Hormones Not to Blame for Cancer in Mammographically Dense Breasts

BOSTON, Aug. 21 -- Circulating hormones may not be responsible for the elevated breast cancer risk associated with mammographic breast density among postmenopausal women as had been thought, researchers here found.

Rather, both were strong, independent risk factors, with additive effects, said Rulla Tamini, Sc.D., of Brigham and Women's Hospital and Harvard, and colleagues, after an analysis of data from the Nurses' Health Study.

Breast density was associated with about four-fold increased risk and circulating estradiol and testosterone were associated with about two-fold relative risk regardless of mutual adjustment, they reported in the Aug. 1 issue of the Journal of the National Cancer Institute.

It had been hypothesized that breast density in postmenopausal women represented cumulative exposure to estrogens based on evidence from hormone replacement therapy, tamoxifen (Nolvadex), and the role of endogenous hormones in breast cancer.

So the researchers set out to prove the association directly in a prospective, nested case-control study.

They looked at data for women who were postmenopausal, had no history of cancer, and were not taking hormone replacement therapy at the time of mammography and blood sample collection. This included 253 women who developed breast cancer and 520 matched controls.

In a multivariate analysis, increasing mammographic breast density measured by a blinded observer was associated with significantly elevated risk of breast cancer (P<0.001 for trend). Women in the highest density quartile had 3.8-times higher relative risk than women in the lowest quartile (95% confidence interval 2.2 to 6.6).

But, they were surprised to find that adjusting for circulating hormone levels did not appear to explain away the association.

When the multivariable-adjusted breast cancer risk from the highest versus the lowest mammographic density was adjusted for hormones, the findings were:

• A slight increase in risk adjusting for circulating estradiol (RR 3.9, 95% CI 2.2 to 6.9, P<0.001 for trend).
• A greater increase in risk controlling for free estradiol quartiles (RR 4.6, 95% CI 2.5 to 8.2, P<0.001 for trend).
• A moderate increase in risk adjusting for circulating testosterone levels (RR 4.1, 95% CI 2.3 to 7.2, P<0.001 for trend).
• A substantial increase in breast cancer risk controlling for free testosterone levels (RR 4.8, 95% CI 2.7 to 8.5).

Likewise, women with the highest quartile of circulating estradiol had 2.4-times higher breast cancer risk than women with the lowest levels after adjustment for case-control matching factors (95% CI 1.4 to 3.9).

Women in the highest quartile for circulating testosterone had 1.8-times higher relative breast cancer risk than those in the lowest quartile in multivariate analysis (95% CI 1.2 to 2.9).

Additionally adjusting for mammographic density had little effect on the hormone associations, suggesting they were independent risk factors (RR 2.4 for circulating estradiol, 95% CI 1.4 to 4.0, and 2.0 for testosterone, 95% CI 1.2 to 3.1).

When analyzed together, breast cancer risk appeared additive. It was six-fold greater for women with the highest levels of both mammographic density and testosterone versus the lowest levels of both (95% CI 2.6 to 14.0). It was 4.1-times greater for the highest tertile of estradiol and mammographic density (95% CI 1.7 to 9.8).

The findings raise questions, Dr. Tamini and colleagues said. "If, in fact, mammographic density does not reflect the levels of endogenous sex hormone, what does it represent?"

The answer may be that the association between mammographic breast density and breast cancer risk is genetic. The researchers noted that studies of twins have shown 63% of variation in mammographic density to be explained by genetics. This may be through circulating growth factors, such as insulin-like growth factor I, they said.

The investigators noted, though, that the study was limited by use of circulating hormone levels rather than "the more biologically relevant" levels in breast tissues, which may be only modestly reflected by circulating hormone levels.

Breast density "is often recorded as part of mammography screening and could, therefore, readily be used in the clinical setting for incorporation into prediction models," Dr. Tamini and colleagues wrote. However, it has only moderate interobserver agreement, they noted.

Furthermore, "the lack of standardization and variability in sex steroid hormone assays currently prohibits these hormones (particularly estradiol) from being measured in the clinical setting for incorporation into clinical prediction models," they added.

Further studies are needed to examine the relationship between mammographic density and hormone levels in premenopausal women, the researchers concluded.