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9125 Background: Racial differences in morbidity and mortality of non-small cell lung cancer (NSCLC) have been demonstrated and some genomic alterations (e.g. EGFR) in NSCLC are known to differ according to race. However, studies have been limited in sample size and hence, limited in their capacity to detect discrepancies in less frequently altered genes. Here, we investigated alteration prevalence in a large real-world NSCLC cohort, stratified by genetic ancestry. Methods: 75,362 NSCLC patients from the United States, were profiled with comprehensive genomic profiling (CGP) of tissue biopsy, as part of routine clinical care (Foundation Medicine Inc., FMI; Frampton GM, et al. Nat Biotechnol 2013). 296 genes targeted across all assays were examined for known/likely pathogenic alterations of all classes. Predominant genetic ancestry was inferred using a SNP-based approach (Newberg J, et al. AACR 2019), and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histological type, age (≥40/ < 40), and sex. The prevalence of high tumor mutational burden (TMB-High), defined as ≥ 10 mutations/mb (Chalmers ZR, et al. Genome Med 2017), and microsatellite instability status (Trabucco, et al. J Mol Diagn 2019) was also calculated. Results: In this NSCLC cohort, ancestry was split 82.2% for EUR, 10.0% for AFR, 4.4% for EAS, 2.7% for AMR, and 0.8% for SAS. 50.4% were female (n = 37,972) and 49.6% male (n = 37,360). The most prevalent alterations in the overall cohort included TP53 (67.5%), KRAS (30.6%), CDKN2A (29.2%), CDKN2B (17.2%), STK11 (16.1%), and EGFR (15.3%). The prevalence of TMB-High status in the overall cohort was 34.6%. Stratified by ancestry, the prevalence of EGFR alterations was significantly enriched in EAS vs. other ancestry groups ( p < 0.001). KRAS and STK11 were enriched in EUR and AFR vs. other groups ( p < 0.001). TMB-High status was significantly enriched in AFR vs. all other groups ( p < 0.001). In EAS and SAS, TMB-High was typically reduced vs. other ancestry groups (TMB-High AFR 41.6%, AMR 20.1%, EAS 14.1%, EUR 35.5%, SAS 11.7%). A similar analysis based on sex revealed differences in prevalence of 80 gene alterations and TMB-High with sex-specific enrichments (e.g., EGFR 19.0% female vs. 11.5% male; KRAS 34.6% vs. 26.6%). With respect to age, the prevalence of 41 gene alterations and TMB-High were significantly different between samples from patients age < 40 and age ≥ 40 (e.g., ALK 21.1% age < 40 vs. 2.7% age ≥ 40; KRAS 13.0% vs. 30.8%; TMB-High 14.4% vs. 34.8%). Conclusions: Comprehensive analysis of this real-world dataset, which includes the largest NSCLC patient cohort, revealed ancestry-associated differences in genomic alterations in NSCLC. Age and sex were also associated with differences in genomic alteration and TMB-High prevalence.

8587 Background: Thymic epithelial tumors (TETs), including thymic carcinomas and thymomas, are rare neoplasms arising in the mediastinum. Chemotherapy is still the mainstay of treatment and few therapeutic options are available for patients with advanced or metastatic TETs. Due to their rarity, the sample size in the previous reports about the genomic profiles of TETs was small and the results varied from study to study, which hinders the development of treatment. Herein, we investigated the comprehensive genomic characteristics of TETs evaluated in a large genomic database profiled in a real-world setting. Methods: Tissue biopsy-based comprehensive genomic profiling was performed in the course of routine clinical care. We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the US (Frampton GM, et al. Nat Biotechnol 2013) and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, which is engaged in a national project for collecting genomic analysis and clinical results from patients. Samples profiled at Foundation Medicine were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated as previously described (Chalmers ZR, et al. Genome Med 2017. Trabucco, et al. J Mol Diagn 2019). Patients’ background including histology, age, and sex were also investigated, and genetic alteration, TMB, and MSI were stratified by them. Results: A total of 794 patients were collected for our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, 414 cases of thymic carcinoma and 308 cases of thymoma were included. CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), CDKN2A (5.8%) and CDKN2B (4.6%) in thymoma. TMB-High (≥ 10muts/Mb) and MSI-High were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Comparison of the thymic carcinoma cohort based on age < 60 vs 60+ years found a significant difference in prevalence of NFKBIA alterations (2.7% age < 60 vs 11.7% age ≥ 60, p = 0.034), while a similar comparison of the thymoma cohort found no significant differences between age groups. An analysis based on sex did not find any significant differences between groups. 55 cases of thymic carcinoma and 17 cases of thymoma were included from C-CAT data. In thymic carcinoma, CDKN2A (27.3%), TP53 (23.6%) and CDKN2B (20.0%) were also frequently altered, while alterations of TSC1 (23.5%) and CD22, LTK, NOTCH1, KMT2A, SETD2, ATM (17.6% each) were found in thymoma. Conclusions: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB, and MSI status of TETs were investigated. We suggest that several gene mutations, TMB, and MSI status might be potential targets for treatment and lead to therapeutic development opportunities, especially in thymic carcinoma.