of estrogen's involvement in breast cancer lies in the fact that early menarche and late menopause--in other words, an extended period of estrogen production--also increase risk. The known effects of estrogen and lack of estrogen on breast tissue make it plausible that extra estrogens of any kind will dramatically increase the risk of breast cancer.

"The fact of the matter is that it is surprising how little taking hormones increases the risk for breast cancer," says Hulka. While not all studies show increased breast cancer risk from either oral contraceptives or HRT, the ones that do typically gauge that risk as 1.3 to 1.7 times the "normal" chance--a number that pales in comparison to the risks seen with the BRCA1 and BRCA2 genes.

The Harvard team found comparably small elevations of risk in its study in June; the Hutchinson group failed to find a correlation in July. However, the two studies employed very different methods.

The Harvard group analyzed data from the Nurses Health Study, begun in 1976, in which 122,000 initially healthy women filled out detailed questionnaires about their health and health practices, including use of hormones. The team looked at only the 70,000 women who had reached menopause by 1992.