Circulating Tumor DNA Clinical Applications in Hepatocellular Carcinoma: Current Trends and Future Perspectives

Globally, liver cancers are the second most lethal malignancy after lung cancer (0.83 million deaths in 2020). Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer and is typically associated with liver fibrosis or cirrhosis. HCC diagnosis relies on histologic examination of surgical specimens or conventional tissue biopsy material. However, standard tissue biopsies are invasive and often do not accurately reflect the tumor heterogeneity. On the other hand, the use of liquid biopsies, represented mainly by circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), has greatly increased in the past 2 decades. Indeed, liquid biopsies are a noninvasive, repeatable, and sensitive approach to studying tumor biology. This review describes current clinical applications of ctDNA analysis in the management of patients with chronic liver disease, cirrhosis, and HCC. There is a substantial clinical potential of ctDNA, but interventional studies are still lacking for the moment. Detection of ctDNA in both asymptomatic individuals and high-risk patients (with chronic liver disease or cirrhosis) contributes to the early diagnosis of HCC. ctDNA analysis also offer tremendous information on the tumor burden and on the risk of early recurrence. The implementation of ctDNA analysis, in association with classical tumor markers (e.g., alpha-fetoprotein), may improve (a) HCC screening in high-risk patients, (b) stratification of the recurrence risk after surgery, and (c) prognosis evaluation of patients with HCC.