Blood-based ctDNA tests show low sensitivity for advanced colorectal neoplasia in asymptomatic adults

BACKGROUND: Blood-based circulating tumour DNA (ctDNA) assays have emerged as a promising tool for minimally invasive colorectal cancer (CRC) screening. However, their diagnostic accuracy in asymptomatic, average-risk populations remains uncertain. This systematic review and meta-analysis aimed to synthesise current evidence on the performance of ctDNA-based blood tests for detecting advanced colorectal neoplasia (ACN), defined as the composite of invasive CRC and advanced precancerous lesions (APL). METHODS: A comprehensive search of PubMed, EMBASE, and the Cochrane Library was conducted through July 2025. Studies evaluating ctDNA-based blood assays against colonoscopy and histopathology in asymptomatic, average-risk adults were included. Pooled estimates were calculated using a bivariate random-effects model following Cochrane DTA guidance. RESULTS: Three population-based prospective studies were included (n = 36,381). For invasive CRC, pooled sensitivity was 0.72 (95% CI 0.49-0.88) and specificity 0.91 (95% CI 0.89-0.92), with an area under the curve (AUC) of 0.92. Sensitivity increased progressively from stage I (0.53) to stage IV (0.89). For APL, pooled sensitivity was 0.13 (95% CI 0.12-0.14) and specificity 0.90 (95% CI 0.88-0.91). When CRC and APL were considered together (ACN), overall sensitivity was 0.16 (95% CI 0.14-0.18) with specificity 0.91 (95% CI 0.89-0.92). CONCLUSIONS: ctDNA-based blood testing demonstrates high specificity and clinically relevant accuracy for invasive CRC, but limited detection of precancerous lesions. These findings consolidate current evidence by defining the complementary role of ctDNA in population screening. As a non-invasive, patient-centred approach, ctDNA testing could increase participation and access in CRC prevention, but large-scale studies are needed to confirm its clinical and economic viability.