title: New molecular therapies for hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is a major health problem. Mortality owing to liver cancer has increased in the past 20 years, with recent studies reporting an incidence of 780,000 cases/year. Most patients with hepatocellular carcinoma 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. Afterwards, up to 7 randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve survival. Potential reasons for this include intertumor heterogeneity, issues with trial design and a lack of predictive biomarkers of response. Advance in our knowledge of the human genome has provided a comprehensive picture of commonly mutated genes in patients with HCC including mutations in the TERT promoter, CTNNB1, TP53 and ARID1A along with other amplifications (FGF19, VEGFA) or homozygous deletions (p16) as the most frequent alterations. This knowledge points toward specific drivers as candidate for druggable therapies. Thus, progressive implementation of proof-of-concept and enrichment might improve results in clinical trials testing of molecular targeted agents. Ultimately, these studies are aimed at long-term to improve current standards of care and influenced clinical decision-making and practice guidelines.
authors.affiliation: Liver Cancer Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Torrecilla
authors.affiliation: Liver Cancer Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Madison avenue 1425, 11F-70, Box 1123, 10029 New York, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: Josep.Llovet@mssm.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D005346:Fibroblast Growth Factors / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000077157:Sorafenib; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D016212:Transforming Growth Factor beta; D009536:Niacinamide; D005346:Fibroblast Growth Factors; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras)