Identification of KRAS(G12C) Mutations in Circulating Tumor DNA in Patients With Cancer

KRAS is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with KRAS mutations remains an arduous challenge. Recently, KRAS(G12C) mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule KRAS(G12C) inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for KRAS(G12C). Here, we performed a comprehensive analysis of KRAS(G12C) mutations in multiple cancer types, as detected by circulating tumor DNA. METHODS: We conducted a 5-year retrospective review of KRAS(G12C) mutations in patients with cancer who had undergone Guardant360 testing between July 1, 2014, and June 30, 2019; our study included treatment-naive and previously treated patients with metastatic solid tumors. RESULTS: KRAS(G12C) mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. KRAS(G12C) mutations were detected most frequently in patients with nonsquamous non–small-cell lung cancer (NSCLC; 7.5%), NSCLC of all subtypes (6.9%), cancer of unknown primary (4.1%), colorectal cancer (3.5%), squamous NSCLC (2.0%), pulmonary neuroendocrine tumors (1.9%), and pancreatic ductal adenocarcinoma (1.2%) and cholangiocarcinoma (1.2%). KRAS(G12C) mutations were predominantly clonal (clonality > 0.9%) in patients with lung adenocarcinoma, non-NSCLC, cancer of unknown primary, NSCLC, and pancreatic ductal adenocarcinoma, and patients with colorectal cancer and breast cancer had bimodal distribution of clonal and subclonal KRAS(G12C) mutations. CONCLUSION: Our study demonstrates the feasibility of using circulating tumor DNA to identify KRAS(G12C) mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.