Next Generation Sequencing of Circulating Tumor DNA Can Optimize Second Line Treatment in RAS Wild Type Metastatic Colorectal Cancer after Progression on Anti-EGFR Therapy: Time to Rethink Our Approach

: Background Management of Raswild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. Development of treatment resistance with prevalence of pre-existing RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. Summary The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation Next Generation Sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify drugable mutations or recovery of RAS-wildness. In this opinion paper we summarize with critical thinking the clinical approach to be followed after the failure of first line treatment in Ras wild-type CRC tumors with the use of NGS. Key Messages Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of Ras wildness, and targeted approach of specific mutations (BRAF inhibitors) amplifications (anti-Her2 treatment) or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic colorectal cancer and guide clinical decisions. NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.