Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests
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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 (<40/≥40 years, <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 <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.
Submitted September 17, 2023; final revision received February 7, 2024; accepted for publication February 21, 2024. Published online August 8, 2024.
Author contributions: Conceptualization: Miura, Shukuya, Kurokawa. Data curation: Greenstein, Kaplan, Suh, Sivakumar, Sokol. Formal analysis: Miura, Greenstein, Kaplan, Suh, Sivakumar, Sokol. Investigation: Miura, Shukuya, Greenstein, Kaplan, Suh, Sivakumar, Sokol. Methodology: Shukuya, Greenstein, Kaplan, Shukuya, Suh, Sivakumar, Sokol. Project administration: Shukuya. Resources: Greenstein, Kaplan, Suh, Sivakumar, Sokol. Supervision: Shukuya, Wakelee, Kato, Carbone, Takahashi. Writing—original draft: Miura. Writing—review & editing: Shukuya, Greenstein, Kaplan, Wakelee, Kurokawa, Furuta, Kato, Suh, Sivakumar, Sokol, Carbone, Takahashi.
Disclosures: K. Miura has disclosed serving on the speaker’s bureau for AstaZeneca, Chugai Pharmaceutical, and Merck & Co., Inc. T. Shukuya has disclosed participating in research for AstraZeneca, Chugai Pharmaceutical, Merck & Co., Inc., and Novartis; serving as a principal investigator for Chugai Pharmaceutical; and serving on the speaker’s bureau for AstaZeneca, Chugai Pharmaceutical, Merck & Co., Inc., Taiho Pharma, Daiichi-Sankyo, Ono Pharmaceutical, Bristol Myers Squibb, Nippon Kayaku, Pfizer Inc., Eli Lilly and Company, and Amgen. R. Greenstein has disclosed being employed by Foundation Medicine; and owning stock in Roche. B. Kaplan has disclosed being employed by Foundation Medicine; and owning stock in Roche. H. Wakelee has disclosed receiving institutional grant/research support from AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Genentech/Roche, Helsinn Healthcare, Merck & Co., Inc., SeaGen, and Xcovery; and serving as a scientific advisor for IO Biotech, Mirati Therapeutics, Bristol Myers Squibb, Genentech/Roche, Merck & Co., Inc., and AstraZeneca. J. Suh has disclosed owning stock in Roche. S. Sivakumar has disclosed being employed by Foundation Medicine; and owning stock in Roche. E.S. Sokol has disclosed being employed by Foundation Medicine; and owning stock in Roche. D.P. Carbone has disclosed serving as a scientific advisor for Regeneron Pharmaceuticals, Genentech, Novocure, OncoHost, AbbVie, AstraZeneca, Amgen, Daiichi-Sankyo, Eli Lilly and Company, and Janssen Pharmaceuticals; serving as a consultant for Bristol Myers Squibb Brazil, and Johnson & Johnson; and serving on the speaker’s bureau for Merck & Co., Inc., Roche, and Pfizer Inc. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2024.7021. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.
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