Reproductive factors associated with breast cancer risk by subtypes: Findings from the Southern Community Cohort Study

Background: Breast cancer is the most common cancer among U.S. women. Reproductive factors may influence breast cancer etiology through hormonal pathways that differ by molecular subtypes. We investigated the associations between reproductive factors and breast cancer risk by subtypes in the Southern Community Cohort Study. Methods: After excluding the first year of follow-up to minimize potential reverse causation, 42,922 women aged 40-79 years (69.2% Black) remained for the study. Cohort members were followed for up to 213 months. Breast cancer cases were classified by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status as luminal A-like (ER/PR+, HER2-), luminal B-like (ER/PR+, HER2+), HER2-enriched (ER/PR-, HER2+), and triple-negative breast cancer (TNBC; ER/PR/HER2-). To account for competing risk, cause-specific Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between reproductive factors and each breast cancer subtypes. Models were adjusted for age, enrollment source, education, race, income, family history of breast cancer, personal history of breast cysts or fibroids, smoking, alcohol intake, body mass index, leisure-time physical activity, healthy eating index, and ever use of oral contraceptive pills and hormone replacement therapy. Subgroup analyses were conducted among Black women. We repeated the above analyses using Fine-Gray subdistribution hazard models. Results: Over follow-up, 1,257 breast cancers occurred (luminal A-like = 612; luminal B-like = 105; HER2-enriched = 62; TNBC = 180; unclassified = 298). In the overall cohort, multiparity, particularly ≥3 births, was inversely associated with luminal A-like (HR = 0.74; 95% CI: 0.57-0.96) and luminal B-like (HR = 0.53; 95% CI: 0.30-0.94) subtypes, but positively with ER-/PR- disease (HR = 1.71; 95% CI: 1.06-2.77). Among Black women, it was also positively associated with TNBC (HR = 2.30; 95% CI: 1.12-4.72). Among parous women, first live birth at ≥ 30 years was associated with a higher risk of ER+/PR+ (HR = 1.59; 95% CI: 1.05-2.40) but a lower risk of ER-/PR- (HR = 0.25; 95% CI: 0.08-0.76) breast cancer. Fine-Gray models showed consistent results with cause-specific models. Conclusions: Parity and age at first birth demonstrate subtype-specific associations with breast cancer risk. Multiparity is associated with a reduced risk of luminal breast cancer subtypes but an increased risk of ER−/PR− tumors. A later age at first childbirth is associated with an increased risk of ER+/PR+ disease and a decreased risk of ER−/PR− subtypes. These findings highlight etiologic heterogeneity by hormonal receptor status and underscore the importance of incorporating reproductive history in subtype-specific risk prediction and prevention strategies.