BACKGROUND: Management of Ras wild-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. SUMMARY: Development of treatment resistance with prevalence of preexisting 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. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable 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. 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 CRC and guide clinical decisions. KEY MESSAGES: 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.

Advanced Radiation Oncology Department IRCCS Sacro Cuore Don Calabria Hospital Cancer Care Center Verona Italy

Department of Biomedical Sciences and Medicine University of Algarve Faro Portugal

Department of Clinical Oncology and Radiotherapy University Hospital Hradec Kralove Hradec Kralove Czechia

Department of Gastroenterology University Hospital of Ioannina Ιoannina Greece

Department of Hematology and Oncology Klinik Ottakring Vienna Austria

Department of Medical Oncology Clinica San Carlo Paderno Dugnano Italy

Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Medical Oncology Institute of Oncology Ljubljana Ljubljana Slovenia

Department of Medical Oncology The Christie NHS Foundation Trust Manchester United Kingdom

Department of Medical Oncology University of Ιoannina Ιoannina Greece

Department of Oncology Faculty of Medicine and Health Örebro University Örebro Sweden

Department of Oncology General Hospital of Rhodes Rhodes Greece

Department of Oncology University Hospital Centre Zagreb University of Zagreb School of Medicine Zagreb Croatia

Department of Radiation Oncology University Hospital LMU Munich Munich Germany

Department of Radiotherapy Radiation Oncology Faculty of Medicine University of Crete Heraklion Greece

Hospitalier Neuchâtelois La Chaux de Fonds Switzerland

Medical Oncology Clinic at Specialized Hospital for Active Treatment in Oncology University Pleven Sofia Bulgaria

Medical Oncology Department Bank of Cyprus Oncology Centre Nicosia Cyprus

Medical Oncology Department Oncology Institute of Vojvodina University of Novi Sad Novi Sad Serbia

Precision Oncology Group Federal University of São Paulo São Paulo Brazil

Scottish Sarcoma Network UK Chair NCRI HN Epidemiology and Survivorship Subgroup The Beatson West of Scotland Cancer Centre Glasgow United Kingdom

University Hospital of Antwerp Antwerp Belgium

University of Brescia Brescia Italy

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