Assessment of breast cancer risk factors reveals subtype heterogeneity

Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiological differences and implicating risk prediction. However, reports are conflicting regarding presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case-control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology-record derived immunohistochemistry markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate odds ratios for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, HRT use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. Polygenic risk score was associated with all subtypes except for the basal-like (p heterogeneity < 0.0001). 'Never breastfeeding' was associated with increased risk of basal-like subtype (OR 4.17; 95% CI 1.89 to 9.21) compared to both nulliparity (reference) and breastfeeding. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The association between basal-like subtype and breastfeeding merits more research into potential causal mechanisms and confounders.

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