Circulating Tumor DNA and Precision Biomarkers in Colorectal Cancer: Implications for Diagnosis, Monitoring, and Management of Advanced Disease

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with outcomes critically dependent on timely diagnosis, accurate risk stratification, and individualized treatment. Traditional markers such as CEA, KRAS/NRAS, BRAF, and MSI status, while foundational, are insufficient to address the full complexity of CRC biology. Over the past decade, a new generation of biomarkers has emerged spanning liquid biopsy, stool-based methylation, genomics, epigenomics, immune profiling, microbiome analysis, radiomics, patient-derived organoids, and multiomics integration-collectively redefining how CRC is detected, classified, and treated. This narrative review synthesizes evidence from 73 human studies published between 2010 and 2024, identified through structured searches of PubMed, Embase, Web of Science, and the Cochrane Library, and quality-assessed using QUADAS-2 and Newcastle-Ottawa tools. Circulating tumor DNA (ctDNA) emerged as the most clinically validated biomarker, demonstrating superior performance in minimal residual disease (MRD) detection, recurrence prediction, and real-time therapy monitoring. Stool DNA methylation assays showed strong sensitivity for early CRC and advanced adenoma detection. Genomic markers including BRAF V600E, POLE/POLD1, HER2, and KRAS G12C now directly inform targeted therapy selection, while immune biomarkers-MSI-H, TMB, and Immunoscore-guide immunotherapy decisions and stratify prognosis beyond TNM staging. Microbiome signatures, particularly Fusobacterium nucleatum and colibactin-producing Escherichia coli, were associated with chemo resistance and tumor progression. Radiomics and AI-driven imaging models provided noninvasive assessment of nodal involvement and neo-adjuvant therapy response. Patient-derived organoids demonstrated capacity to predict individual drug sensitivity, and multiomic integration enabled refined molecular subtyping. Despite this progress, widespread clinical adoption remains limited by assay variability, lack of prospective multicenter validation, and implementation barriers including cost and infrastructure. As these technologies mature, their integration into standardized, multidisciplinary workflows will be essential to translating biomarker innovation into improved patient outcomes across all stages of CRC care.