Liquid biopsy for colorectal cancer screening: chances and challenges

Liquid biopsy refers to the analysis of tumor-derived components in blood to enable minimally invasive cancer detection and characterization. Circulating tumor cells, circulating tumor DNA, and tumor-derived extracellular vesicles have demonstrated diagnostic and prognostic potential in colorectal cancer (CRC). As liquid biopsy allows for real-time, repeatable assessment of the tumor burden and may capture molecular heterogeneity across primary and metastatic sites, it has emerged as a promising tool for CRC screening. Early studies have suggested the feasibility of CRC detection; however, its sensitivity for the detection of advanced adenomas remains limited. To date, no adequately powered randomized trial has demonstrated that liquid biopsy-based screening reduces the rate of CRC-specific mortality. Evidence has been derived largely from case-control or single-round prospective studies, and validation results have been inconsistent. Assay heterogeneity, lack of standardization, uncertain downstream clinical pathways, and limited real-world cost-effectiveness data further constrain its implementation. Modeling studies have indicated that reduced specificity and increased test positivity could substantially increase colonoscopy demand, which challenges the capacity of health systems. Although liquid biopsy offers practical advantages, including high acceptability and potential integration into routine care, current evidence does not support the replacement of established modalities, such as fecal immunochemical testing or colonoscopy, in organized CRC screening programs. Further rigorous prospective validation and health system-level evaluations are required before liquid biopsy can be successfully applied in CRC screening.