Liquid biopsy biomarkers for early detection of gastrointestinal cancers: Current landscape and emerging technologies

Early detection of gastrointestinal (GI) cancers remains a critical unmet clinical need, as most patients are diagnosed at advanced stages when prognosis is poor. Liquid biopsy has emerged as a transformative approach for minimally invasive cancer detection by analysing tumour-derived analytes in blood and other body fluids. Recent advances in circulating tumour DNA (ctDNA) sequencing, cell-free DNA methylation profiling, fragmentomics, extracellular vesicle and exosome characterisation, circulating tumour cell isolation and tumour-educated platelets have markedly improved sensitivity and specificity for detecting incipient malignancies. Despite these advances, sensitivity in stage I disease remains limited due to low tumour burden and minimal analyte scaling, resulting in false-negative results for small or indolent lesions. In addition, clonal haematopoiesis derived alterations can confound mutation-based assays, highlighting the need for epigenetic and multi-analyte approaches to improve specificity. Ultimately, widespread clinical adoption will require standardised, prospective trials demonstrating diagnostic accuracy and a reduction in cancer-specific mortality. Multi-analyte and machine learning-driven approaches, integrating DNA, RNA, protein and epigenomic signals, are now in late-stage clinical trials and poised for clinical translation. United States Food and Drug Administration approvals of blood-based colorectal cancer screening tests and laboratory-developed assays for hepatocellular carcinoma exemplify the translational momentum in this field. Here, we review the current landscape of liquid biopsy biomarkers for GI cancers, emphasising technological innovations, clinical performance and ongoing trials. We also discuss key challenges, including sensitivity in stage I disease, specificity amidst clonal haematopoiesis and integration with established screening paradigms. The continued evolution of assay technologies and translational research heralds a paradigm shift towards precision early detection of GI cancers, with the potential to substantially reduce mortality through earlier intervention. KEY POINTS: Liquid biopsy technologies are advancing rapidly for early detecion of GI cancers, using ctDNA, methylation profiling, fragmentomics, EVs, CTCs, and TEPs. Limited sensitivity in stage I disease remains a key barrier, largely due to low tumor burden and analyte scarcity. Clonal hematopoieses confounds mutation-based assays, emphasizing the need for epigenetic and multi-analyte strategies to improve specificity. Multi-analyte, machine-learning-driven platforms are nearing clinical translation, supported by late-stage trials and recent FDA approvals.