The prevalence of KRASG12C mutations utilizing circulating tumor DNA (ctDNA) in 80,911 patients with cancer.

Abstract

3547 Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most commonly mutated proto-oncogene identified in cancer and still remains an arduous therapeutic challenge. Recently, KRASG12C mutation has become special interest since it has now been considered potentially druggable after the introduction of covalent small-molecule KRASG12C inhibitors. Advances in next-generation sequencing (NGS) and embracing utilization of ctDNA have uncovered more genetic alterations in many cancers. We present a comprehensive analysis on the prevalence of KRASG12C mutations identified by ctDNA. Methods: We conducted a 5-year (July 2014 to June 2019) retrospective review of ctDNA NGS analysis in the Guardant360 CLIA database inclusive of treatment-naïve and previously treated patients with metastatic solid tumors. Data were retrieved from the 80,911 unique patients with ctDNA detected. Clonality and co-occurrence of cancer type were analyzed. Clonality was defined as variant allele fraction(AF) / maximum somatic AF in the sample. Results: 80,911 patients, which included more than 100 tumor histologies, were identified. 2,985 patients (3.7%) with > 40 tumor types had KRASG12C mutations identified in ctDNA. KRASG12C prevalence by cancer type were as follows: sarcomatoid lung carcinoma (13.5%), lung cancer NOS (9%), large cell lung carcinoma (9%), lung adenocarcinoma (7.4%), NSCLC (6.9%), carcinoma of unknown primary (CUP) (4.1%), lung carcinoid (4%), CRC (3.5%), squamous cell lung carcinoma (2%), small cell lung carcinoma (1.5%), pancreatic ductal adenocarcinoma (PDAC) (1.2%), cholangiocarcinoma (1.2%), bladder cancer (0.6%), ovarian cancer (0.6%) and breast cancer (0.3%). 53 additional patients with KRASG12C were identified across 24 other tumor types. The KRASG12C mutation was found to be clonal (clonality > 0.9%) in the majority of patients with lung adenocarcinoma, NSCLC, CUP, squamous cell lung carcinoma, and PDAC, compared to patients with CRC and breast cancer who had bimodal distribution of clonal and sub clonal mutations. Conclusions: To our knowledge, this is the largest analysis on the prevalence of KRASG12C mutations identified by ctDNA. Our study demonstrated the feasibility of utilizing ctDNA to identify KRASG12C mutations across solid tumors with the highest prevalence in lung cancer as previously reported in tissue. The clonality information available from ctDNA-based genotyping may provide insights into the clinical efficacy of targeting KRASG12C in different tumor types.