Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2019; 25(29): 3870-3896
Published online Aug 7, 2019. doi: 10.3748/wjg.v25.i29.3870
Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma
Elena De Mattia, Erika Cecchin, Michela Guardascione, Luisa Foltran, Tania Di Raimo, Francesco Angelini, Mario D’Andrea, Giuseppe Toffoli
Elena De Mattia, Erika Cecchin, Michela Guardascione, Tania Di Raimo, Francesco Angelini, Giuseppe Toffoli, Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
Luisa Foltran, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
Tania Di Raimo, Francesco Angelini, Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
Mario D’Andrea, Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
Author contributions: De Mattia E performed the literature review and analysis, contributed to writing the manuscript, and elaborated the tables; Cecchin E conceptualized and edited the manuscript; Guardascione M, Foltran L and D’Andrea M contributed to writing the manuscript; Di Raimo T and Angelini F contributed to writing the manuscript and elaborated the figures; and Toffoli G was the guarantor. All authors reviewed the manuscript.
Supported by the European Union’s Horizon 2020 Research and Innovation Programme, No. 668353.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Elena De Mattia, PhD, Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy.
Telephone: +39-434-659765 Fax: +39-434-659799
Received: March 17, 2019
Peer-review started: March 18, 2019
First decision: May 14, 2019
Revised: May 23, 2019
Accepted: July 1, 2019
Article in press: July 3, 2019
Published online: August 7, 2019

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.

Keywords: Hepatocellular carcinoma, Pharmacogenetics, Genetic markers, Sorafenib, Regorafenib, Immune checkpoint inhibitors, Cytochromes, UDP glucuronosyltransferase 1A

Core tip: Patients with advanced hepatocellular carcinoma (HCC) have few effective therapeutic options. Although multikinase inhibitors-such as sorafenib as first-line treatment and regorafenib in sorafenib progressors-show some overall survival benefit, unmet needs persist in the treatment of advanced HCC. Particularly, the identification of potential prognostic and predictive biomarkers for better stratifying and personalizing the treatment remains a challenge. Germ-line polymorphisms have been suggested to contribute significantly to inter-individual variability in HCC therapy outcome in terms of both toxicity and effectiveness, opening new avenues for pharmacogenetic investigation.