Landscape of <i>KRAS</i><sup>G12C</sup>, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in <i>KRAS</i>-Mutated Cancers
Mohamed E. Salem, Sherif M. El-Refai, Wei Sha, Alberto Puccini, Axel Grothey, Thomas J. George, Jimmy J. Hwang, Bert O'Neil, Alexander S. Barrett, Kunal C. Kadakia, Laura W. Musselwhite, Derek Raghavan, Eric Van Cutsem, Josep Tabernero, Jeanne Tie
Abstract
PURPOSE 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.