Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients' Management and Therapy Outcomes.

Silvia Mezzalira,Giuseppe Toffoli,Erika Cecchin,Elena De Mattia,Michela Guardascione,Chiara Dalle Fratte

doi:10.3390/ijms20215498

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic mutations found in a HCC tumor may represent targets for innovative drugs as well as prognostic/predictive markers. Nonetheless, surgical or bioptic tissue is hardly accessible in HCC and a single tumor sample is poorly representative of the tumor genetic heterogeneity. In this context, analyzing the circulating cell-free DNA (ccfDNA) and its tumor-derived fraction (ctDNA) could represent a promising strategy of liquid biopsy. Recent data suggested that the fluctuation of the ccfDNA quantity in the plasma of HCC patients could anticipate the detection of tumor progression. The presence of somatic mutations in p53 signaling, Wnt/β-catenin, chromatin remodeling, response to oxidative stress and telomerase maintenance pathways can also be studied in ccfDNA bypassing the need to perform a tumor biopsy. The profiling of ccfDNA fragmentation and the methylation pattern could further improve the clinical management of HCC patients. Performing a dynamic monitoring in the course of systemic treatment with sorafenib or regorafenib is a possible way to provide insights into the resistance mechanism, and to identify predictive and prognostic genetic alterations, helping the clinicians in terms of treatment decision making. This review will discuss the most recent literature data about the use of ccfDNA to monitor and improve the treatment of HCC.

Highlights

Liver cancer is globally the fourth most common cause of cancer-related death and the sixth in terms of incidence [1]
The most consistent results to date concern the longitudinal analysis of the plasma level of circulating cell-free DNA (ccfDNA), as a dynamic real time marker of disease burden allowing researchers to anticipate the diagnosis of disease recurrence or tumor progression in patients receiving either a systemic or a local treatment
Recently and thanks to the advancement of digital-sequencing technology some studies highlighted how ccfDNA could be used as a source for somatic mutation detection

Summary

Introduction

Liver cancer is globally the fourth most common cause of cancer-related death and the sixth in terms of incidence [1]. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. The Barcelona Clinic Liver Cancer (BCLC) algorithm is the most widely applied staging system, which classifies patients as being in one of five stages and it provides treatment recommendations for each one [1]. Liver transplantation and local ablation are considered curative therapeutic practices for early-stage HCC, while other modalities, such as transarterial chemoembolization (TACE) and systemic therapy represent palliative options for the treatment of intermediate-advanced stage disease [3,4]. A number of small-molecule tyrosine kinase inhibitors such as sorafenib, regorafenib, cabozantinib and lenvatinib have demonstrated some survival benefits in advanced HCC and, more recently, promising data on the use of immune checkpoint inhibitors [5] are emerging

Objectives

Methods

Findings

Conclusion