In a study reported in a letter to the editor in The New England Journal of Medicine, Nassar et al identified the prevalence of the formerly “undruggable” KRAS G12C mutation across tumor types, race, and sex.
As stated by the investigators, a recently reported early-phase clinical trial has shown “promising clinical benefit” of the KRAS G12C inhibitor sotorasib in a group of patients with predominantly non–small cell lung cancer (NSCLC) or colorectal cancer harboring the mutation.
Study Details
The study involved data from the registry of the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE, version 8.03). Distribution of KRAS G12C mutations was analyzed among 32,138 patients with cancer across race (Asian, Black, and White), sex, and 10 cancer types. A total of 27,738 patients (86.3%) were White, 2,355 (7.3%) were Black, and 2,045 (6.4%) were Asian. In risk analyses, P values were corrected by the Benjamini-Hochberg method to determine false discovery rate–corrected Q values (significance at < .05).
“Overall, we found that KRAS G12C somatic mutations are common in NSCLC, colorectal cancer, appendiceal and small bowel cancers, and cancers of unknown primary site, with a mutation frequency of 3% to 14%. With the promising efficacy of sotorasib, recruiting patients with all these cancer types in future clinical trials will be important.”— Nassar et al
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Key Findings
KRAS G12C mutations were identified in 1,867 patient samples (5.8%), with the highest prevalence being identified in patients with NSCLC (1,443 of 10,444; 13.8%), cancer of unknown primary site (74 of 2,105; 3.5%), appendiceal cancer (12 of 368; 3.3%), colorectal cancer (234 of 7,402; 3.2%), and small bowel cancer (7 of 223; 3.1%).
Among patients with colorectal cancer and NSCLC, female vs male patients had a higher prevalence of KRAS G12C mutations.
Among patients with NSCLC, a higher prevalence of mutations was found in White patients (1,153 of 8,892; 13.0%) and Black patients (94 of 862; 10.9%) compared with Asian patients (25 of 690; 3.6%; overall P < .001). Also among patients with NSCLC, the mutation was more common among White female vs male patients (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 1.3–1.6, Q < .001) and more common in Asian male vs female patients (OR = 5.2, 95% CI = 1.9–17.9, Q = 0.01).
Among patients with colorectal cancer, the mutation was more common in White female vs male patients (OR = 1.4, 95% CI = 1.1–1.9, Q = 0.04).
The investigators concluded, “Overall, we found that KRAS G12C somatic mutations are common in NSCLC, colorectal cancer, appendiceal and small bowel cancers, and cancers of unknown primary site, with a mutation frequency of 3% to 14%. With the promising efficacy of sotorasib, recruiting patients with all these cancer types in future clinical trials will be important.”
They noted, “These data illustrate the presence of differences according to sex and ethnic group in the prevalence of KRAS G12C mutations in various cancer types and emphasize the importance of mutation analysis of larger numbers of non-White populations and in rare cancers. Such efforts will address racial disparities, aid in future clinical trial design, and ideally lead to better insight into the reasons for these differences.”
Disclosure: For full disclosures of the study authors, visit nejm.org.
