Abstract PS7-68: Racial disparities within basal-type breast cancer: Clinical and molecular features of African American and Caucasian obese patients
Authors: Sharma Dipali , Blumencranz Lisa E. , Kling Heather M. , Uygun Sahra , Untch Sarah , Audeh William , Crozier Jennifer A. , Habibi Mehran , Nunes Raquel 
Published: February 2021

Background: African American breast cancer patients (AA) are diagnosed at a younger age and present more frequently with triple-negative/Basal tumors than Caucasian American patients (CA). High prevalence of obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome in AA may confound attempts to evaluate the influence of race on gene expression. Previously we showed that differentially expressed genes (DEGs) between AA and CA within the Basal subtype were related to metabolism, translation, and cell signaling pathways (Nunes et al. 2019). However, AA had higher obesity and T2DM rates than CA, and we were unable to distinguish between the influence of metabolic factors and race. In the current analysis, we aim to dissect these factors by comparing clinical and molecular features of Basal-type breast tumors in obese AA and CA.

Methods: The prospective, observational FLEX Registry (NCT03053193) includes stage I-III breast cancer patients who receive 70-gene signature (MammaPrint, MP)/80-gene signature (BluePrint, BP) testing and consent to full transcriptome and clinical data collection. This interim substudy included 50 AA and 96 CA (n=146), enrolled from 2017 to present, all obese by body mass index (BMI, ≥30) and whose tumors were MP High Risk and BP Basal subtype. AA were significantly younger (mean, 55 years) than CA (mean, 60 years, p=0.02); thus, an age distribution-matched subset (n=49 AA, n=49 CA) was added for comparison. Gene expression data were quantile normalized using R limma package; DEGs were compared between groups in the following: (1) all AA (n=50) and CA (n=96), (2) AA and 3 random selections of CA (n=50 pairs), and (3) age-matched AA and CA (n=49 pairs).

Results: Clinical factors, including tumor stage, nodal stage, and T2DM status were similar between AA and CA, regardless of age-matching. Most tumors were T1/2 (83% AA, 88% CA) and negative for nodal involvement (77% AA, 68% CA). 94% of tumors from AA and 74% of tumors from CA were grade 3 (p=0.17). Notably, 32% of tumors from AA and 46% of tumors from CA were ER+ by immunohistochemistry. Age-matched AA and CA had a 20% rate of T2DM. 152 DEGs were significant (adjusted p&lt;0.05) in at least one comparison, with 115 genes more highly expressed in AA and 37 genes more highly expressed in CA. Across all comparisons, 6 genes were consistently more highly expressed in AA: PSPH, NOTCH2NL, POLR1A, AC069240.1, ORAI1, and RPS26P10. Except ORAI1, these genes were also found in the previous comparison between Basal-type AA and CA, and the current analysis confirmed 11/16 DEGs previously reported (Nunes et al. 2019). Genes more highly expressed in AA are associated with transcription, angiogenesis, and Notch signaling pathways, as well as breast cancer aggressiveness and treatment resistance.

Conclusions: Higher prevalence of obesity/T2DM in AA has been proposed as a key factor to explain racial disparities in breast cancer incidence and prognosis, but the current results suggest that race may influence DEGs more than differences in tumor subtype, age, or metabolic factors. This comparison also emphasizes the importance of matched clinical features for DEG analysis and suggests disparities in AA beyond those attributable to clinical differences within the population. DEGs in AA suggest upregulation of Notch-associated aggressiveness, which may be particularly relevant under hypoxic conditions (e.g., obesity), and pathways associated with stemness, metastasis, and chemotherapy resistance. Notch pathway also interacts with key oncogenic pathways, and future studies will reveal the molecular networks underlying racial disparity in AA and CA breast cancer patients.

Citation Format: Dipali Sharma, Lisa E. Blumencranz, Heather M. Kling, Sahra Uygun, Sarah Untch, William Audeh, Jennifer A. Crozier, Mehran Habibi, Raquel Nunes. Racial disparities within basal-type breast cancer: Clinical and molecular features of African American and Caucasian obese patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-68.