Plasma Circulating Cell-free DNA in Advanced Hepatocellular Carcinoma Patients Treated With Radiation Therapy

Background/Aim: Although radiation therapy (RT) is an effective and safe treatment when administered locally for various stages of hepatocellular carcinoma (HCC), adequate biomarkers that are predictive of therapeutic efficacy have not been identified. We evaluated the clinical utility of circulating cell-free DNA (cfDNA) to predict treatment response of patients with HCC treated with RT. Patients and Methods: We prospectively recruited 37 patients diagnosed with HCC between March 2019 and May 2020. All patients were treated with RT as salvage therapy. Whole peripheral blood was collected twice, one before RT (baseline; V1) and another aliquot one week after the end of RT (V2). We determined whether cfDNA genomic copy number variations (CNVs) could predict treatment outcome. An I-score was calculated from the plasma cfDNA that reflected CNVs of cfDNA, which is evidence of genomic instability. Results: The I-score at V1 exhibited a strong correlation with the planning target volume (PTV) (coefficient=0.65) and was a predictive marker for progression-free survival (PFS). In particular, a mean Iscore value at V1 of ≥6.3 had a significant positive correlation with PFS (p=0.017). Compared with patients who had a complete response (CR) following RT, non-CR patients had a higher mean I-score value at V2 ≥6.2 (p=0.034). Furthermore, I-score values at V1 and V2 and the delta I-score ratio were significantly associated with a pre- RT alpha-fetoprotein level ≥200 among non-CR patients. Conclusion: I-score values calculated from plasma cfDNA represent a potential biomarker for predicting treatment outcomes in patients with advanced HCC receiving RT.