Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer

Abstract

Background: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordancebetween the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establisheligibility for anti-epidermal growth factor receptor (EGFR) therapy. Patients and methods: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients wastested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumortissue. Results: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71-0.90) and BEAMingin tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74-0.92). Fifteen cases (10.3%) showed discordanttissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possiblydue to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explainedby low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second-or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allelefractions in plasma below 1%.Conclusions: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translateinto an alternative tool for anti-EGFR treatment selection.