Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up

Plasma estrogen and androgen levels are positively associated with postmenopausal breast cancer risk, but how long a single blood measurement can predict risk and whether the associations vary by tumor hormone receptor status remain unclear. We conducted nested case–control analyses within the Nurses’ Health Study. Blood samples were collected in 1989–1990 and again in 2000–2002. Among postmenopausal women not using postmenopausal hormones at blood collection, 707 cases were diagnosed through June 2010, with two matched controls per case. We used unconditional logistic regression analyses to estimate the relative risks controlling for other breast cancer risk factors. The intra-class correlation coefficients for two blood measurements collected 10 years apart ranged from 0.54 (dehydroepiandrosterone sulfate, DHEAS) to 0.74 (sex hormone-binding globulin, SHBG). Overall, women in the top (vs. bottom) 25 % of levels of estradiol, free estradiol, testosterone, free testosterone, and DHEAS were at a 50–110 % higher risk of breast cancer (p _trend < 0.001). SHBG was inversely associated with risk (p _trend = 0.004). RRs were similar when comparing cases diagnosed 1–10 versus 11–20 years (or 16–20 years) after blood collection (p _interaction > 0.2). Except for DHEAS, the associations varied significantly by hormone receptor status (p _{heterogeneity} ≤ 0.02). For example, the RRs (95 % CIs) comparing the highest versus lowest quartile were 2.8 (2.0–4.0; p _trend < 0.001) for ER +/PR + tumors versus 1.1 (0.6–2.1; p _trend = 0.98) for ER−/PR− tumors for estradiol, and 1.8 (1.3–2.5; p _trend < 0.001) versus 0.6 (0.3–1.2; p _trend = 0.35) for testosterone. One measure of circulating sex hormones in postmenopausal women can predict risk of hormone receptor positive breast cancer for up to 16–20 years.