Assessing the causal and independent impact of parity-related reproductive factors on risk of breast cancer subtypes.
Level 3 - non-randomized controlled study
Mendelian randomization analysis using summary genetic data from observational cohorts (UK Biobank and BCAC)
PubMed 41034901 · doi:10.1186/s12916-025-04375-6
What was done
The authors conducted univariable and multivariable Mendelian randomization (MR) analyses using genetic data from the UK Biobank (for parity-related factors: ever-parous status, age at first birth, age at last birth, number of births, and adiposity) and the Breast Cancer Association Consortium (for overall, estrogen receptor [ER]-positive, ER-negative, and subtype breast cancer). They evaluated the causal and direct effects of these reproductive factors while adjusting for age at menarche, age at menopause, and adiposity.
What was found
In univariable analysis, older age at first birth was associated with lower ER-negative breast cancer risk (OR 0.76; 95% CI: 0.61, 0.95 per SD increase), but this attenuated after adjustment for age at menarche (OR 0.83; 95% CI: 0.62, 1.06) or age at menopause (OR 0.80; 95% CI: 0.66, 1.01). Older age at first birth was associated with reduced HER2-enriched breast cancer risk only after adjusting for number of births (OR 0.28; 95% CI: 0.11, 0.57). Multivariable MR showed little evidence of direct effects for ever-parous status, age at last birth, or number of births on breast cancer risk.
Why it matters
These findings challenge traditional observational evidence suggesting that early childbearing protects against breast cancer, suggesting prior associations may be confounded by timing of menarche or menopause.
Limits
Participant sample sizes and case counts are not reported in the abstract. Multivariable analyses for ever-parous status and age at last birth suffered from weak instrumental variables. The analysis relies on genetic proxies that may not fully capture environmental or behavioral nuances of reproductive history.
Cited by
- context Giving birth before age 40 reduces the long-term risk of developing breast cancer.