Abstract SS1-04: Comprehensive genomic and transcriptomic profiling of molecular subtypes reveal ancestral differences in the activity of signaling pathways between patients with African and European ancestry

Background: Breast cancer demonstrates heterogeneity in biological features, and the therapeutic strategy depends on tumor subtype. African-Ancestry (AA) patients experience a disproportionally high rate of triple negative breast cancer (TNBC) and worse outcomes than European-Ancestry (EA) patients. However, the biological drivers causing this disparity between ancestral populations are not deeply understood. To address the issue, we performed genomic and transcriptomic sequencing of breast tumors for comparison between AA and EA patients according to breast cancer molecular subtypes. Materials and Methods: The study included 221 AA and 341 EA patients. Collected samples underwent the Tempus xT next-generation sequencing panel. Following DNA-panel and whole-transcriptome RNA-sequencing, we compared gene mutation rates, homologous recombination deficiency (HRD) scores, degree of immune infiltration and tumor mutational burden (TMB) between ethnicities and molecular subtypes. Additionally, differences between the activity of relevant signaling pathways were evaluated from RNA-sequencing data. Results: Relative to EA TNBC, AA TNBC tumors exhibited higher mutation rates in TP53 (94% vs 86%), KMT2C (17% vs 9%), APOB (19% vs 10%), BRCA2 (11% vs 5%), EP300 (8% vs 2%), NOTCH1 (12% vs 4%), and EGFR (11% vs 4%). Conversely, AA TNBC tumors had relatively lower rates of PIK3CA (10% vs 18%), RB1 (8% vs 15%), and NF1 (5% vs 11%) mutations. Among patients with HR+/HER2- breast cancer, AA tumors had higher mutation rates in CCND1 (23% vs 10%) and FGF3 (16% vs 10%) than EA tumors, but lower rates in TP53 (32% vs 39%). HRD scores were higher in TNBC and HR-/HER2+ tumors compared with the other subtypes (P Citation Format: Minoru Miyashita, Joshua SK Bell, Yonglan Zheng, Toshio Yoshimatsu, Padma Sheila Rajagopal, Anna Woodard, Jean Baptiste Reynier, Elisabeth Sveen, Galina Khramtsova, Fang Liu, Abiola Ibraheem, Gini Fleming, Nora Jaskowiak, Rita Nanda, Benjamin Leibowitz, Nike Beaubier, Kevin White, Dezheng Huo, Olufunmilayo I Olopade. Comprehensive genomic and transcriptomic profiling of molecular subtypes reveal ancestral differences in the activity of signaling pathways between patients with African and European ancestry [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 SS1-04.