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

Promising single-agent activity from sotorasib and adagrasib in KRAS(G12C)-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 KRAS(G12C) 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 KRAS(G12C) and 12,126 (88.1%) harboring other KRAS variants (KRAS(non-G12C)). Compared with KRAS(non-G12C) across all tumor subtypes, KRAS(G12C) 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%). KRAS(G12C) 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 KRAS(non-G12C)-mutated, KRAS(G12C)-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRAS(G12C)-mutated tumors exhibited a distinct comutation profile from KRAS(non-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 KRAS(G12C). The KRAS(G12C) mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRAS(G12C) tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.