Reproductive risk factors in relation to molecular subtypes of breast cancer: Results from the nurses' health studies

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Several intrinsic breast cancer subtypes, possibly representing unique etiologic processes, have been identified by gene expression profiles. Evidence suggests that associations with reproductive risk factors may vary by breast cancer subtype. In the Nurses' Health Studies, we prospectively examined associations of reproductive factors with breast cancer subtypes defined using immunohistochemical staining of tissue microarrays. Multivariate-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over follow-up, we identified 2,063 luminal A, 1,008 luminal B, 209 HER2-enriched, 378 basal-like and 110 unclassified tumors. Many factors appeared associated with luminal A tumors, including ages at menarche (pheterogeneity = 0.65) and menopause (pheterogeneity = 0.05), and current HT use (pheterogeneity = 0.33). Increasing parity was not associated with any subtype (pheterogeneity = 0.76), though age at first birth was associated with luminal A tumors only (per 1-year increase HR = 1.03 95%CI (1.02–1.05), pheterogeneity = 0.04). Though heterogeneity was not observed, duration of lactation was inversely associated with risk of basal-like tumors only (7+ months vs. never HR = 0.65 95%CI (0.49–0.87), ptrend = 0.02), pheterogeneity = 0.27). Years between menarche and first birth was strongly positively associated with luminal A and non-luminal subtypes (e.g. 22-year interval vs. nulliparous HR = 1.80, 95%CI (1.08–3.00) for basal-like tumors; pheterogeneity = 0.003), and evidence of effect modification by breastfeeding was observed. In summary, many reproductive risk factors for breast cancer appeared most strongly associated with the luminal A subtype. Our results support previous reports that lactation is protective against basal-like tumors, representing a potential modifiable risk factor for this aggressive subtype.

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The major breast cancer subtypes—luminal A, luminal B, HER2 type, and basal type—are distinguished in part by the presence or absence of hormone receptors. Evidence suggests that they may also be distinguished by risk factors, namely reproductive events such as menarche, parity, and lactation. This study shows that many reproductive risk factors are associated with luminal A tumors, which account for the greater number of breast cancers. An inverse association between breastfeeding duration and the basal-like phenotype supports previous findings that lactation is a modifiable risk factor for the basal subtype, which is associated with poorer clinical outcomes.

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