Diagnostic Accuracy of Blood-Based cfDNA/ctDNA Tests for Colorectal Cancer—A Systematic Review and Meta-Analysis

Background/Objective: Blood-based assays for colorectal cancer (CRC) screening have emerged as promising non-invasive screening modalities, yet their real-world diagnostic performance across platforms remains unclear. Existing studies evaluating circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) based assays as non-invasive alternatives to stool-based tests vary substantially in methodology, population, and study design. In our systematic review and meta-analysis, we quantify the diagnostic yield of contemporary cfDNA/ctDNA for CRC detection through pooled sensitivity and specificity. Methods: A systematic search of diagnostic accuracy studies published through December 2025 was conducted by two researchers in PubMed and the Cochrane Library. Studies reporting sensitivity and specificity were included. Pooled proportions with the 95% confidence interval (CI) were calculated using a hierarchical bivariate random-effects model. Subgroup analyses were conducted stratified by cancer stage and advanced adenoma. (PROSPERO CRD420261290686). Results: Fifty-eight studies involving 63,309 subjects were included. The pooled sensitivity and specificity for colorectal cancer detection were 82.9% (95% CI: 79.9–85.5%) and 90.7% (95% CI: 89.2–92.0%), respectively. HSROC analysis demonstrated excellent overall diagnostic accuracy with an AUC of 0.937. Pooled sensitivity for advanced adenoma was suboptimal at 46% (CI: 32–59%). Detection sensitivity increased progressively by stage, from 70% (CI: 62–78%) in stage I CRC to 90% (CI: 87–92%) in stage IV CRC. Conclusions: These findings position next-generation cfDNA/ctDNA assays as promising, scalable, patient-friendly CRC screening tools with performance characteristics comparable to established non-invasive tests. Integration of cfDNA/ctDNA assays into population-level screening programs may substantially expand screening uptake by overcoming key barriers associated with stool-based modalities.