Circulating tumor DNA for minimal residual disease and recurrence surveillance in hepatocellular carcinoma: current evidence and a translational roadmap.

Recurrence remains a major cause of failure after curative-intent therapy for hepatocellular carcinoma (HCC), including resection, ablation, and liver transplantation. Current surveillance relies on imaging and serum biomarkers, but radiologic relapse may lag behind biological recurrence. This gap has focused attention on circulating tumor DNA (ctDNA) and related cell-free DNA (cfDNA) approaches as candidate tools for minimal residual disease (MRD) assessment and molecular surveillance. In HCC, however, recurrence is biologically heterogeneous. Post-treatment relapse may arise from residual malignant clones, occult intrahepatic spread, or de novo hepatocarcinogenesis in a chronically injured liver. This complexity shapes assay selection, result interpretation, and the need for multimodal risk assessment. Tumor-informed ctDNA assays are best suited to tracking residual clonal disease, whereas methylation-based and composite cfDNA approaches may also capture low-shedding disease and recurrence-prone liver-field biology. Available studies suggest that postoperative ctDNA positivity, persistent serial positivity, rising molecular burden, and selected high-risk methylation signals are associated with recurrence risk after curative-intent therapy. Yet the evidence base is uneven across treatment settings and assay classes, laboratory methods are not yet standardized, and binary detectable-versus-undetectable reporting is rarely sufficient for clinical interpretation. The central translational question is therefore how ctDNA/cfDNA information should be used in realistic HCC surveillance pathways. Current evidence supports these assays as adjunctive molecular risk signals, not as standalone treatment triggers. This review synthesizes the evidence, compares assay strategies, outlines multimodal implementation barriers including standardization and cost, and proposes a cautious roadmap for ctDNA-guided recurrence surveillance in HCC.