Landscape of KRAS^G12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers

Abstract

PURPOSE Promising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. MATERIALS AND METHODS Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. RESULTS Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants ( KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR- P] = .0006), current or prior smokers (85% v 56%, FDR- P < .0001), and patients age > 60 years (73% v 63%, FDR- P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR- P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR- P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR- P < .01). CONCLUSION This study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.

KRAS G12C-Mutant Non-Small-Cell Lung Adenocarcinoma: First Documented Report in the Arabian Gulf

“…KRAS G12C transversion mutations account for 41% of KRAS mutations and are almost exclusively detected in lung adenocarcinoma, with a nearly 90% incidence rate in smokers, which is consistent with our findings wherein both patients who reported their smoking status were smokers [ 31 , 32 ]. When compared to other KRAS mutations, KRAS G12C signaling preferentially activates downstream Ral A/B and RAF/MEK/ERK pathways while decreasing phosphorylated AKT, a factor also seen with KRAS G12V mutations.…”

Characteristics and Treatment Outcomes in Advanced-Stage Non-Small Cell Lung Cancer Patients with a KRAS G12C Mutation: A Real-World Study

“…We described that NSCLC patients harboring KRAS G12C were predominantly current or former smokers (55% were heavy smokers) and 55% were above 65 years old; this is in line with previously reported data, as KRAS G12C mutations were reported to be associated with age, disease stage, and smoking status [21,25,28]. Additionally, we noted that 40% of the patients had an ECOG ≥1, 45% of them were overweight, and most had a number of comorbidities.…”

“…A slightly higher prevalence of 16% KRAS G12C mutations was recently reported in stage IV non-squamous NSCLC patients from the Netherlands (tested in 2017) [ 20 ]. A prevalence of KRAS G12C mutations of 9% was reported in a retrospective analysis among NSCLC patients in the United States [ 20 , 21 ]. The variability in the prevalence of alterations between regions may partly be explained by differences in risk factors, tumor subtype, and testing strategy.…”

“…At least at the time of diagnosis, KRAS mutations were described to be mutually exclusive with other alterations in NSCLC patients such as EGFR and BRAF mutations, as well as ALK and ROS rearrangements [ 24 ]. However, rare co-occurrence with EGFR (1.2%) and BRAF (1.2%) has been found, and co-occurring mutations with TP53 , PTEN , and STK11 have been described previously [ 21 , 23 , 25 , 26 ]. Concurrent mutations could have contributed to the diverse treatment outcomes observed in NSCLC patients harboring KRAS mutations.…”

“…We found that 31% of KRAS G12C -mutated NSCLC showed PD-L1 expression ≥50% (TPS), and 65% had TPS ≥ 1%, which appeared to be in line with previously published data on KRAS G12C NSCLC (34% with TPS) and unselected NSCLC patients (22–30%, 52–63%, respectively) [ 35 ]. Moreover, smoking behavior is associated with a high tumor mutational burden (TMB) and could predict a better response; in a recent large retrospective analysis, the authors described that KRAS G12C -mutated lesions were significantly associated with a high TMB status [ 21 ]. However, most phase III clinical trials evaluating all those with NSCLC treated with immunotherapy did not stratify by KRAS status, and only post hoc analyses provided information regarding their efficacy.…”