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Hormones play a critical role in breast carcinogenesis. Determining the association between circulating sex steroid hormones and breast cancer risk provides insight into etiology and may help identify high-risk women who would benefit from increased screening or chemoprevention. Although the relationship of circulating estrogen and androgen levels to risk is established among postmenopausal women, data on premenopausal women are sparse, in part due to the complexity of measuring hormones that vary cyclically. From 1996 to 1999, 18,506 premenopausal Nurses' Health Study II participants provided two blood samples timed within the menstrual cycle. Blood samples were drawn on the 3rd−5th day of the menstrual cycle (early follicular phase) and 7−9 days before the anticipated start of their next cycle (mid-luteal phase). We conducted a nested case-control study of 197 cases, diagnosed after blood collection and before June 2003, and 397 matched controls. Logistic regression models, controlling for matching and breast cancer risk factors, were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). Women in the top (versus bottom) 25% of follicular total and free estradiol levels had a significantly increased risk of breast cancer (RR=2.1, 95% CI (1.1–4.1), p-trend=0.08; RR=2.2, 95% CI (1.2–4.2), p-trend=0.03, respectively). The associations were stronger among cases with invasive cancer (e.g., free estradiol RR=2.6, 95% CI (1.3–5.2), p-trend=0.03) or those with estrogen and progesterone receptor (ER/PR) positive tumors (e.g., free estradiol RR=2.8, 95% CI (1.2−6.1), p-trend=0.02). No associations were observed with total or free estradiol in the luteal phase (e.g., top versus bottom 25% for free estradiol RR=1.3, 95% CI (0.7–2.5), p-trend=0.43). Higher levels of total and free testosterone and androstenedione in both phases of the menstrual cycle were associated with modest, nonsignificant increased risks overall. Stronger, statistically significant increased risks were observed among invasive cases (e.g., top versus bottom 25% for luteal total testosterone RR=2.1, 95% CI (1.1–3.9), p-trend=0.03) or ER+/PR+ cases (comparable RR=3.7, 95% CI (1.6–8.3), p-trend<0.01). No clear associations were observed with estrone, estrone sulfate, progesterone, or sex hormone binding globulin levels. Overall, our data suggest that circulating levels of sex steroid hormones are important independent predictors of breast cancer risk in premenopausal women.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]