Abstract B070: Characterizing breast cancer etiologic subtypes in the Ghana Breast Health Study
Authors: Hurson Amber N. , Butler Ebonee N. , Hamilton Alina M. , Petershie Bernard , Ahearn Thomas U. , Troester Melissa A. , Figueroa Jonine , Titiloye Nicolas , Garcia-Closas Montserrat , Abubakar Mustapha 
Published: December 2023

Abstract
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. &lt;3 births) was associated with lower risk of luminal tumors (OR [95% CI] = 0.68 [0.49, 0.92]), but not with non-luminal tumors (0.95 [0.69, 1.30]). Likewise, later age at first birth (≥26 vs. &lt;19 years) was more strongly associated with risk of luminal than non-luminal tumors (2.16 [1.37, 3.40] and 1.30 [0.84, 2.00], respectively). Consistent with previous findings, TP53 status was also an important etiologic factor and risk factor patterns mirrored those for luminal/non-luminal subtypes. Finally, we evaluated cross-classification of these two etiologic markers to identify risk factors that represent the dual action of both an estrogenic and a DNA-repair pathway. Age at first birth seems to suggest dual action. Conclusions: This study used high-quality RNA expression data to show that intrinsic subtype and TP53 status are useful breast tumor markers for describing etiologic heterogeneity, with cross-classification leading to improved understanding of the etiologic underpinnings of certain risk factors. This work has important implications for the use of gene-expression-based subtyping for breast cancer classification in this population.
Citation Format: Amber N. Hurson, Ebonee N. Butler, Alina M. Hamilton, Bernard Petershie, Thomas U. Ahearn, Melissa A. Troester, Jonine Figueroa, Nicolas Titiloye, Montserrat Garcia-Closas, Mustapha Abubakar. Characterizing breast cancer etiologic subtypes in the Ghana Breast Health Study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B070.