Abstract B070: Characterizing breast cancer etiologic subtypes in the Ghana Breast Health Study

Background: Breast cancer subtyping has largely been based on immunohistochemical markers of estrogen receptor status. However, RNA-based intrinsic subtypes, including luminal (hormone receptor-positive) and non-luminal (hormone receptor-negative) have been shown to be etiologically relevant, with studies also suggesting other tumor markers (e.g., TP53 status) to be important contributors to etiologic heterogeneity. Compared to luminal tumors, non-luminal tumors are more likely to be TP53 mutant than wildtype-like. TP53 mutant breast cancers are associated with more aggressive tumor features and these mutations are more common among cases of African descent. However, few RNA-based subtyping studies have described etiologic heterogeneity in indigenous African populations. Therefore, we evaluated associations between established breast cancer risk factors and risk of PAM50 intrinsic subtypes and tumor subtypes defined by RNA-based TP53 functional status in the population-based Ghana Breast Health Study (GBHS). Methods: We analyzed data from 600 invasive breast cancer cases and 2,528 controls in the GBHS. RNA was extracted from formalin-fixed paraffin-embedded tumor samples and run on the nCounter® Breast Cancer 360™ Panel. Samples were then classified for intrinsic subtype (N=285 luminal, N=315 non-luminal) using a research version of the PAM50 assay and for TP53 functional status (N=333 wildtype-like, N=300 mutant-like) using a validated RNA signature. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for risk factors using polytomous logistic regression models adjusted for potential confounders. Results: About 1 in 4 tumors classified as ER-positive by immunohistochemistry were non-luminal by RNA expression. Similarly, about 1 in 5 ER-negative tumors were reclassified as luminal. Etiologic heterogeneity was observed by luminal subtype for certain reproductive factors. Higher parity (≥3 vs.