Landscape of <i>KRAS</i>^G12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in <i>KRAS</i>-Mutated Cancers.

Abstract

Promising single-agent activity from sotorasib and adagrasib in <i>KRAS</i>^G12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of <i>KRAS</i>-variant prevalence, genomic alterations, and the relationship between <i>KRAS</i> and immuno-oncology biomarkers is lacking. 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 <i>KRAS</i> variants. Logistic regression assessed <i>KRAS</i>^G12C comutations with other oncogenes and the association between <i>KRAS</i> variants and immuno-oncology biomarkers. Of the 79,004 samples assessed, 13,758 (17.4%) harbored <i>KRAS</i> mutations, with 1,632 (11.9%) harboring <i>KRAS</i>^G12C and 12,126 (88.1%) harboring other <i>KRAS</i> variants (<i>KRAS</i>^non-G12C). Compared with <i>KRAS</i>^non-G12C across all tumor subtypes, <i>KRAS</i>^G12C was more prevalent in females (56% <i>v</i> 51%, false discovery rate-adjusted <i>P</i> value [FDR-<i>P</i>] = .0006), current or prior smokers (85% <i>v</i> 56%, FDR-<i>P</i> < .0001), and patients age > 60 years (73% <i>v</i> 63%, FDR-<i>P</i> ≤ .0001). The most frequent <i>KRAS</i> variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). <i>KRAS</i>^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 <i>KRAS</i>^non-G12C-mutated, <i>KRAS</i>^G12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% <i>v</i> 8.4%, odds ratio [OR] = 2.38; FDR-<i>P</i> < .0001). <i>KRAS</i>^G12C-mutated tumors exhibited a distinct comutation profile from <i>KRAS</i>^non-G12C-mutated tumors, including higher comutations of <i>STK11</i> (20.59% <i>v</i> 5.95%, OR = 4.10; FDR-<i>P</i> < .01) and <i>KEAP1</i> (15.38% <i>v</i> 4.61%, OR = 3.76; FDR-<i>P</i> < .01). This study presents the first large-scale, pan-cancer genomic characterization of <i>KRAS</i>^G12C. The <i>KRAS</i>^G12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. <i>KRAS</i>^G12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.