Abstract P3-14-12: Distinct and targetable molecular features of breast cancer in African American women

Abstract

Abstract Introduction: Despite having a lower incidence of breast cancer, African American (AA) women suffer disproportionately worse outcomes; with more aggressive cancer and higher mortality rates, as well as higher incidence of triple negative breast cancer (TNBC). The cause of these disparities is unclear, but may be driven by different biologic and molecular features. Information about targetable molecular profiles for breast cancer in AAs is limited, and may not be representative of racial minorities. A better understanding of actionable targets is needed to improve treatment and outcomes of breast cancer for AA women. Materials and methods: This study utilized molecular data from three TCGA Breast Invasive Carcinoma studies (Cell 2015, Firehose Legacy, and PanCancer Atlas) on CBioPortal. Data was stratified by C/White and AA/Black to identify the most commonly affected genes, the most significantly differentially affected genes between the two populations, and 35 actionable genes. Genes were compared between racial subgroups (455 AA cases, 2103 C cases) for analysis of mutation types (point mutations, splice site, deletions, and amplifications) mutation load, overall survival, and mRNA expression vs. copy number variation (CNV). Data was assessed for differences, with p-value set at <0.05, and OncoPrints generated using tools in CBioPortal. Results: 2282 genes were differentially altered between white and black subgroups (P<0.05). Of the most commonly altered genes, only three were significantly different between AA and C: TP53, PIK3CA, and CSMD1 (p<0.001). PIK3CA missense mutations were more common in C (36.28% (C) vs 22.47% in AA). TP53 missense mutations were more prevalent in AA (40.09% vs. 28.58% in C). CSMD1 deletions, a tumor suppressor gene, were more prevalent in AA (19.78%) vs. 10.79% in C. We identified a cluster of genes at 8q24.21 (MYC, CASC8, POU51B, CCAT2) showing frequent co amplification in AA and C. For TNBC cases (18 AA cases, 52 C cases), the alteration rate of following genes was significantly between AA and C groups USF3 (27.8% in AA, 0% in C); PIK3C2B (27.8% AA, 1.9% C); SLC41A1 (27.8% AA, 3.85% C); PDHX, PRICKLE4, TOMM6 (all 27.8% AA, 5.8% C); and EHF and PRPF4B (both 27.8% AA, 7.7% C). Some of the genes with highest frequency in both groups include: TP53 (83.3% in AA, 78.9% C); PVT1 (38.9% AA, 46.2% C); CASC8, MYC, and POU51B (33.3% AA, 46.2% C). For actionable targets, PIK3CA, RAD51B, MSH6, KRAS, and NTRK3 were significantly different between AA and C (p<0.05). Of note, FGFR1 and NTRK1 amplifications were common in both AA and C subgroups, 17% AA/13% C and 15% AA/11% C respectively, and are potential targets for emerging therapeutics. Of note, TTN missense mutations were common in both subgroups (15.93% in AA and 18.11% in C), and may be an important marker of tumor mutational burden and predictive for immunotherapy responsiveness. ERBB2 was also commonly amplified in both groups (14% in AA and 12% in C). Survival analysis showed significantly worse outcomes for AA women with PIK3CA alterations (50% disease free for PIK3CA vs. 75% for unaltered at 75 months), while C women with PIK3CA alterations had improved outcomes (85% disease free for PIK3CA vs. 80% for unaltered at 75 months). Conclusion: Significant and diverse molecular differences exist in breast cancer between AA vs. C subgroups. Many of these molecular alterations are linked to specific treatment opportunities. The results indicate that comprehensive molecular profiling may have a major role in assessing treatments for patients with breast cancer, and that AA women may develop breast tumors with unique molecular features requiring novel treatment strategies. Citation Format: Genevra Magliocco, Roy Khalife, Anthony Magliocco. Distinct and targetable molecular features of breast cancer in African American women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-12.