Circulating tumor DNA as a minimal residual disease assessment and recurrence risk in hepatocellular carcinoma: A systematic review and meta-analysis.

Abstract

e15055 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the mainstay of curative treatment for patients (pts) with HCC confined to the liver remains hepatectomy, thermal ablation, or liver transplantation. However, despite these approaches, cancer relapses are still high and strongly correlated with the presence of residual disease following curative-intent treatment. Hence, endeavours to refine risk stratification and identify pts more likely to recur is critical. To this end, circulating tumour DNA (ctDNA) is promising. This meta-analysis seeks to assess the prognostic role of plasma ctDNA in pts diagnosed with HCC undergoing curative treatment. Methods: A systematic search of MEDLINE, EMBASE, and Cochrane databases up to November 2024 was carried out to identify studies investigating plasma ctDNA collection in pts with early or intermediate- stage Barcelona Clinic Liver Cancer (BCLC) HCC undergoing curative-intent treatment, baseline (before radical treatment) and landmark time points (after radical treatment). The hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled for recurrence- free survival (RFS) and overall survival (OS) using a random-effects model. Results: A total of 10 retrospective studies, encompassing 928 pts with plasma samples available at baseline and landmark timepoints, were included. Plasma samples were obtained up to 12 weeks postoperatively. Six studies utilized a tumor-informed approach for ctDNA analysis, 2 employed a tumor-agnostic approach, and 1 incorporated a combined analysis of both methods. ctDNA detection varied, with 6 studies using next-generation sequencing (NGS) and 3 using NGS combined with droplet digital polymerase chain reaction (ddPCR). Pts with detectable postoperative ctDNA had significantly shorter RFS compared to those with undetectable ctDNA levels (HR: 4.48, 95% CI [2.46, 8.16]; I² = 80%, p < 0.001). Baseline ctDNA detection was significantly associated with shorter RFS (HR 4.71, 95% CI [2.35–9.41]; I² = 0%, p < 0.001). Likewise, ctDNA positivity at the landmark time point correlated with reduced OS (HR 2.99, 95% CI [1.94–4.61]; I² = 47%, p < 0.001). Four studies with available data were analyzed, with sensitivities ranging from 33% to 82% and specificities ranging from 41% to 100%, highlighting variability in diagnostic performance across studies. Leave-one-out analysis confirms ctDNA's prognostic value for higher RFS (HR 4.48, 95% CI [2.48–8.16]) without any study disproportionately influencing results. Conclusions: The detection of ctDNA following curative-intent treatment in pts with early-stage HCC was prognostic. There is potential to leverage plasma ctDNA in prospective studies, which may improve risk stratification and aid treatment selection.