The steroid metabolome and breast cancer risk in women with a family history of breast cancer: the novel role of adrenal androgens and glucocorticoids.

Background: No study has comprehensively examined how the steroid metabolome is associated with breast cancer (BC) risk in women with familial risk. Methods: We examined 36 steroid metabolites across the spectrum of familial risk (5-year risk ranged from 0.14 to 23.8%) in pre- and post-menopausal women participating in the NY site of the Breast Cancer Family Registry (BCFR). We conducted a nested case-control study with 62 cases/124 controls individually matched on menopausal status, age and race. We measured metabolites using GC-MS in urine samples collected at baseline before the onset of prospectively ascertained cases. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) per doubling in hormone levels. Results: The average proportion of total steroid metabolites in the study sample were glucocorticoids (61%), androgens (26%), progestogens (11%) and estrogens (2%). A doubling in glucocorticoids (aOR=2.7; 95%CI=1.3-5.3) and androgens (aOR=1.6; 95%CI=1.0-2.7) was associated with increased BC risk. Specific glucocorticoids (THE, THF αTHF, 6β-OH-F, THA, and α-THB) were associated with 49-161% increased risk. Two androgen metabolites (AN and 11-OH-AN) were associated with 70% (aOR=1.7; 95%CI=1.1-2.7) and 90% (aOR=1.9; 95%CI=1.2-3.1) increased risk, respectively. One intermediate metabolite of a cortisol precursor (THS) was associated with 65% (OR=1.65; 95%CI=1.0-2.7) increased risk. E1 and E2 estrogens were associated with 20% and 27% decreased risk. Conclusions: Results suggest that glucocorticoids and 11-oxygenated androgens are positively associated with BC risk across the familial risk spectrum. Impact: If replicated, our findings suggest great potential of including steroids into existing BC risk assessment tools.