Background: Metastatic triple negative breast cancer (mTNBC) is often associated with aggressive biology, particularly in younger women. We hypothesized that the tumor genomic profile might vary based on age. The primary objective of this study was to compare the genomic profile, utilizing plasma-based targeted sequencing of common cancer related genes, in patients ≤45 years and >45 years with mTNBC. The age cut-off of ≤ 45 was selected based on prior literature in TNBC using a similar cut-off for younger age stratification (Dolle, 2009). Methods: A retrospective review of patients with mTNBC who had cell-free DNA (cfDNA) analysis (next generation sequencing, Guardant360®, 73 gene panel) collected at an academic institution after mTNBC diagnosis as part of clinical care from 1/2016-10/2019 was conducted. Patient age, demographics, and genotyping results were collected. Clinical and genomic characteristics were compared for patients ≤45 and >45 using the Wilcoxon rank-sum test (continuous variables) and Pearson’s chi-squared test (categorical variables). Results:Of 74 patients with mTNBC and cfDNA results available, 17 were ≤45 years (median age 39 at mTNBC diagnosis), and 57 were > 45 years (median age 58). In comparing patients ≤45 years with those > 45 years, similar rates of de novo disease (≤45: 24%, >45: 9%, p=0.10), visceral disease (≤45: 65%, >45: 67%, p=0.88), and median number of prior lines of chemotherapy (≤45: 2, > 45: 1, p=0.49) were observed. The percentage of patients with more than 1 detectable mutation (≤45: 94%, >45: 93%, p=0.87), and median number of detected mutations (≤45: 5, >45: 4, p=0.67) was similar between groups. However, the median mutant allele fraction (MAF; maximum) was significantly higher in patients ≤45 (≤45: median 29.8%; >45: median 4.6%, p=0.006), and this finding remained significant after correcting for number of prior therapies. Table 1 depicts the mutation spectrum. While TP53 mutations were commonly seen in both cohorts, the median TP53 MAF was significantly higher in patients ≤45 years (≤45: 29.8%, >45: 4.0%, p=0.015). PTEN mutations were found in a portion of patients >45, but not identified in those ≤45 years. Amplifications in MYC, BRAF, PI3KCA, AR, CDK6, EGFR, MET, KIT, and CCND2 were seen more often in those ≤45 years, although these findings did not reach statistical significance. Survival outcomes will be presented at the meeting. Conclusions:Patients with mTNBC diagnosed at ≤45 years had a significantly higher cfDNA MAF than those >45, likely reflecting higher detectable tumor genomic burden. Mutations often associated with aggressive biology such as MYC, MET, and EGFR were more commonly found in patients ≤45, but the small sample size and limited statistical power makes it difficult to draw strong conclusions about differences in individual genes in this study. Further research with a larger multi-center cohort is ongoing to validate these findings. Citation Format: Neelima Vidula, Andrzej Niemierko, Katherine Hesler, Steven Isakoff, Dejan Juric, Jennifer Shin, Laura Spring, Jeffrey Peppercorn, Jerry Younger, Irene Kuter, Beverly Moy, Leif W. Ellisen, Aditya Bardia. Comparison of metastatic genomic profile in patients ≤45 years and patients >45 years with triple-negative breast cancer [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 PS18-19.