Role of liquid biopsy in diagnosis, prognosis, and monitoring of hepatocellular carcinoma: A systematic review.

480 Background: Hepatocellular carcinoma (HCC) remains a major global health burden, primarily driven by risk factors such as chronic viral hepatitis (HBV/HCV), alcohol-related liver disease, cirrhosis, and non-alcoholic fatty liver disease. A liquid biopsy is a minimally invasive method that can help improve the diagnosis, prognosis, and monitoring of hepatocellular carcinoma (HCC). This systematic review summarizes recent evidence on the clinical value of liquid biopsy biomarkers in HCC. Methods: We searched PubMed for systematic reviews, meta-analyses, randomized controlled trials, and clinical trials published in English from 2019 to 2024. We included studies focused on HCC reporting diagnostic, prognostic, or monitoring outcomes using liquid biopsy biomarkers. Studies lacking relevant outcomes or focused on other GI cancers, case reports, series, and cross-sectional studies were excluded. Data from 10 relevant studies were extracted and analyzed. Results: Ten studies published between 2019 and 2024, including approximately 20,000 HCC patients, were analyzed. For diagnosis, circulating RNAs (mRNA, circRNA, microRNAs, and long non-coding RNAs), methylated SEPTIN9, and cell-free DNA (cfDNA) showed good accuracy with sensitivities of 54–84% and specificities of 75–91%. Combining methylated SEPTIN9 with ultrasound or AFP improved detection. Plasma cfDNA showed better accuracy than serum. For prognosis, higher levels of circulating tumor DNA (ctDNA) and cfDNA were linked to worse survival and more metastases. Mutations in the TERT and SOCS3 gene promoters detected in ctDNA predicted poor outcomes. Circulating tumor cells expressing cancer stem cell and epithelial-mesenchymal transition markers predict early recurrence and poor survival. For monitoring, cfDNA levels changed with treatment response and disease progression, supporting its role in tracking therapy effectiveness. Limitations: The included studies showed heterogeneity in biomarker types and methods, with many conducted in Asian populations, which may limit generalizability. Small sample sizes and lack of standardized protocols also affect the strength of conclusions. Conclusions: Liquid biopsy biomarkers show promising potential in diagnosing, predicting outcomes, and monitoring treatment response in HCC. Larger studies are needed to confirm these findings and translate them into clinical practice.