Dietary phytoestrogen intake and risk of receptor-defined breast cancer subtypes: a prospective analysis of the PLCO Cancer Screening Trial cohort

BACKGROUND: Phytoestrogens may influence breast carcinogenesis through hormone-related and non-hormone-mediated mechanisms, yet prospective evidence by receptor-defined subtype in U.S. populations remains limited. We evaluated associations between dietary phytoestrogen intake and risk of estrogen receptor (ER), progesterone receptor (PR), and HER2-defined breast cancer. METHODS: We analyzed 51,530 postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Baseline intake of total and individual phytoestrogens was assessed using a validated food frequency questionnaire. Incident breast cancers were classified by ER, PR, and HER2 status. Cause-specific Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) across tertiles of intake, adjusting for established breast cancer risk factors. RESULTS: During follow-up, 2,364 incident breast cancers were identified. Higher coumestrol intake was associated with lower hazard of ER- breast cancer (tertile 3 vs. tertile 1: HR 0.67; 95% CI, 0.50-0.91; p-trend=0.014) and PR- breast cancer (HR 0.74; 95% CI, 0.59-0.93; p-trend=0.013). Higher total isoflavone intake was associated with lower hazard of HER2-positive disease (HR 0.62; 95% CI, 0.45-0.87; p-trend=0.005), with similar findings for daidzein. No significant associations were observed for ER+ or PR+ tumors. CONCLUSIONS: Associations between phytoestrogen intake and breast cancer differed by receptor-defined subtype, with inverse associations observed primarily for receptor-negative and HER2-positive tumors. IMPACT: These findings suggest that associations between dietary phytoestrogen intake and breast cancer may vary across receptor-defined subtypes and highlight the need for replication using biomarker-based measures and populations with higher exposure levels.