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  • Review Article
  • Published:

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

An Erratum to this article was published on 23 June 2015

This article has been updated

Key Points

  • The global incidence of liver cancer is increasing, with reports indicating that disease-specific mortality has doubled in the past 20 years

  • Curative treatments that include resection, transplantation or ablation are applicable to less than 30% of newly diagnosed patients with this disease

  • Patients with advanced-stage disease are candidates for treatment with sorafenib, a molecular targeted therapy with inhibitory activity against BRAF, VEGFRs and PDGFRs

  • Genomic-profiling studies have enabled the classification of hepatocellular carcinoma based on common molecular traits, with mutations in the TERT promoter, CTNNB1 and TP53 as the most frequent alterations

  • Up to seven randomized phase III trials testing new molecular therapies in first-line and/or second-line settings have failed to improve upon the outcomes achieved with sorafenib

  • Progressive implementation of proof-of-concept and enrichment trials might improve results in clinical trials designed to test molecular targeted agents

Abstract

Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

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Figure 1: Mortality trends of patients with different malignancies in the USA between 1990–2009.3
Figure 2: Schematic representation of molecular classification of patients with HCC using gene signatures.
Figure 3: Molecular therapies acting on immune checkpoints and the microenvironment.
Figure 4: Molecular targeted therapies for HCC and their target signalling pathways.

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Change history

  • 23 June 2015

    In the version of the article published in print, the legends for Figures 3 and 4 were published in the incorrect order. These errors have been corrected for the HTML and PDF versions of the article published online.

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Acknowledgements

J.M.L. gratefully acknowledges funding from the Asociación Española Contra el Cáncer (AECC), European Commission Framework Programme 7 (Heptromic, proposal number 259,744) and the Samuel Waxman Cancer Research Foundation, Grant I+D Program (SAF2013-41027). The authors would also like to thank Sara Torrecilla of the Liver Cancer Lab, BCLC Group, Liver Unit, IDIBAPS—Hospital Clínic, for her contributions to Table 1.

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J.M.L., A.V. and A.L. researched data for the article, J.M.L. made a substantial contribution to discussions of content, J.M.L. and R.S.F. wrote the manuscript and reviewed/edited the manuscript before submission.

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Correspondence to Josep M. Llovet.

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Competing interests

J.M.L. has served as an advisory board member for Bayer Pharmaceuticals, Boehringer Ingelheim and Bristol Myers Squibb and an advisor for Biocompatibles, Blueprint, Celgene, Celsion, GlaxoSmithKline, Lilly Pharmaceuticals and Novartis. A.V. and R.S.F. declare they have acted as advisors for Bayer Pharmaceuticals and Onyx Pharmaceuticals, R.S.F. has also acted as an advisor for Bristol Myers Squibb, Novartis and Pfizer. A.L. declares no competing interests.

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Llovet, J., Villanueva, A., Lachenmayer, A. et al. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 12, 408–424 (2015). https://doi.org/10.1038/nrclinonc.2015.103

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