Evidence for etiologic subtypes of breast cancer in the Carolina Breast Cancer Study

Background:Distinctions in the etiology of triple-negative versus luminal breast cancer have become well established using immunohistochemical surrogates [notably estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)]. However, it is unclear whether established immunohistochemical subtypes are the sole or definitive means of etiologically subdividing breast cancers.Methods:We evaluated clinical biomarkers and tumor suppressor p53 with risk factor data from cases and controls in the Carolina Breast Cancer Study, a population-based study of incident breast cancers. For each individual marker and combinations of markers, we calculated an aggregate measure to distinguish the etiologic heterogeneity of different classification schema. To compare schema, we estimated subtype-specific case–control odds ratios for individual risk factors and fit age-at-incidence curves with two-component mixture models. We also evaluated subtype concordance of metachronous contralateral breast tumors in the California Cancer Registry.Results:ER was the biomarker that individually explained the greatest variability in risk factor profiles. However, further subdivision by p53 significantly increased the degree of etiologic heterogeneity. Age at diagnosis, nulliparity, and race were heterogeneously associated with ER/p53 subtypes. The ER−/p53+ subtype exhibited a similar risk factor profile and age-at-incidence distribution to the triple-negative subtype.Conclusions:Clinical marker–based intrinsic subtypes have established value, yet other schema may also yield important etiologic insights.Impact:Novel environmental or genetic risk factors may be identifiable by considering different etiologic schema, including cross-classification based on ER/p53.