Identification of <i>KRAS</i>^<i>G12C</i> Mutations in Circulating Tumor DNA in Patients With Cancer.

Abstract

<i>KRAS</i> is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with <i>KRAS</i> mutations remains an arduous challenge. Recently, <i>KRAS</i>^<i>G12C</i> mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule <i>KRAS</i>^<i>G12C</i> inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for <i>KRAS</i>^<i>G12C</i>. Here, we performed a comprehensive analysis of <i>KRAS</i>^<i>G12C</i> mutations in multiple cancer types, as detected by circulating tumor DNA. We conducted a 5-year retrospective review of <i>KRAS</i>^<i>G12C</i> 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. <i>KRAS</i>^<i>G12C</i> mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. <i>KRAS</i>^<i>G12C</i> 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%). <i>KRAS</i>^<i>G12C</i> 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 <i>KRAS</i>^<i>G12C</i> mutations. Our study demonstrates the feasibility of using circulating tumor DNA to identify <i>KRAS</i>^<i>G12C</i> mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.