Beyond Sidedness: DNA Methylation as a Biomarker to Refine Anti-EGFR Treatment Selection in RAS/BRAF Wild-type Metastatic Colorectal Cancer.

Primary tumor sidedness is a major determinant of biologic-agent selection in RAS/BRAF wild-type metastatic colorectal cancer (mCRC), but it remains an anatomic surrogate rather than a mechanistic biomarker. Genome-wide DNA methylation status has emerged as a biologically informative classifier that may refine anti-EGFR treatment selection within this conventional framework. Highly methylated colorectal cancer (HMCC) is consistently associated with inferior outcomes after anti-EGFR therapy, whereas low-methylated colorectal cancer (LMCC) appears relatively more sensitive. This review critically summarizes evidence from discovery, assay-development, first-line, second-line, and later-line studies, with emphasis on JACCRO CC-13AR, T-CORE1201, and the EPIC translational analysis. We also discuss mechanistic links between DNA methylation, AREG/EREG expression, EGFR ligand dependency, downstream signaling, host immune factors including antibody-dependent cellular cytotoxicity, and acquired resistance. Current evidence supports DNA methylation as a promising refinement biomarker, but not yet as a stand-alone decision tool. Prospective validation, assay standardization, and integration with ctDNA-guided resistance assessment are required before routine implementation.