Background: Associations of reproductive history with breast cancer risk differ by oestrogen receptor (ER±) status and possibly by the joint expression of ER and the human epidermal growth factor receptor-2 (ER±/HER2±). However, large sample sizes are needed to establish ER-specific risks by HER2± expression.

Methods: We linked a cancer registry covering nearly 95% of the primary breast cancer diagnoses in Denmark with a research parity database to assess associations for parity, number of live births and age at first live birth (AFLB) with receptor-specific risk. Relative risks (RRs) for associations were estimated with Poisson regression models.

Results: With nearly 31 million women-years of follow-up, 45 786 Danish women aged 20-84 years developed invasive breast cancer during 1992-2011. ER± expression was available for the entire study period and HER2± after 2006. Of the breast cancers with known ER expression, 79% were ER+. Most breast cancers with known ER and HER2 were HER2- (90% of ER+ cancers and 65% of ER- cancers). RRs differed by ER± expression for all reproductive variables ( p -homogeneity < 0.001). Associations were stronger for ER+ than ER- cancers and for those diagnosed before age 50. Parity and early [not later] AFLB showed a protective association with ER+/HER2- and risk association with ER-/HER2- cancers.

Conclusion: Associations of reproductive history with breast cancer risk varied among Danish women by ER± and ER±/HER2± expression and age-at-diagnosis, consistent with receptor-specific and age-related etiological heterogeneity. Further stratification by HER2 status demonstrated dual (or opposite) effects for ER+/HER2- and ER-/HER2- cancers.