Reproductive history and risk of three breast cancer subtypes defined by three biomarkers

Breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 expression are biologically distinct and thus, may have distinct etiologies. In particular, it is plausible that risk factors operating through hormonal mechanisms are differentially related to risk of such tumor subtypes. Using data from the Breast Cancer Surveillance Consortium, we explored associations between reproductive history and three breast cancer subtypes. Data on parity and age at first birth were collected from 743,623 women, 10,896 of whom were subsequently diagnosed with breast cancer. Cases were classified into three subtypes based on tumor maker expression: (1) ER positive (ER+, N = 8,203), (2) ER negative/PR negative/HER2 positive (ER-/PR-/HER2+, N = 288), or (3) ER-, PR-, and HER2-negative (triple-negative, N = 645). Associations with reproductive history, evaluated using Cox regression, differed significantly across tumor subtypes. Nulliparity was most strongly associated with risk of ER+ breast cancer [hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.23-1.39]; late age at first birth was most strongly associated with risk of ER-/PR-/HER2+ disease (HR = 1.83, 95% CI: 1.31-2.56). Neither parity nor age at first birth was associated with triple-negative breast cancer. In contrast to ER+ and ER-/PR-/HER2+ subtypes, reproductive history does not appear to be a risk factor for triple-negative breast cancer.