Background: Some genomic alterations in non–small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. Methods: Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, 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 histologic type, age (&lt;40/≥40 years, &lt;75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. Results: Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR , ALK , BRAF , and KRAS alterations were significantly enriched in females, whereas TP53 , STK11 , KEAP1 , and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK , RET , MET , EGFR , STK11 , KEAP1 , BRAF , and KRAS , as well as TMB-High, were significantly different between patients aged &lt;40 years and those aged ≥40 years. Conclusions: Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.

Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests