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

• Published in: JCO precision oncology Vol. 6; p. e2100245
• Main Authors: Salem, Mohamed E, El-Refai, Sherif M, Sha, Wei, Puccini, Alberto, Grothey, Axel, George, Thomas J, Hwang, Jimmy J, O'Neil, Bert, Barrett, Alexander S, Kadakia, Kunal C, Musselwhite, Laura W, Raghavan, Derek, Van Cutsem, Eric, Tabernero, Josep, Tie, Jeanne
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• Subjects: Acetonitriles; Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - genetics; Female; Genomics; Humans; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms - genetics; Middle Aged; NF-E2-Related Factor 2; Piperazines; Proto-Oncogene Proteins p21(ras) - genetics; Pyrimidines; Retrospective Studies
• DOI: 10.1200/PO.21.00245

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