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

PURPOSE

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.

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 variants. Logistic regression assessed comutations with other oncogenes and the association between variants and immuno-oncology biomarkers.

RESULTS

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).

CONCLUSION

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.