Circulating Tumour DNA and Extracellular Vesicle‐Associated DNA as Biomarkers for Cancer Detection: A Systematic Review and Meta‐Analysis

Liquid biopsy is an emerging tool that allows the detection and monitoring of tumours through the analysis of various analytes in biofluids like blood. An important component of liquid biopsy is circulating tumour (ct) DNA, small fragments of DNA that are released by cancer cells, which have been shown to be a robust biomarker and are already in use clinically. Recent research indicates that cancer cells can also release DNA via extracellular vesicles (EVs), and this EV-associated DNA (EV-DNA) has emerged as another promising biomarker for several tumour types. However, its clinical utility remains under investigation. In this meta-analysis, we compared the sensitivity and specificity of EV-DNA and ctDNA for detecting cancer-related mutations. Using the extracellular vesicle-associated DNA database (EV-ADD), which compiles all published literature on EV-DNA, we systematically mined data comparing ctDNA and EV-DNA in liquid biopsy as a cancer biomarker. After applying our inclusion criteria, we identified and analysed 12 studies involving 765 patients. Summary estimates showed a sensitivity of 64.6% (95% credible interval: 48.8%-79.4%) and specificity of 93.3% (95% credible interval: 86.8%-96.9%) for EV-DNA, compared to a sensitivity of 70.0% (95% credible interval: 54.7%-83.4%) and a specificity of 90.6% (95% credible interval: 80.8%-96.0%) for ctDNA. Additionally, studies with higher EV-ADD metric scores, reflecting adherence to MISEV guidelines, demonstrated higher probability of increased sensitivity and specificity for EV-DNA and increased sensitivity for ctDNA. This analysis underscores the potential of EV-DNA as a complementary biomarker to ctDNA in cancer detection. Future research should focus on larger patient cohorts and expand to other biofluids.