The worldwide data from prospective studies of the relationship between levels of endogenous sex hormones and breast cancer risk in postmenopausal women show multiple and complex relationships.1 Nine prospective studies (different from those reported here) of women not taking exogenous sex hormones when their blood was collected to determine hormone levels showed that the risk for breast cancer increased significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non–sex hormone binding globulin (SHBG)-bound estradiol, estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone.
The relative risks for women with increasing quintiles of all hormone concentrations, relative to the lowest quintile, ranged from a marginal increase in risk to more than doubling of risk, and high SHBG was associated with a decrease in breast cancer risk. Interestingly, estradiol levels are generally higher in North American women than Asian women, and urinary estrogens are higher in North American teenagers, who face higher lifetime risks for breast cancer.
Earlier Data
Earlier studies among women at increased risk for osteoporotic fractures who had traditional risk factors for breast cancer showed that the risk for breast cancer was more than three times greater among women with the highest concentrations of bioavailable estradiol compared with women with the lowest concentrations.2
In addition, investigators in the Women’s Health Initiative, a randomized study of hormone replacement therapy in postmenopausal women, measured total estradiol, bioavailable estradiol, estrone, and estrone sulfate in the study subjects prior to enrollment in the trial. Conjugated equine estrogens plus progestin increased all measured estrogens and SHGB after 1 year of use. The effect of combination hormonal therapy on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. Women with lower pretreatment endogenous estrogen levels were at greater risk of breast cancer during combined hormonal therapy compared with those with higher levels.3
Complex Relationship
The relationship of circulating hormone levels to the risk of breast cancer, and to the type of cancer that develops, is complex. In a case-cohort study within the Women’s Health Initiative Observational Study among postmenopausal women aged 50 to 79 years, investigators examined associations between endogenous testosterone and estradiol levels and the risks of estrogen receptor (ER)-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in both invasive breast cancer cases and in control women.
Compared with women in the lowest quartile of testosterone level, those in the other three quartiles had half the risk of ER-negative cancer, independent of other risk factors. Perhaps not surprisingly, estradiol level was not associated with ER-negative breast cancer. Thus, higher serum levels of bioavailable testosterone appear to be associated with lower risks of ER-negative breast cancer in postmenopausal women.4
Women With Other Risk Factors
Hormone levels may not be predictive in women who have other risk factors for breast cancer. Among women at increased risk for breast cancer in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial,5 the relative risk of breast cancer for women in the placebo group was not associated with sex hormone levels.6 In addition, the reduced risk of invasive breast cancer in tamoxifen-treated women compared with placebo-treated women was not associated with sex hormone levels.
Consistent with these observations, in the Multiple Outcomes of Raloxifene Evaluation (MORE) study of raloxifene (Evista) in older postmenopausal women at risk for osteoporotic fractures, the majority of women had very low levels of estradiol.7 This observation raises the question of a possible “threshold effect” (ie, low risk at very low estradiol levels and high risk at estradiol levels above a “threshold” value).
Contrary to the data from the Breast Cancer Prevention Trial, in a prospective, nested case-control study within the Nurses’ Health Study, estrone sulfate was associated with breast cancer risk among women with either low (< 1.66%) or high (≥ 2.52%; 75th percentile) Gail model-predicted risk of breast cancer.8 It is likely that there is a plateau in circulating hormone concentrations in women at the highest risk.
Additional data were reported from the UK Collaborative Trial of Ovarian Cancer Screening, in which 200 postmenopausal women who developed ER-positive breast cancer 0.6 to 5 years after sample donation were identified and matched to 400 controls. Estrogen receptor alpha and estrogen receptor beta serum bioactivity were both significantly higher before diagnosis in cases compared with controls, while estrogens showed no difference.
Women had a twofold increased breast cancer risk if ER alpha serum bioactivity was in the top quintile more than 2 years before diagnosis or if estrone was in the top quintile less than 2 years before diagnosis. Androstenedione levels were significantly higher compared with controls and showed a strong association, with an almost threefold increased breast cancer risk independent of time to diagnosis.9
Multiethnic Cohort
These effects do not appear to be unique to white women. The ongoing Multiethnic Cohort study includes Japanese American, White, Native Hawaiian, African American, and Latina women. Investigators conducted a nested case-control study to examine the association between sex hormones and breast cancer risk. Levels of estradiol (E2), estrone (E1), androstenedione, dehydroepiandrosterone (DHEA), and testosterone were quantified by appropriate methods. E1 sulfate, DHEA sulfate (DHEAS), and SHBG were quantified by direct immunoassays.
