State of the art of the molecular hyperselection to guide treatment with anti-EGFR antibodies in RAS WT mCRC: implications for clinical practice and future perspectives.

Introduction: Adding monoclonal antibodies to chemotherapy drastically changed the landscape of advanced colorectal cancer. The prediction of benefit from anti-EGFR therapies is mainly based on the absence of mutations in RAS and BRAF genes, the primary tumor sidedness and microsatellite MSS/MSI status. Molecular hyperselection may optimize the outcome of patients receiving anti-EGFR while detecting additional resistance alterations, both in chemo-naïve and in chemo-refractory settings.

Areas covered: Our review focuses on negative molecular hyperselection, both on tissue samples and ctDNA, and the impact of this further patient selection on response rate and survival outcomes. We searched electronic database, selecting relevant English-language publications from 2017 to 2024.

Expert opinion: Negative hyperselection beyond RAS and BRAF in advanced colorectal cancer appears to be a powerful tool for predicting outcomes to anti-EGFR therapy and spare patients from unnecessary treatment. This improvement appears in both naïve and pre-treated patients. However, data come mainly from retrospective studies. Therefore, to validate and integrate these findings in the clinical practice, prospective studies should be conducted. It will be interesting to elucidate the role of ctDNA in this setting and the choice of molecular techniques, considering costs and accessibility, to guarantee its implementation in the clinic.