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<0.001). However, there was no significant difference between the HRD scores of AA and EA tumors within TNBC or HR-/HER2+ populations. The highest percentage of immune infiltration was observed in HR-/HER2+ tumors (P=0.036), with no difference between AA or EA groups. TMB did not differ across ancestries or subtypes. Although immune pathways were generally more active in TNBC compared to the other subtypes, there was no difference in pathway-specific immune activation between ethnicities. The G2M and E2F pathways were significantly more active in TNBC (P<2e-16 for both), in particular more active in AA than EA tumors (G2M, P=0.035; E2F, P=0.037). On the other hand, PI3K, ROS, and xenobiotic metabolism (XM) pathways were significantly less active in TNBC compared to the other subtypes
(PI3K, P=2.4e-5; ROS, P=0.014; and XM, P<2e-16). Furthermore, these pathways were significantly less active in AA than EA tumors across all subtypes (PI3K, P=0.026; ROS, P=0.00035; and XM, P=0.00041) and within TNBC (PI3K P=0.012, ROS P=0.014, and XM P=0.00018).

Conclusion: These data demonstrate significant differences in breast tumor heterogeneity and mutation spectrum in TNBC and HR+/HER2- breast cancers between AA and EA patients. Ancestral differences were also observed in the activity of relevant signaling pathways for TNBC. Overall, the results identify previously unexplored pathways and molecular phenotypes of aggressive disease, providing opportunities for development of more effective biomarker informed treatment of breast cancer in diverse populations.

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