Abstract 6120: Genomic profiling of KRAS and EGFR-altered non-squamous non-small cell lung cancer reveal ancestry-specific co-alterations with therapeutic implications
Authors: Sisoudiya Saumya D. , Houle Armande A. , Fernando Tharu M. , Wilson Timothy R. , Schutzman Jennifer L. , Lee Jessica K. , Schrock Alexa B. , Sokol Ethan S. , Sivakumar Smruthy , Shi Zhen , Pathria Gaurav 
Published: March 2024

Background: Racial and ethnic disparities are highly prevalent in cancer care and impact treatment outcomes, with an underrepresentation of minority populations in clinical studies. The impact of genetic ancestry on the genomic landscape of tumors remains understudied. To address this, we sought to comprehensively characterize the ancestry-based genomic co-alteration landscape and immunotherapy-related biomarkers in KRAS and EGFR-altered tumors, two major driver populations in non-squamous non-small cell lung cancer (non-Sq NSCLC).

Methods: Our study consisted of 68,197 adult patients with non-Sq NSCLC who underwent comprehensive genomic profiling using FoundationOne® or FoundationOne®CDx during routine clinical care in the United States. Genetic ancestry was inferred using a SNP-based approach. Tumor mutational burden (TMB) was calculated across 0.8-1.2 megabases. PD-L1 expression was determined by immunohistochemistry using the Dako 22C3 PD-L1 antibody.

Results: Overall, 81% of the patients were of European (EUR; n= 55,430), 10% of African (AFR; n=7,062), 5% of East Asian (EAS; n=3,297), 3% of Admixed American (AMR; n=2,011) and less than 1% of South Asian ancestry (SAS; n=497). KRAS was the most frequently altered oncogene in EUR (39%) and AFR (33%), whereas EGFR was most frequently altered in EAS (53%), SAS (36%), and AMR (30%) ancestry groups. While STK11 and KEAP1 alterations co-occurred with KRAS across all ancestry groups, they were significantly (FDR p &lt;= 0.05) less frequent in EAS (16%) and AMR (15%) compared to EUR (28%). Additional ancestry-specific co-alteration patterns in KRAS-altered tumors included co-occurrence with GNAS alterations in AMR (Odds ratio, OR: 3.5, p &lt; 10-5), co-occurrence with ARID1A alterations in SAS (OR: 4.7, p = 0.02), and mutual exclusivity with NF1 alterations in EUR (OR: 0.4, p &lt; 10-5) and AFR (OR: 0.4, p &lt; 10-5). In contrast, EGFR-altered tumors had a more conserved co-alteration landscape across all ancestry groups. Despite the known mutual exclusivity of KRAS and EGFR alterations, 13% of patients of EAS ancestry (compared to 2-4% of other ancestry groups) with KRAS alterations had co-occurring EGFR alterations; notably, a majority of these patients had an amplification in KRAS and/or EGFR, potentially representing treatment resistance mechanisms. Among immunotherapy-associated biomarkers, PD-L1 expression was similar across ancestries. Of note, patients of AFR ancestry with KRAS or EGFR alterations had higher TMB and the SAS ancestry group had the lowest TMB.

Conclusion: Our study provides a comprehensive landscape of ancestry-specific patterns in KRAS and EGFR-altered non-Sq NSCLC. These findings can help better understand cancer disparities, aid in the development of new therapeutic strategies and inform more inclusive clinical trials and treatment decisions.

Citation Format: Saumya D. Sisoudiya, Armande A. Houle, Tharu M. Fernando, Timothy R. Wilson, Jennifer L. Schutzman, Jessica K. Lee, Alexa B. Schrock, Ethan S. Sokol, Smruthy Sivakumar, Zhen Shi, Gaurav Pathria. Genomic profiling of KRAS and EGFR-altered non-squamous non-small cell lung cancer reveal ancestry-specific co-alterations with therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6120.