Age at first live birth modifies the association between age at menarche and breast cancer risk in the UK Biobank cohort

Abstract Background Early menarche is an established risk factor for breast cancer (BC), but it remains unclear whether this elevated risk can be modified by later-life reproductive events. Methods We analysed data from 254,578 women in the UK Biobank using Cox proportional hazards models to assess the associations of age at menarche and later-life factors (reproductive events and exogenous hormonal use) with BC incidence rate. Effect modification of the early menarche–BC incidence rate association by age at first live birth and other later-life factors was evaluated on multiplicative and additive scales, and 10-year absolute risks were estimated. Multivariable linear regression models were applied to compare circulating hormone profiles across strata defined by the identified effect modifier. Results Over a median follow-up of 13.9 years, 11,133 BC cases occurred. Each one-year delay in age at menarche was associated with a 2% lower BC incidence rate (HR = 0.98; 95% CI 0.97–0.99). Among women with menarche ≤ 11 years, first live birth ≤ 30 years showed effect modification on the multiplicative scale (LR P = 0.002) and a negative additive interaction (RERI = − 0.28; 95% CI − 0.48 to − 0.09). In stratified analysis, first live birth ≤ 30 years was associated with a 28% lower relative rate of BC compared with first live birth > 30 years among women with menarche ≤ 11 years (adjusted HR = 0.72; 95% CI 0.63–0.84). Model-based absolute risk estimates for the same subgroup showed an approximately 0.9%-point lower 10-year absolute BC risk at age 60 years. No other later-life factors showed significant effect modification. Among women with early menarche, those with a first live birth ≤ 30 years exhibited circulating hormone profiles that have been previously reported to be associated with lower BC risk. Conclusions Earlier age at first live birth may attenuate the increased BC risk associated with early menarche.