Pooled analysis of nine cohorts reveals breast cancer risk factors by tumor molecular subtype

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) exhibit etiological differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiological heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER+ or PR+/HER2-), 1,368 luminal B-like (ER+ or PR+/ HER2+), 521 HER2-enriched (ER-/PR-/HER2+), and 1,152 triple-negative (ER-/PR-/HER2-) disease. Ever parous compared to never was associated with lower risk of luminal A-like (HR=0.78, 95% CI 0.73 - 0.83) and luminal B-like (HR=0.74, 95% CI 0.64 - 0.87) as well as a higher risk of triple negative disease (HR=1.23, 95% CI 1.02 - 1.50; p-value for overall tumor heterogeneity <0.001). Direct associations with luminal-like, but not HER2-enriched or triple negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (p-value for overall tumor heterogeneity <0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer (p-value for tumor heterogeneity=0.02). These results provide the strongest evidence for etiological heterogeneity of breast cancer to date from prospective studies.

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