ctDNA retesting to guide anti-EGFR therapy in later-line metastatic colorectal cancer.

Circulating tumor DNA (ctDNA) represents a promising tool for dynamic molecular profiling in metastatic colorectal cancer (mCRC), enabling monitoring of clonal tumor evolution and the detection of mechanisms of acquired resistance during treatment. The relevance of ctDNA has increased, particularly in the context of anti-EGFR therapy, where the emergence of RAS gene mutations constitutes a key resistance mechanism. The aim of this study was to evaluate the clinical utility of reassessing mutational status using ctDNA prior to rechallenge with anti-EGFR therapy in later treatment lines in patients with mCRC. A total of 17 patients with confirmed RAS and BRAF wild-type status in tumor tissue before initiation of first-line therapy were included in the analysis. All patients received anti-EGFR monoclonal antibody-based therapy in the first line and subsequently underwent ctDNA analysis from peripheral blood prior to initiation of third-line treatment using the Idylla™ qPCR platform. RAS gene mutations were detected in ctDNA in 4 patients, while 13 patients retained a wild-type status. Patients without detectable mutations achieved longer progression-free survival in the third-line setting compared with patients harboring RAS mutations. Overall survival from the start of third-line therapy was also prolonged in the wild-type ctDNA group. These findings suggest that the absence of resistant RAS clones in ctDNA may predict greater clinical benefit from anti-EGFR rechallenge. Liquid biopsy-based retesting may therefore represent an important tool for treatment individualization in later lines of mCRC therapy. This study also illustrates the translational potential of ctDNA analysis, linking dynamic molecular characterization of tumor evolution with clinically relevant treatment decision-making and the implementation of personalized oncology approaches.