Clinical Feasibility of Circulating Tumor DNA in Patients with Advanced Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab

Introduction: The development of targeted therapies and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) reinforces the need for individualized treatment. However, precision medicine is hindered by the lack of mandatory tissue biopsy for genomic profiling in HCC. Liquid biopsy enables genomic profiling of circulating tumor DNA (ctDNA), which could compensate for the lack of tissue-based analysis. This study evaluated the concordance between ctDNA and tumor tissue genomic profiling and its feasibility in advanced HCC treated with atezolizumab plus bevacizumab (atezo/bev). Methods: This cohort study prospectively collected pretreatment plasma samples from 130 patients with advanced HCC who underwent tissue-based sequencing before systemic therapy from June 2020 to October 2022. Tumor tissue sequencing was performed using the Oncomine Comprehensive Assay, and ctDNA sequencing was conducted using Guardant360. Results: ctDNA variants revealed 72.6% (69/95; 95% CI, 62.9-80.6%) sensitivity and 75.0% (69/92; 95% CI, 65.3-82.7%) positive predictive value compared to tumor tissue. With an interval of ≤30 days between ctDNA and tumor tissue sampling, the sensitivity increased to 96.3% (26/27; 95% CI, 81.7-99.3%). In patients treated with first-line atezo/bev, maximum variant allele frequency (maxVAF) of ctDNA was significantly correlated with poor survival outcomes even after adjustment for clinicogenomic variables. Conclusion: In advanced HCC, ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue-based profiling, providing a reliable alternative when tissue samples are limited. Additionally, ctDNA maxVAF demonstrated independent prognostic value in patients treated with first-line atezo/bev. Liquid biopsy using ctDNA can help address challenges associated with limited tissue-based genomic profiling in advanced HCC.