title: Advances in targeted therapies for hepatocellular carcinoma in the genomic era.
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.
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11F-70, Box 1123, New York, NY 10029, USA.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11F-70, Box 1123, New York, NY 10029, USA.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Lachenmayer
authors.affiliation: Department of Medicine, Division of Haematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D015195:Drug Design; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation
chemical_list: D000970:Antineoplastic Agents