Abstract P5-03-12: DNA Repair Genes Are More Frequently Mutated in Non-White Populations of Metastatic Breast Cancer (MBC) Patients

Abstract Background: Although improvements in detection, therapeutic development and molecular profiling have decreased MBC mortality over the last twenty years, clinical outcomes are not being equally realized among all patients. Representation and enrollment into clinical trials are often not reflective of the general MBC population in terms of race and ethnicity, with Black and Hispanic patients being largely and often underrepresented. Not only does this imbalance translate into overall access to novel agents, but the lack of understanding of therapeutic efficacy in minority populations and tumor-based molecular differences reduce the use of truly personalized treatments for these groups. There is an opportunity to improve clinical outcomes for all patients with MBC, starting with a better understanding of the degree of any potential differences in underlying tumor molecular biology between racial groups. Methods: We utilized data from two cohorts of patients whose tumors underwent molecular profiling to examine differences in the frequency of genetic mutations across racial groups with MBC. The first cohort included 856 MBCs whose genomic profiles were retrieved from the AACR Genomics Evidence Neoplasia Information Exchange (GENIE) publicly available database. The second cohort included a separate set of 91 patients with MBC from an ongoing precision medicine program sponsored by the Side-Out Foundation (SOF). While the GENIE data were collected at 19 large academic cancer centers, the SOF data are derived from patients treated in the community setting. We compared the relative distributions of age and reported ethnicity between datasets, and compared the 20 most frequently mutated genes in each racial group across datasets. The analysis across races included 73 genes that were examined for differences in mutation frequency using Fisher’s Exact test and Pearson Chi-Square test (p< 0.05 uncorrected). Results: Although the GENIE set was significantly larger, race distribution was not statistically significant across the two populations. The combined populations included 831 white patients (88.4%), 43 Black patients (4.6%), 30 Asian patients (3.2%), and 35 Hispanic patients (3.7%). The age of initial (59.61) and metastatic (61.19) diagnosis was older in the SOF population compared to the GENIE population (48.81, 53.14; p < 0.001). Hispanic patients (46.92) were diagnosed with MBC at a younger age compared to White patients (53.78; p < 0.001). Of the 73 genes analyzed, 11 genes were found less frequently mutated in whites compared to non-whites including, NTRK1, SDHA, MSH6, TCF3, FANCC, GNAS, COP1, RECQL4, WRN, BCL6, and U2AF1. When the same 73 genes were examined for differences across racial groups, alterations of 22 genes reached statistical significance. The gene(s) with the largest difference compared to white patients were RECQL4 in black patients (13.95% vs 5.29%; p = 0.019), WRN in Asian patients (16.63% vs 2.53%; p < 0.001), and RECQL4 and ERBB2 in Hispanic patients (16.13% vs 5.29%; p = 0.019, p = 0.020). Of the 22 genes that were more frequently altered in the non-white population, 6 have roles in DNA repair including RECQL4, WRN, ERCC2, BLM, MSH6, FANCC. 4/22 are receptor tyrosine kinases (RTKs), including NTRK2, RET, ERBB3, and ERBB2, and 3/22 have roles in immune function, including BCL6, CIITA, and TLR4. Conclusion: Analysis of genomic alterations derived from 2 independent real-world molecular profiling-based cohorts identified in non-whites MBC patients a set of candidate “actionable” genes involved in DNA damage repair, RTK expression, and immune function. Although these results require further validation, considering the relatively small samples sizes of the non-white populations, these findings may provide actionable targets for non-white patients with MBC that could be utilized in future trials. Citation Format: Sydney Hilley, Rick Dunetz, Edik Blais, Mariaelena Pierobon, Emanuel F. Petricoin, Elisa Baldelli. DNA repair genes are more frequently mutated in non-white populations of metastatic breast cancer (MBC) patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-12.