Abstract 5360: Comprehensive analysis of breast cancer genomic alterations across diverse populations using a large real-world database
Authors: Vasily N. Aushev, Samuel Riviero-Hinojosa, Carly B. Scalise, Rich Green, J. Bryce Ortiz, Alyssa Antonopoulos, Adam C. ElNaggar, Angel Rodriguez, Minetta C. Liu, Alexey Aleshin, Laura Chambers, Marla D. Lipsyc-Sharf
Journal: Cancer Research (2025)

Background: Breast cancer is genetically and phenotypically heterogeneous, with tumor-specific alterations influencing clinical outcomes. This variability underscores the importance of accounting for factors such as genetic ancestry in genomic studies to better understand tumor biology and improve patient care. However, most genomic studies have focused on individuals of European ancestry, leaving gaps in knowledge about other ancestries. Here, we analyzed genomic data from over 55,000 breast cancer patients in Natera’s proprietary Real-World Database to assess the mutational landscape stratified by genetic ancestry. Methods: Whole-exome sequencing (WES) data of tumor samples from patients with breast cancer were analyzed. WES was performed on tumor tissue for designing Signatera™ molecular residual disease testing, ordered from June 2019 - November 2024. After exclusions, 33,058 patients were included in the analysis. Mutect2 and VarScan2 callers were used for variant calling. Only non-synonymous mutations were included in prevalence analysis. Genetic ancestry was determined using the EthSeq algorithm with four groups: Africa (AFR), East Asia (EAS), Europe (EUR), and South Asia (SAS). Results: The distribution of stage at diagnosis was: 26.6%, 26.7%, 19.4%, and 14.8% for Stage I, II, III, and IV, respectively; 12.5% of patients had unknown stage. Ancestry distribution was 81.7% EUR, 11.7% AFR, 4.9% EAS, and 1.8% SAS. TP53 and PIK3CA were the most frequently mutated genes, with prevalence rates of 34.8% and 27.2%, respectively. PIK3CA variants were the most prevalent, with frequencies of H1047R (10.4%), E545K (5.2%), and E542K (3.0%). Estrogen receptor-negative (ER-) cases exhibited a lower prevalence of PIK3CA H1047R mutations and a higher prevalence of TP53 mutations compared to ER+ cases. For genetic ancestry, individuals of AFR ancestry showed higher mutation rates in GATA3 (11.2% vs. 9.9%, p &amp;lt; 0.001) and TP53 (48.2% vs. 34.3%, p &amp;lt; 0.001) compared to individuals of EUR ancestry. In contrast, EUR individuals exhibited higher mutation rates in PIK3CA (29.4% vs. 23.4%, p &amp;lt; 0.001), MAP3K1 (7.4% vs. 5.6%, p &amp;lt; 0.001), and AKT1 (3.2% vs. 2.5%, p &amp;lt; 0.001) compared to the AFR group. PIK3CA variants E542K (3.3% vs. 2.2%, p = 0.04) and E545K (5.9% vs. 3.2%, p &amp;lt; 0.001) were higher in EUR compared to AFR, whereas the TP53 R213 variant was enriched in AFR individuals when compared to EUR (2.1% vs. 0.9%, p &amp;lt; 0.001). Conclusions: Our analysis reveals differences in breast cancer genomic landscapes across ancestral groups. The variation in somatic alterations between AFR and EUR ancestries suggests potential differences in tumor biology and therapeutic opportunities that may be targeted to improve racial/ethnic disparities in clinical outcomes. Equitable representation in genomic profiling is essential to understand breast cancer and ensure precision oncology benefits all populations. Citation Format: Vasily N. Aushev, Samuel Riviero-Hinojosa, Carly B. Scalise, Rich Green, J. Bryce Ortiz, Alyssa Antonopoulos, Adam C. ElNaggar, Angel Rodriguez, Minetta C. Liu, Alexey Aleshin, Laura Chambers, Marla D. Lipsyc-Sharf. Comprehensive analysis of breast cancer genomic alterations across diverse populations using a large real-world database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5360.