Circulating Tumor DNA (ctDNA) for Minimal Residual Disease (MRD) Detection in Colorectal Cancer (CRC): Current Evidence, Clinical Applications, and Future Directions

Minimal residual disease (MRD) is a major contributor to colorectal cancer (CRC) recurrence following curative-intent treatment, yet conventional surveillance methods may fail to detect residual disease at its earliest stages. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for MRD detection and postoperative monitoring. We conducted a structured PubMed-based literature review and included 94 publications evaluating ctDNA in CRC. Across the literature, postoperative ctDNA positivity was consistently associated with increased recurrence risk and poorer disease-free and overall survival, while serial monitoring improved detection sensitivity and enabled assessment of treatment response. ctDNA frequently identified molecular recurrence approximately 2.5–11.5 months before conventional surveillance. Both tumor-informed and tumor-naive strategies were represented, using PCR/ddPCR, targeted next-generation sequencing, whole-exome or whole-genome sequencing, methylation-based assays, and emerging multiomic approaches. Although ctDNA demonstrates strong prognostic value, evidence supporting treatment modification based solely on ctDNA status remains limited. Further prospective randomized trials, assay standardization, and consensus clinical guidelines are required before routine implementation. Overall, ctDNA is a promising tool for recurrence prediction, surveillance, and precision management of CRC.