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1、Journal Pre-proofMolecular targeted therapies:ready for“prime time”in biliary tract cancerAngela Lamarca,Jorge Barriuso,Mairad G.McNamara,Juan W.VallePII:S0168-8278(20)30165-3DOI:https:/doi.org/10.1016/j.jhep.2020.03.007Reference:JHEPAT 7655To appear in:Journal of HepatologyReceived Date:14 January
2、2020Revised Date:2 March 2020Accepted Date:3 March 2020Please cite this article as:Lamarca A,Barriuso J,McNamara MG,Valle JW,Molecular targetedtherapies:ready for“prime time”in biliary tract cancer,Journal of Hepatology(2020),doi:https:/doi.org/10.1016/j.jhep.2020.03.007.This is a PDF file of an art
3、icle that has undergone enhancements after acceptance,such as the additionof a cover page and metadata,and formatting for readability,but it is not yet the definitive version ofrecord.This version will undergo additional copyediting,typesetting and review before it is publishedin its final form,but
4、we are providing this version to give early visibility of the article.Please note that,during the production process,errors may be discovered which could affect the content,and all legaldisclaimers that apply to the journal pertain.2020 Published by Elsevier B.V.on behalf of European Association for
5、 the Study of the Liver.ContentsContentsTitlepage.3Abstract.4Keypoints:.4Introduction.5Currentstateofplay.5Adjuvanttherapy.5Firstlinepalliativechemotherapy.6Secondlinechemotherapy.6Othertherapeuticoptions.7TargetedtherapiesinCCAandGBC.7Currentgeneticlandscapeandactionableaberrations.8IsocitrateDehyd
6、rogenase(IDH)asatarget.9TheroleofFibroblastGrowthFactorReceptor(FGFR).12OthertargetsinCCAandGBC.16HERreceptorfamily.16RNF43.16TargetingNTRK(neurotropictyrosinekinasereceptor)fusions.17BRAF.17Currentcaveatsandfutureperspectives.17Conclusions.19Conflictofinterest.19Acknowledgement.19References.20Table
7、sandfigures.36Figure1:Molecularprofilingofbiliarytractcancers.37Figure2:IDHinvolvementincellmetabolism.40Figure3:FGFRpathway.4212Figure4:Currentoverviewof“PrecisionMedicine”inbiliarytractcancers.43Table1:CurrentstatusofdevelopmentofFGFR2inhibitorsiniCCA.44TitlepageTitle:Moleculartargetedtherapies:re
8、adyfor“primetime”inbiliarytractcancerArticletype:InvitedreviewarticleJournal:JournalofHepatologyReferencesoftware:ReferenceManagerAuthors:AngelaLamarca1,2,JorgeBarriuso1,2,MairadGMcNamara1,2,JuanWValle1,21DepartmentofMedicalOncology,TheChristieNHSFoundationTrust,Manchester,UK2DivisionofCancerScience
9、s,SchoolofMedicalSciences,FacultyofBiology,MedicineandHealth,UniversityofManchester,Manchester,UKCorrespondingauthorsJuanWValle;MedicalOncologyDepartment,TheChristieNHSFoundationTrust,WilmslowRoad,Manchester,M204BX,UnitedKingdom.Email:juan.vallechristie.nhs.ukAngelaLamarca;MedicalOncologyDepartment,
10、TheChristieNHSFoundationTrust,WilmslowRoad,Manchester,M204BX,UnitedKingdom.Email:angela.lamarcachristie.nhs.ukShorttitle;TargetedtherapiesinBiliaryTractCancerKeywords:Biliarytractcancer,Targetedtherapies,FGFR,IDH,mutation,fusionElectronicwordcount:6,000wordsNumberoffiguresandtables:4figures,1table3A
11、uthors contributions:Angela Lamarca designed the content and was involved in the writingprocessofthismanuscripttogetherwithdesignoffigures;allcoauthorsreviewedandapprovedthefinalversionofthemanuscript.AbstractAbstractPatientswithbiliarytractcancers(cholangiocarcinoma(CCA)andgallbladdercancer(GBC)hav
12、eapoorprognosesandincidenceisincreasing.Mostpatientsarediagnosedwithadvanceddiseasewhenoptionsoftreatmentarelimitedtopalliativeapproaches,mainlyfocusedonchemotherapy.Inrecentyears,noveltreatmenttargetsofrelevancetobiliarytractcancers,mainlypresentinpatientswithintrahepaticcholangiocarcinoma(iCCA),ha
13、vebeenidentifiedandarerapidlychangingthefield.Theseincludefibroblastgrowthfactorreceptor(FGFR)fusionsandisocitratedehydrogenase(IDH)1and 2 mutations which are each present in around 1020%of patients with iCCA patients.Inaddition,inhibitionofotherpathwaysiscurrentlybeingexplored,suchashumanepidermalg
