Blood-Based Circulating Tumor DNA Assays for Early Colorectal Cancer Detection: A Systematic Review of Performance in Asymptomatic Screening Populations

Early detection of colorectal cancer (CRC) via population-based screening programs can reduce incidence and mortality. Current screening approaches are limited by cost, accessibility, compliance, and colonoscopy capacity. Blood-based screening of circulating tumor (ct) DNA may resolve some of these limitations. This systematic review evaluated the screening potential of blood-based ctDNA assays in asymptomatic screening populations. We systematically searched the PubMed database (final search June 20th, 2025) for studies detecting advanced adenomas (AAs) or CRC in asymptomatic cohorts, where a blood-based ctDNA assay had been evaluated with data on specificity, sensitivity, and/or AUC at early stages of disease. Newcastle-Ottowa scale was used for quality assessment. Only 20 studies of 454 unique hits met our inclusion criteria. Of these, 12 studies used assays targeting specific DNA alterations, while the remaining 8 studies used complex assays. Generally, comprehensive assays such as Shield, ColonSecure, and FMBT-CRC had the best performance for early-stage CRC detection with sensitivities of 71%–85% and specificities of 88%–90%. Despite being tested in a small cohort, the Coloscape assay was the only assay to reach sufficient AA detection with 59% sensitivity and 92% specificity. None of the reviewed ctDNA assays demonstrated sufficient sensitivities for both AA and early-stage CRC detection to be considered future screening tools. Screening tools based on ctDNA assays have not proved superior to fecal-based immunochemical test (FIT) yet. Future studies need to test ctDNA screening tools in large, prospective, asymptomatic cohorts emphasizing AA, and early-stage CRC.