Endogenous Hormones and Breast Cancer

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Circulating levels of sex steroids (estradiol, testosterone) and breast density (as determined by mammography) are known risk factors for the development of breast cancer. In a nested case-control analysis of a subset of postmenopausal participants in the Nurses' Health Study, circulating levels of estradiol and mammographic density were shown to be strong and independent risk factors for breast cancer development.

Source: Tamimi RM, et al. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007;99:1178-1187.

Both mammographic density and circulating sex hormones are established predictors of breast cancer risk.1,2 It has been unclear whether mammographic density is just a reflection of the level of sex hormone or an independent indicator of risk. Tamini and colleagues conducted a nested case-control study within the Nurses' Health Study cohort of 253 cases with breast cancer and 522 control subjects. The Nurses' Health Study, originally initiated in 1976 includes 121,700 registered nurses in the United States who were between the ages of 30 and 55 years at that time. During the period from January 1, 1989, through December 31, 1990, blood samples were collected from 32,826 of these subjects. From this group, 322 were diagnosed with breast cancer in the subsequent years (through June 1, 1998). From this, a complete assessment was possible on 253 case subjects and these were closely matched with 522 controls on the basis of age and blood sample availability. Mammograms from the same time period were made available for this analysis. The median time between mammography and blood draw was eight months. Because menopausal status and postmenopausal hormone use were potential confounders in the determination of hormone level and mammographic density, the analysis was restricted to women who were postmenopausal and who were not using exogenous hormones at the time of mammography.

The laboratory assays included the measurement of estradiol and testosterone. The assessment of mammographic density involved a computer-assisted determination based upon optical density in uniform craniocaudal views of both breasts. The results were reported as percent density and these values were highly reproducible.

Those who developed breast cancer were more likely to have had a family history of breast cancer and to report prior breast disease than control subjects. They were also found to have a slightly higher body mass index and a higher mammographic density.

With regard to mammographic density, those within the highest quartile were younger, thinner, and had fewer children. They were also more likely to have a history of benign breast disease and to have used postmenopausal hormones than women in the lowest quartile of mammographic density. Those within the highest quartile of mammographic density had the greatest risk of breast cancer when compared to those in the lowest quartile (relative risk [RR] = 2.7, 95% confidence interval [CI] = 1.7 to 4.3; P < 0.001).

When the analyses were adjusted for matching factors (ie, age, month of blood draw, fasting status, and time of blood draw) the highest quartile of circulating estradiol was also associated with an increased risk of breast cancer compared with the lowest quartile (RR = 2.3, 95% CI = 1.5 to 3.5; P < 0.001). Circulating testosterone was also associated with an increased risk of breast cancer, comparing the highest quartile with the lowest (multivariable RR equals 1.8, 95% CI equals 1.2 to 2.9). Thus, circulating levels of estradiol and of testosterone were both associated with breast cancer risk after adjusting for a mammographic density. Further analysis demonstrated that mammographic density and circulating steroids remained statistically significantly associated with breast cancer risk when neutrally adjusted for one another, providing evidence that both are strong breast cancer risk factors independent of each other.

Commentary

This very thorough and careful analysis demonstrated the independent association of circulating hormone levels and mammographic density with regard to breast cancer risk in postmenopausal women. The circulating sex steroid hormones were associated with a two-fold increased risk of breast cancer when comparing the highest and lowest quartiles and mammographic density was associated with an approximate four-fold increased risk by comparable analysis. Both circulating sex steroid and mammographic density had been demonstrated previously to be risk factors for breast cancer, but there had been a sense that the two were directly linked. Previously, data derived from randomized control trials examining the use of hormone replacement therapy demonstrated both increased mammographic density and breast cancer risk.3 A natural interpretation was that mammographic density appeared to reflect at least in part cumulative exposure to estrogens and an association between the levels of estrogen and breast density were suspected. There have been, however, a number of studies that raised questions regarding this hypothesis. For example, Boyd and colleagues4 observed an inverse association between levels of circulating estradiol and mammographic density among 189 postmenopausal women, after adjusting for age and waist measurements. Indeed, even the Nurses' Health Study and inverse association between estradiol and mammographic density had been reported.5 Thus, there was some reason to suspect that mammographic density and circulating hormone levels were both risk factors for breast cancer, but by independent mechanisms. This would certainly be the conclusion from the current report as well.

The mechanism by which mammographic density confers an independent risk for breast cancer is not intuitive and remains to be determined. However, it is notable that in twin studies6 mammographic density has been shown to be a heritable trait. Thus, the genetic determinants of mammographic density may mediate the association between mammographic density and breast cancer risk.

Epidemiologic studies often raise additional questions that need resolution. The current report shakes the notion that circulating hormones and mammographic density are linked with regard to breast cancer risk. Now, the factors that associate mammographic density as a breast cancer risk need elucidation.

References

1. Byrne C, et al. Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst. 1995;87(21):1622-1629.

2. Missmer SA, et al. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst. 2004;96(24):1856-1865.

3. Greendale GA, et al. Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst. 2003;95(1):30-37.

4. Boyd NF, et al. The association of breast mitogens with mammographic densities. Br J Cancer. 2002;87(8):876-882.

5. Tamimi RM, et al. Endogenous sex hormone levels and mammographic density among postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14(11 Pt 1):2641-2647.

6. Boyd NF, et al. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med. 2002;347(12):886-894.