The Current Role of Circulating Cell Free DNA in the Management of Hepatocellular Carcinoma

Circulating cell-free DNA (cfDNA) has emerged as a compelling candidate of liquid biopsy markers for diagnosis and prognosis of several cancers. We systematically reviewed the data on the role of cfDNA markers in diagnosis, prognosis and treatment of hepatocellular carcinoma (HCC). Early studies suggested that levels of circulating cfDNA, mitochondrial DNA and cfDNA integrity are higher in patients with HCC than chronic liver diseases. Numerous subsequent studies showed that methylation changes in circulating tumor DNA (ctDNA) as well as cfDNA fragmentation patterns and circulating nucleosomes offer excellent diagnostic accuracy with high sensitivity (>60%) and excellent specificity (>90%) for HCC diagnosis. The predictive role of cfDNA markers and ctDNA has been assessed in a few studies including untreated patients with HCC providing promising results for prediction of survival, but detection of such markers or copy number variations indicators of cfDNA post-hepatectomy seems to reflect minimum re-sidual disease and thus high risk for HCC recurrence. The same markers can be useful for pre-diction after transarterial chemoembolization, radiofrequency ablation, radiotherapy and even systemic therapies. In conclusion, cfDNA markers can be useful in HCC surveillance improving early diagnosis rates as well as for monitoring treatment effectiveness and minimal residual disease post-treatment.