Abstract PO5-03-12: Genomic differences of primary triple negative breast cancer in patients younger than 45 years vs. patients older than 45 years of age

Abstract Background: Triple negative breast cancer (TNBC) is often associated with an aggressive clinical course, especially in younger women. We previously demonstrated that there are differences in the genomic spectrum of metastatic TNBC in patients who are ≤45 years and those who are 45 years of age (Vidula et al, SABCS, 2020). Here we explore genomic differences of primary TNBC in patients ≤45 years and patients 45 years to understand variations in the overall number of non-silent mutations and proportion of patients with specific gene mutations. Methods: We obtained filtered mutation calls generated by the Multi-Center Mutation Calling in Multiple Cancers (MC3) working group (Ellrott et al, Cell Syst, 2018), from whole exome sequencing data of 9079 The Cancer Genome Atlas (TCGA) samples across 33 cancer types that had been used for the comprehensive characterization of cancer driver genes and mutations (Bailey et al, Cell, 2018). Receptor subtype and age at diagnosis of 1247 TCGA breast cancer samples were obtained from the UCSC Xena browser (Goldman et al, Nat Biotechnol, 2020). These datasets were combined to identify 119 patients with primary TNBC with harmonized high confidence mutation calls for analysis. We compared the overall number of non-silent mutations between patients ≤45 years vs. 45 years using the Wilcoxon rank sum test. We also compared the proportion of patients with non-silent mutations in genes mutated at 10% frequency between age groups using the Fisher Exact test. Results: Altogether, 25 patients ≤45 years and 94 patients 45 years were identified with primary TNBC. No significant difference in the number of non-silent mutations among patients ≤45 years vs. 45 years was seen (median range, ≤45 years: 65 5-228 vs. 45 years: 74 2-742, Wilcoxon rank sum p=0.57). In total, 35 unique genes were mutated at 10% frequency in either patients ≤45 years (30 genes) or 45 years (7 genes); notably, TP53 mutations were commonly seen in both age groups (≤45 years: 76%; 45 years: 79%, p=0.79) and TTN mutations were also frequently mutated in both cohorts (≤45 years: 20%; 45 years: 27%, p=0.61). Among the 35 genes identified, 12 genes were mutated at significantly different frequencies among patients ≤45 years vs. those 45 years, as depicted in Table 1. Conclusions: Relatively high frequencies of TP53 and TTN mutations were seen in both patients ≤45 years and those 45 years with primary TNBC. However, many genes associated with varying cellular functions including motility, signaling receptors, and growth were more frequently mutated in patients ≤45 years. These results suggest that there are genomic differences of primary TNBC in patients ≤45 years vs. those 45 years. Further research is needed to validate these findings in a larger cohort of primary TNBC since genomic differences may affect tumor biology and clinical behavior. Table 1. Significant Gene Mutation Differences in Primary TNBC Based on Age. Citation Format: Neelima Vidula, Leif Ellisen, Aditya Bardia, Christina Yau. Genomic differences of primary triple negative breast cancer in patients younger than 45 years vs. patients older than 45 years of age abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-12.