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Clinical Studies

Circulating tumour DNA for a minimal residual disease assessment and recurrence risk in hepatocellular carcinoma: a systematic review and meta-analysis

British Journal of Cancer (2025)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) relapse remains high after curative-intent treatment due to occult minimal residual disease. Circulating tumour DNA (ctDNA) has emerged as a noninvasive biomarker. Systematic search of MEDLINE, EMBASE and the Cochrane Library up to November 2024 identified studies evaluating plasma ctDNA in non-metastatic HCC patients undergoing curative-intent treatment. Hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence-free survival (RFS) and overall survival (OS) were pooled using random-effects models; sensitivity and specificity for predicting recurrence were summarised. Ten retrospective studies (n = 793) met inclusion criteria. Postoperative ctDNA positivity was associated with shorter RFS (HR 4.48; 95% CI 2.56–7.82; I² = 78%; p < 0.001) and worse OS (HR 2.99; 95% CI 1.94–4.61; I² = 47%; p < 0.001). Baseline ctDNA detection predicted reduced RFS (HR 3.54; 95% CI 1.97–6.38; I² = 35%; p < 0.001). Sensitivity ranged 33–82% and specificity 41–100%, reflecting methodological heterogeneity. Leave-one-out analyses confirmed robustness. Plasma ctDNA is a potent prognostic marker of recurrence and survival in non-metastatic HCC. Prospective trials incorporating ctDNA could optimise postoperative surveillance and guide adjuvant therapy selection.

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Fig. 1: Forest plot of the association between postoperative ctDNA levels and RFS according treatment modality.
Fig. 2: Forest plot of the association between baseline ctDNA levels and RFS.
Fig. 3: Forest plot of the association between postoperative ctDNA and overall survival.
Fig. 4: Summary receiver operating characteristic (SROC) Curve for ctDNA detection.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Universidade Federal da Bahia, Salvador, Brazil

    Isabella R. Buonopane, Júnior Samuel Alonso de Menezes & Thiago Francischetto

  2. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada

    Erick F. Saldanha

  3. Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA

    Erick F. Saldanha

  4. Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil

    Lucas Diniz da Conceição & Luís Felipe Leite

  5. Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil

    Camila Mariana de Paiva Reis

  6. Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada

    Renata D’Alpino Peixoto

  7. Moffitt Cancer Center, Tampa, FL, USA

    Tiago Biachi de Castria

  8. Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Tiago Biachi de Castria

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  1. Isabella R. Buonopane
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Contributions

Isabella Buonopane and Erick F. Saldanha conceptualised the study and coordinated the systematic review process. Júnior Samuel Alonso de Menezes and Lucas Diniz da Conceição performed the literature search and data extraction. Camila Mariana de Paiva Reis and Luís F. Leite da Silva contributed to quality assessment and data analysis. Thiago Francischetto assisted in data interpretation and drafting of the manuscript. Renata D’Alpino Peixoto and Tiago Biachi de Castria provided critical revisions and contributed to the final approval of the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Isabella R. Buonopane.

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This study is a systematic review and meta-analysis of previously published data. No new data involving human participants, human tissue, or personally identifiable information were collected or analysed. Therefore, ethical approval and informed consent were not required. All included studies had obtained prior approval from their respective institutional ethics committees. This meta-analysis was conducted in accordance with the principles of the Declaration of Helsinki.

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Buonopane, I.R., Saldanha, E.F., de Menezes, J.S.A. et al. Circulating tumour DNA for a minimal residual disease assessment and recurrence risk in hepatocellular carcinoma: a systematic review and meta-analysis. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03296-8

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