Circulating tumor DNA as a predictive biomarker for prognosis in hepatocellular carcinoma: a systematic review and meta-analysis

The prognosis of patients with hepatocellular carcinoma (HCC) is often poor, making prediction of prognosis and risk stratification highly significant. However, existing indicators are insufficient for accurately predicting the prognosis of patients with HCC. This study aimed to systematically summarize the value of circulating tumor DNA (ctDNA) as a prognostic biomarker for HCC patients. PubMed, Web of Science, Embase, Cochrane Library, Scopus, and clinical trials.gov databases were searched to collect observational studies and randomized clinical trials from January 2016 to November 2024. Studies focusing on ctDNA status or ctDNA methylation and prognostic outcomes in HCC patients were included. Pooled hazard ratios ( HR s) were calculated for the primary outcomes: relapse-free survival (RFS) and overall survival (OS). Random-effects models were applied considering the potential heterogeneity. A total of 25 studies involving 2,490 HCC patients were included. Positive ctDNA status both before and after surgery were significantly associated with shorter RFS (before surgery: HR = 3.88, 95% confidence interval [ CI ] : 1.46–10.33, P = 0.007; after surgery: HR = 5.08, 95% CI: 3.35–7.72, P < 0.001). Compared with ctDNA-negative groups, ctDNA-positive before and after surgery groups both exhibited shorter OS (before surgery: HR = 6.59, 95% CI: 2.47–17.55, P < 0.001; after surgery: HR = 7.01, 95% CI: 2.21–22.27, P = 0.001). Sensitivity analyses yielded results similar to the main analysis. Additionally, ctDNA may detect recurrence 2–5 months earlier than radiographic imaging. ctDNA detection was significantly associated with poorer prognosis in HCC patients. The potential applications of ctDNA in prognostic prediction are promising, and the predictive value of ctDNA dynamic change warrants further exploration.