The sex hormones were positively associated and SHBG was negatively associated with breast cancer risk. The odds ratio associated with a doubling of E2 levels was greater than 2, and the risk associated with a doubling of testosterone levels was increased by more than 30%. The associations in Japanese American women, who constituted 54% of the sample, were similar to or nonsignificantly stronger than in the overall group. These data provide evidence, therefore, that the association between sex hormones and breast cancer risk is generalizable to an ethnically diverse population.10
Mammographic Density
Circulating hormones have potential physiologic and morphologic effects on breast parenchymal tissue that can be assessed mammographically. In nested case-control studies within the Nurses’ Health Study, investigators examined plasma levels of estradiol, free estradiol, testosterone, and free testosterone along with mammographic density assessed by computer-assisted analysis of the mammograms.
Levels of circulating sex steroids and mammographic density were both statistically significantly and independently associated with breast cancer risk. Circulating levels of estradiol and testosterone were both associated with at least a doubling of breast cancer risk, before and after adjustment for mammographic density. These data suggest that both circulating sex steroid levels and mammographic density are independently associated with the risk of breast cancer in postmenopausal women.11
Further Considerations
The data reported by Key and colleagues in the Endogenous Hormones and Breast Cancer Collaborative Group, reviewed in this issue of The ASCO Post, are unique in that they report a relationship of circulating sex hormones to the risk of breast cancer among premenopausal women similar to that reported in postmenopausal women, although the magnitude of the effect in premenopausal women is modest when compared to the effect in older women.12 Key et al appear to have accounted for the menstrual cycle variability that occurs in the plasma levels of the hormones, and they have made appropriate statistical adjustments to control for known breast cancer risk factors, lending credence to their results.
Polymorphisms in the genes coding for enzymes that metabolize sex steroids may also alter the risk of breast cancer. Several other genetic polymorphisms may influence sex hormone concentrations, including CYP17, CYP19, and CYP1B1. Associations between these polymorphisms and serum concentrations of estrogens, androgens, and SHBG and urinary concentrations of 2- and 16 alpha-hydroxyestrone have been studied,13 but whether the circulating levels of hormones or their metabolism is more important is not known.
Additional indirect evidence of the role of endogenous hormones in the etiology of breast cancer comes from the adjuvant therapy trials with aromatase inhibitors.14 These agents interrupt hormonal synthesis, cause a greater than 90% decrease in the levels of circulating estrogens in postmenopausal women, and have shown a greater than 50% reduction in primary contralateral breast cancers as a first event among women treated with anastrozole when compared with women receiving tamoxifen. Similarly, the rate of contralateral breast cancer is half as great among postmenopausal women receiving letrozole compared with women taking tamoxifen in two adjuvant treatment trials.15,16
Practical Applications
How might we use these data in clinical settings to reduce the risk of breast cancer?
In the MORE trial mentioned above, women with the highest estradiol levels (≥ 12 pmol/L) had a twofold increased risk for invasive breast cancer compared with women with lower levels of estradiol.7 In the placebo group, women with estradiol levels greater than 10 pmol/L had a nearly sevenfold higher rate of breast cancer than women with undetectable estradiol levels.17 Women with estradiol levels greater than 10 pmol/L in the raloxifene group had a rate of breast cancer that was 76% lower than that of women with estradiol levels greater than 10 pmol/L in the placebo group. Importantly, raloxifene reduced breast cancer risk in both the low- and high-estrogen subgroups for all risk factors examined, but the reduction was greatest in those with the highest estradiol levels. In contrast, women with undetectable estradiol levels had similar breast cancer risk whether or not they were treated with raloxifene. Older postmenopausal women whose testosterone levels were in the highest two quintiles had a fourfold increased risk of ER-positive breast cancer.18
A strategy that combines quantitative risk assessment, mammographic density, and measurement of circulating hormone levels is likely to identify those women most likely to benefit from breast cancer risk reduction strategies such as chemoprevention. ■
Dr. Vogel is Director, Breast Medical Oncology/Research, Geisinger Health System, Danville, Pennsylvania.
Disclosure: Dr. Vogel reported no potential conflicts of interest.
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