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Hepatocellular carcinoma

Abstract

Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies — resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches.

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Figure 1: The global burden of HCC.
Figure 2: Liver cancer incidence according to region and sex.
Figure 3: Cancer progression and driver genes.
Figure 4: BCLC staging system and therapeutic strategy.
Figure 5: Molecular targeted therapies for HCC and their target signalling pathways.

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Acknowledgements

J.M.L. has grants from the US National Cancer Institute (NCI) (P30CA165979), the European Commission Horizon 2020 (HEP-CAR, proposal number 667273–2), the Samuel Waxman Cancer Research Foundation, the Grant I+D Program (SAF2013-41027) and the Asociación Española Contra el Cáncer (AECC). J.Z.-R. has received funding from INSERM, the French National Cancer Institute (INCa) and The Ligue Contre le Cancer (équipe Labellisée). E.P. receives funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the European Research Council and the Israel Science Foundation. The authors thank R. Montal, S. Torrecilla, A. Farré and M. Boteller (Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS — Hospital Clinic, Barcelona, Spain) for their support in editing references, figures and tables for this manuscript.

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Contributions

Introduction (J.M.L.); Epidemiology (G.G.); Mechanisms/pathophysiology (J.Z.-R. and E.P.); Diagnosis, screening and prevention (M.Sh. and G.G.); Management (M.Sc., B.S. and J.M.L.); Quality of life (M.Sh.); Outlook (J.M.L., G.G. and E.P.); overview of Primer (J.M.L.).

Corresponding author

Correspondence to Josep M. Llovet.

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Competing interests

J.M.L. receives research support and grants from Bayer Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb and Boehringer Ingelheim, and is a consultant for Bayer Pharmaceuticals, Bristol-Myers Squibb, Blueprint Medicines, Eli Lilly and Company, Celsion, Biocompatibles, Boehringer Ingelheim, Novartis and GlaxoSmithKline. M.Sh. is a consultant for Bayer Pharmaceuticals, Celsion, ArQule, H3 Biomedicine and Merck. J.Z.-R. is a consultant for IntegraGen. B.S. has received lecturing and consulting fees from Bayer Healthcare and Sirtex Medical. G.G. is in the Data Safety and Monitoring committee for a Bayer Pharmaceuticals trial in hepatocellular carcinoma. M.Sc. and E.P. have nothing to disclose.

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Llovet, J., Zucman-Rossi, J., Pikarsky, E. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2, 16018 (2016). https://doi.org/10.1038/nrdp.2016.18

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