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Judd J , Abdel Karim N , Khan H , Naqash AR , Baca Y , Xiu J , VanderWalde AM , Mamdani H , Raez LE , Nagasaka M , Pai SG , Socinski MA , Nieva JJ , Kim C , Wozniak AJ , Ikpeazu C , de Lima Lopes G Jr , Spira AI , Korn WM , Kim ES , Liu SV , Borghaei H
Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer
Mol Cancer Ther. 2021 Sep 13
PMID: 34518295   
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KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.
1538-8514 Judd, Julia Abdel Karim, Nagla Khan, Hina Naqash, Abdul Rafeh Orcid: 0000-0001-7622-720x Baca, Yasmine Xiu, Joanne VanderWalde, Ari M Orcid: 0000-0002-6842-2563 Mamdani, Hirva Orcid: 0000-0003-3874-8703 Raez, Luis E Orcid: 0000-0003-2669-5771 Nagasaka, Misako Orcid: 0000-0001-5308-615x Pai, Sachin Gopalkrishna Orcid: 0000-0002-6755-3895 Socinski, Mark A Nieva, Jorge J Orcid: 0000-0003-1605-4719 Kim, Chul Orcid: 0000-0003-0191-8684 Wozniak, Antoinette J Ikpeazu, Chukwuemeka de Lima Lopes, Gilberto Jr Spira, Alexander I Korn, W Michael Orcid: 0000-0002-0124-6841 Kim, Edward S Liu, Stephen V Orcid: 0000-0002-4852-3914 Borghaei, Hossein Journal Article United States Mol Cancer Ther. 2021 Sep 13. doi: 10.1158/1535-7163.MCT-21-0201.