5、消化系统肿瘤消化系统肿瘤 (20).pdf
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1、Authors Accepted ManuscriptBiomarker-Driven and Molecular Targeted Therapiesfor Hepatobiliary CancersWilliam P.Harris,Kit Man Wong,Supriya Saha,Imane El Dika,Ghassan K.Abou-AlfaPII:S0093-7754(17)30127-6DOI:https:/doi.org/10.1053/j.seminoncol.2018.03.002Reference:YSONC52043To appear in:Seminars in On
2、cologyCite this article as:William P.Harris,Kit Man Wong,Supriya Saha,Imane ElDika and Ghassan K.Abou-Alfa,Biomarker-Driven and Molecular TargetedTherapies for Hepatobiliary Cancers,Seminars inOncology,doi:10.1053/j.seminoncol.2018.03.002This is a PDF file of an unedited manuscript that has been acc
3、epted forpublication.As a service to our customers we are providing this early versionof the manuscript.The manuscript will undergo copyediting,typesetting,andreview of the resulting galley proof before it is published in its final citableform.Please note that during the production process errors ma
4、y be discoveredwhich could affect the content,and all legal disclaimers that apply to thejournal and Molecular Targeted Therapies for Hepatobiliary Cancers Authors and Affiliations First Author:William P.Harris,M.D.University of Washington,Department of Medicine,Division of Medical Oncology Fred Hut
5、chinson Cancer Research Center,Clinical Research Division Second Author:Kit Man Wong,M.D.University of Washington,Department of Medicine,Division of Medical Oncology Fred Hutchinson Cancer Research Center,Clinical Research Division Third Author:Supriya Saha,M.D.,PhD University of Washington,Departme
6、nt of Medicine,Division of Medical Oncology Fred Hutchinson Cancer Research Center,Human Biology Division Fourth Author:Imane El Dika,M.D.Memorial Sloan Kettering Cancer Center,Department of Medicine Last Author/Corresponding Author:Ghassan K.Abou-Alfa,M.D.,MBA Memorial Sloan Kettering Cancer Center
7、,Department of Medicine Corresponding author address:300 East 66th St.,New York,NY,10065 Telephone:(646)888-4184 Email:abou-algmskcc.org Dr.Harris reports grants from Halozyme,Eisai,Arqule,BMS,Agio,other from Bayer,Eisai outside the submitted work.Dr.Abou-Alfa reports grants from Agios,Array,Astra Z
8、eneca,Bayer,BMS,Casi,Celgene,Exelixis,Genentech,Incyte,Lilly,Mabvax,Medimmune,Momenta,OncoMed Pharmaceuticals,Roche,other from Agios,Amgen,Aptus,Aslan,Astellas,Astra Zeneca,Bayer,BMS,Boston Scientifc,Carsgen,Celgene,Casi,CytomX,Daiichi,Debio,Delcath,Gilead,Halozyme,Inovio,Ipsen,Merck,Medimmune,Onxeo
9、,PCI Biotech,Roche,Sanofi,Servier,Silenseed,Sillajen,Sirtex,Yakult during the conduct of the study.Drs.Wong,Saha and El Dika have nothing to disclose.Abstract:The recent accumulation of molecular profiling data for primary hepatobiliary malignancies including hepatocellular carcinoma and biliary tra
10、ct cancers has led to a proliferation of promising therapeutic investigations in recent years.Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results.Key molecular alterations in common hepatobiliary cancers and ongoing inte
11、rventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.Keywords:hepatobiliary,hepatocellular carcinoma,HCC,biliary tract cancer,cholangiocarcinoma,intrahepatic cholangiocarcinoma,ICC,immuno-oncology,immunotherapy,
12、targeted therapeutics,clinical trials,molecular therapy,liver cancer,systemic therapy.Introduction Hepatocellular carcinoma(HCC)and biliary tract cancers(BTC)represent the first and second most common hepatobiliary tumors.To date,development of successful systemic therapeutics has been hampered by a
13、n incomplete understanding of tumor biology and by comorbidities associated with a patient population typically affected by underlying hepatic dysfunction,symptoms secondary to presentation at a late clinical stage,or both.Recent efforts focused on deciphering the molecular alterations for each dise
14、ase can increasingly be leveraged for patient benefit,especially in the context of a rapidly expanding armamentarium of molecularly targeted therapeutics.Recent and ongoing efforts to identify targeted therapeutics for HCC and BTC,with a focus on the rapidly developing treatment of intrahepatic chol
15、angiocarcinoma(ICC),are reviewed here.Targeted therapy in hepatocellular carcinoma Current systemic therapy in advanced hepatocellular carcinoma HCC is the second-leading cause of global cancer-related mortality with rising incidence in the United States population.1,2 Despite current therapeutic op
16、tions,patients in the United States with locally advanced or metastatic disease achieve 5-year survival rates of 11%and 3%from time of presentation,respectively.2 Standard cytotoxic chemotherapy has failed to demonstrate significant benefit in advanced disease,while clinical benefits were shown in t
17、he positive randomized phase 3 trials of the multi-tyrosine kinase inhibitors(TKIs)sorafenib and lenvatinib in the first-line setting and regorafenib as second-line therapy.3-5 Ongoing barriers to optimization of systemic therapeutics in HCC include the lack of validated predictive biomarkers for ex
18、isting agents and the requirement to account for the competing risk of underlying hepatic dysfunction in this patient population.An increased understanding of the molecular alterations associated with hepatocarcinogenesis and tumor progression,in conjunction with the development of targeted therapeu
19、tics and well-designed clinical trials,holds promise in advancing the field of systemic therapeutic intervention in HCC.Molecular characteristics of hepatocellular carcinoma HCC is increasingly recognized as demonstrating significant genetic heterogeneity and complexity.Multiple genomic profiling st
20、udies have shown that distinct molecular pathways are implicated in its pathogenesis and progression,and are associated with different etiologies.6-8 It is estimated that up to 28%of identified mutations from exome sequencing of HCC could be potentially targetable with currently available targeted a
21、gents.6 Several prior genome-wide association studies and a recent multi-platform integrative analysis by the Cancer Genome Atlas Research Network have documented critical insights into the molecular characteristics of HCC9.Common somatic mutations include TERT promoter mutations(often an early mole
22、cular event present in up to 60%of cases),and high rates of recurrent somatic mutations in chromatin-remodeling factors including ARID1A,ARID2 and BAP(25-60%),alterations in the WNT pathway including CTNNB1 oncogenic mutations(25-40%)or related inactivation of AXIN1 and APC,and finally TP53 inactiva
23、ting mutations(25-40%).8-13 Somatic copy number alterations of relevance include recurrent focal amplifications of chromosome 11q(including oncogenes CCND1 and FGF19),7q(MET),and 6p(VEGFA)among others9.A small cluster of samples with extensive hypermethylation was identified,associated with IDH1 or
24、IDH2 mutations,suggesting a potential molecular shift toward a biliary phenotype.Moreover,overexpression has been documented to occur in EGFR,TOPO1,PD-1,TOP2A,SPARC and c-MET(25-83%).14 Finally,gene expression cluster analysis suggests that 44%of all tumors demonstrated dysregulated WNT axis signali
25、ng,and that generally mutations within the receptor tyrosine kinase/RAS/PI3K pathway were implicated in tumor progression although specific mutations did not occur at high frequency.9 Additional observations include that tumors harboring CTNNB1 mutations more likely overexpressed PD-L1 in one study(
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