Davide Mauri1, Konstantinos Kamposioras2, Dimitrios Matthaios3, Maria Tolia4, Ioanna Nixon5, Mario Dambrosio6, Georgios Zarkavelis1, Konstantinos Papadimitriou7, Branka Petricevic8, Pantelis Kountourakis9, Jindrich Kopecky10, Cvetka Grašič Kuhar11, Lazar Popovic12, Nataliya P Chilingirova13, Ramon Andrade De Mello14,15, Natalija Dedić Plavetić16, Konstantinos Katsanos17, Bianca Mostert18, Filippo Alongi19,20, Berardino de Bari21, Stefanie Corradini22, Eleytherios Kampletsas1, Ioanna Gazouli1, Stefania Gkoura1, Anna-Lea Amylidi1, Antonios Valachis23. 1. Department of Medical Oncology, University of Ιoannina, Ιoannina, Greece. 2. Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. 3. Department of Oncology, General Hospital of Rhodes, Rhodes, Greece. 4. Department of Radiotherapy/Radiation Oncology, Faculty of Medicine, University of Crete, Heraklion, Greece, mariatolia1@gmail.com. 5. Scottish Sarcoma Network (SSN) UK Chair NCRI HN Epidemiology and Survivorship Subgroup, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. 6. Department of Medical Oncology, Clinica San Carlo, Paderno Dugnano, Italy. 7. University Hospital of Antwerp, Antwerp, Belgium. 8. Department of Hematology and Oncology, Klinik Ottakring, Vienna, Austria. 9. Medical Oncology Department, Bank of Cyprus Oncology Centre, Nicosia, Cyprus. 10. Department of Clinical Oncology and Radiotherapy, University Hospital Hradec Kralove, Hradec Kralove, Czechia. 11. Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia. 12. Medical Oncology Department, Oncology Institute of Vojvodina, University of Novi Sad, Novi Sad, Serbia. 13. Medical Oncology Clinic at Specialized Hospital for Active Treatment in Oncology, University Pleven, Sofia, Bulgaria. 14. Department of Biomedical Sciences & Medicine, University of Algarve, Faro, Portugal. 15. Precision Oncology Group, Federal University of São Paulo (UNIFESP), & Nine of July University (UNINOVE), São Paulo, Brazil. 16. Department of Oncology, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia. 17. Department of Gastroenterology, University Hospital of Ioannina, Ιoannina, Greece. 18. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 19. Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, Verona, Italy. 20. University of Brescia, Brescia, Italy. 21. Hospitalier Neuchâtelois, La Chaux-de-Fonds, Switzerland. 22. Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany. 23. Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Abstract
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.
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.