Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer

Abstract

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.

Figure 1.

KRAS mutational distribution in all NSCLC (A) and adenocarcinoma (B) and squamous cell (C) NSCLC histologies. The prevalence of KRAS mutations was 37.2% among adenocarcinoma and only 4.4% in squamous cell samples, however KRAS mutational distribution was similar in both histologies.

Figure 2.

Frequency of KRAS mutation subtypes in never smokers/light smokers (<15 packs/year) and current smokers. Smoking status data was only available in 1,841 of 4,706 patients with KRAS mutations in this cohort.

Figure 3.

Immune checkpoint therapy associated markers among KRAS-mutated tumors (A) and comparison of these markers between KRAS G12C mutated (G12C mt) and all other subtypes (non G12C mt; B). Prevalence of patients with NSCLC with high TMB (defined by ≥ 10 mt/Mb), MSI-H/MMR, and PD-L1 TPS (IHC 22c3) expression across major cut offs (TPS ≥ 1%, ≥ 10% and ≥ 50%) among each KRAS mutation subtype. B, The prevalence of patient with NSCLC with G12C mutations who had tumors with a high TMB (P = 0.01; q = 0.013), PD-L1 TPS ≥1% (P < 0.001; q < 0.001), and PD-L1 TPS ≥ 50% (P < 0.001; q < 0.001) was significantly greater than any other KRAS subtype. ** represents q < 0.05 (statistically significant).

Figure 4.

TMB distribution among KRAS mutations. TMB distribution values with beeswarm plot displaying all patient data points. Median TMB displayed for KRAS WT and each KRAS mutation subtype.

Figure 5.

Mutation rates of key biomarkers in KRAS-mutated NSCLC cohorts. Frequency of the 10 most common co-occurring mutations including TP53, STK11, NF1, KEAP1, CDKN2A, ATM, BRAF, U2AF1, GNAS, and EGFR are displayed for each KRAS mutation subtype as well as KRAS WT group.