14、rowthfactorreceptor(HER)family,theWntpathway,neurotropictyrosinekinasereceptor(NTRK)fusionsandBRAFmutations.TheIDH1inhibitorivosidenibhasalreadybeentestedinaphaseIIIclinicaltrialsinpretreatedCCAandshowedbenefitintermsofprogressionfreesurvival(theprimaryendpoint).MultipleFGFRinhibitorsarecurrentlyind
15、evelopmentinphaseIIandIIItrials.Therehasbeenaconsistentlyhighresponseratereportedforthesecompounds(rangingbetween20.7%and35.5%),especiallyforpatientsharbouringFGFR2fusions.Thisreviewprovidesanoverviewofthestatusoftargetedtherapiesinbiliarytractcancers.Detaileddiscussionregardingcurrentclinicaldevelo
16、pmentofIDHandFGFRinhibitorsisprovided,withanoverviewofcurrentcaveatsandfuturesteps.Keypoints:Keypoints:Biliarytractcancersarepoorprognosismalignancies PrecisionMedicineisofespecialrelevanceforpatientswithintrahepaticcholangiocarcinoma(iCCA)The IDH1 inhibitor ivosidenib has shown benefit in phase III
17、 trials for IDH1mutantcholangiocarcinoma FGFR2inhibitorshaveshownpromisingresultsinpretreatedFGFR2fusionpositiveiCCA Othertargetsarebeingdeveloped:NTRK,HER2,BRAFandRNF43.4IntroductionIntroductionBiliary tract cancers,including cholangiocarcinoma(CCA)and gallbladder cancer(GBC),are rare(particularlyi
18、nWesterncountries)andrepresent3%ofallgastrointestinalmalignanciesinadults.The incidence is increasing,mainly due to intrahepatic cholangiocarcinoma(iCCA)(1);whileincidence for other subgroups of biliary tract cancer(extrahepatic cholangiocarcinoma(eCCA)furtherdividedintohilarcholangiocarcinoma(hCCA)
19、anddistalcholangiocarcinoma(dCCA)andGBCremainstable(24).Unfortunately,prognosisremainspoorwitha5yearsurvivalofaround515%(allstagesjointlyanalysed)(5,6).Thereisanurgentneedtoimproveoutcomesforpatientsdiagnosedwithbiliarytractmalignancies(7).In addition to the development of strategies for earlydetect
20、ion and novel biomarkers,developmentofnoveltherapeuticapproachesareneeded,sincethemajorityofpatientsarestilldiagnosedwithadvancedstagediseasewhenpalliativetreatmentistheonlyoption(811).Treatmentforpatientswithadvanceddiseasecurrentlyreliesontheuseofpalliativechemotherapy(1214).However,theemergenceof
21、targetedtherapiesisrapidlychangingthetreatmentparadigmforbiliarytractcancer,specificallyforiCCAforwhomtargetingoffibroblastgrowthfactorreceptor(FGFR)fusionsandisocitratedehydrogenase(IDH)1and2mutations(15)isbecomingareality.Theaimofthisreviewistoprovideanoverviewofthecurrentdevelopmentoftargetedther
22、apiesforbiliarytractcancer,focusingonthoselaterinclinicaldevelopment.CurrentstateofplayCurrentstateofplayAdjuvanttherapyAdjuvanttherapy Surgery remains the cornerstone of cure for patients with biliary tract cancer,however,only aminority of patients diagnosed with biliary tract malignancies are suit
23、able for curative surgery.Unfortunately,evenforthosepatientstheriskoftumourrelapseremainshigh(16,17),despiterecentdevelopmentswithadjuvantchemotherapy(18).Untilrecently,adjuvantchemotherapyinCCAandGBCwasnotconsideredstandardpracticeinmany countries(1921).Since 2017,data from three phase III randomis
24、ed studies have beenreported(2224)andeventhoughinterpretationofsuchstudieshasbeenchallenging,mainlyduetodiscrepantfindings(25),currently,theuseofadjuvantcapecitabine(18)isconsideredtobeanewstandardofcarefollowingcurativeresection(26).5FirstlinepalliativechemotherapyFirstlinepalliativechemotherapy Th
25、emostactivechemotherapycompoundsforCCAandGBCaregemcitabineandplatinumagents(27,28).The role of palliative chemotherapy was first shown in 1999,when gemcitabine wasestablishedasthefirstlineoftherapyforadvancedbiliarytractcancer(2932).In2010,theABC02phaseIIIclinicaltrialrandomized410patientswithadvanc
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