Genotyping of Circulating Tumor DNA Reveals the Clinically Actionable Mutation Landscape of Advanced Colorectal Cancer.

Circulating tumor DNA (ctDNA) enables genomic profiling of colorectal cancer. We investigated therapeutic targets by performing ctDNA panel-captured sequencing of 152 blood samples from advanced stage patients, from which somatic mutations and potentially actionable targets were evaluated. An additional 11 matched tissue samples were retrospectively obtained to verify target validity. The mutation frequencies of 1,127 collective genetic variants identified in our study strongly correlated with those of multiple public databases (Pearson R 2 = 0.92, P < 0.0001). The clonal fraction of driver genes was 90.3%, which was significantly higher than that of potential passenger genes (58.12%). Totally, 90 drug-sensitive genes from 56 patients (36.84%) were identified, including recurring targets PIK3CA, FBXW7, EGFR, BRAF, and NRAS Various resistance mechanisms of anti-EGFR antibodies were revealed via ctDNA profiling, with 29 patients individually exhibiting multiple mechanisms, suggesting considerable resistance heterogeneity in our study population. Of the matched tissue/blood pairs, 88.14% of tissue-derived mutations were detected in ctDNA, and 88.9% of actionable targets were validated. The mutational landscape of ctDNA was highly consistent with tissue databases, and ctDNA profiling showed favorable concordance with tumor tissues in our matched analysis. Thus, comprehensive ctDNA genotyping is a promising noninvasive alternative to biopsy-derived analysis for determining targeted therapy in advanced colorectal cancer.