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      Targeted therapy for hepatocellular carcinoma

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          Abstract

          The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.

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          Most cited references173

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          Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study

          Background & Aims Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death. Methods Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions. Results Forty-two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001). Conclusions Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.
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            Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.

            Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease.
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              Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

              There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation.
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                Author and article information

                Contributors
                zhou.jian@zs-hospital.sh.cn
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                11 August 2020
                11 August 2020
                2020
                : 5
                : 146
                Affiliations
                [1 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, , Fudan University, ; Shanghai, China
                [2 ]GRID grid.419897.a, ISNI 0000 0004 0369 313X, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, ; Shanghai, China
                [3 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, , Fudan University, ; Shanghai, China
                [4 ]GRID grid.269014.8, ISNI 0000 0001 0435 9078, Department of Hepatobiliary and Pancreatic Surgery, , University Hospitals of Leicester NHS Trust, ; Leicester, UK
                [5 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Institute of Biomedical Sciences, , Fudan University, ; Shanghai, China
                [6 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, State Key Laboratory of Genetic Engineering, , Fudan University, ; Shanghai, China
                Article
                264
                10.1038/s41392-020-00264-x
                7419547
                32782275
                6f9ad5ee-9183-4326-991c-32f40e41981d
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 April 2020
                : 10 July 2020
                : 15 July 2020
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2020

                gastrointestinal cancer,cancer,cancer therapy
                gastrointestinal cancer, cancer, cancer therapy

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