BiomarkersinProstateCancer在前列腺癌生物标记

WhyareBiomarkersImportantProstateCancerdiagnosedin200,000menannuallyintheunitedstates30,000cancerspecificdeathsperyearYet,asubstantialportionofcancersdiagnosedthroughPSAscreeningdonotprogresstoclinicallysignificantdisease.现在是1页\一共有23页\编辑于星期日ProblemwithPSAscreeningItisnotspecific,resultinginanegativebiopsyrateofupto70%insomeseriesEuropeanrandomizedtrial:1410menscreenedand48treatedtoprevent1deathfromprostatecancerSweedishRandomizedtrialofwatchfulwaiting:Relativeriskforsurgery:0.62(0.44-0.87)NNT15overalland7formenyoungerthan65y现在是2页\一共有23页\编辑于星期日Howdoweimprovescreeningandtreatmentdecisions?ClinicalnomogramsIncludeGleasonScore,positivecores,percentinvolvementofcores,andPSAOtherriskfactors:familyhistory,age,raceBiomarkersSupplementknownclinicalinformation现在是3页\一共有23页\编辑于星期日ClinicalNomogram:KattanNomogramStephensonetal,JnatlCI,2006现在是4页\一共有23页\编辑于星期日Howcanbiomarkersimprovemanagement?现在是5页\一共有23页\编辑于星期日CategoriesofbiomarkersUrineBasedBloodBasedTissuBased现在是6页\一共有23页\编辑于星期日UrineBasedBiomarkersProteinsUrinary/serumpsaratioAnnexinA3MMP9ProteomicsDNAGlutathione-S-transferaseP1Othermethylation-specificPCRassaysRNAPCA3TMPRSS2-ERGgenefusionRooboletal,Actaoncologica,2011现在是7页\一共有23页\编辑于星期日UrinaryPCA3DevelopedfromdifferentialexpressionofnoncodingRNA’sinprostatecancerversusotherprostateconditionsCommerciallyavailable,approveddiagnostictestCollectedfromurinesamplefollowingafirmDRECouldfunctionasafirstlinescreenorprognosticindicator现在是8页\一共有23页\编辑于星期日UrinaryPCA3:FirstlinescreenSeveralstudiesshowsuperioroverallspecificitytoPSA:80-90%,butincludeonlypatientswithelevatedPSAIntheREDUCEtrialtheplacebotestcharacteristicsforPSAwere:Se=0.518Sp=0.629PCA3inpatientswithPSA4-10ng/ml:Specificity:71-93%Sensitivity:53-84%IsPCA3BetterthanPSAforCaPdiagnosis?

ERSPC:prostatebiopsytrigger: PSA≥3orPCA3≥10In721biopsied,PCA3performedonlymarginallybetter:

AUC:PCA3=0.64PSA=0.58Rooboletal,EurUrol,2010现在是9页\一共有23页\编辑于星期日PCA3andTMPRSS2-ERGfusionFusionofastrongandrogenpromoter(transmembraneserineprotease)andanoncogeneFurtherimproveddiagnosticaccuracy(AUC)PCA3:0.65PCA3+Fusion:0.77PCA3+gene-fusion+PSA:0.80Aubinetal,JUrol,2008现在是10页\一共有23页\编辑于星期日PCA3:prognosticindicatorConflictingstudiesshowapositiverelationship1withcanceraggressivenessornorelationship2ReduceTrial-chemopreventionofCaPwithDutasteride3:WeakassociationofPCA3withGl7orhighercancerOR:1.017(CI95%:1.01-1.03)Thoughlownumbersofhighgradeprostatecancerweakenstheanalysis1.Hesselsetal,Prostate,20102.Whitmanetal,JUrol,20083.Aubinetal,Urology,2011现在是11页\一共有23页\编辑于星期日BloodBasedbiomarkersDiagnosisPSAPSAvelocityFreePSAPro-PSABPH-associatedPSAPrognosisHumanKallikrein2UrokinaseplasminogenactivatorTransformingGrowthfactorβ1Interleukin-6Endoglin现在是12页\一共有23页\编辑于星期日LimitationsofTotalPSANeoplasticcellsproducevaryinglevelsofPSABiologicvariation:OscillationsofPSAupto30%inrangeof0.1-20ng/mlDifferentAssays(WHOstandard)Sensitivity:52%Specificity:63%WhatCut-off?PSA(ng/ml)PercentCaP(%)<0.66.60.6-1.010.11.1-2.017.02.1-3.023.93.1-4.026.9PCPTThompsonetal,NEJM,2004现在是13页\一共有23页\编辑于星期日PSA:Long-termriskMalmoPreventativeMedicineStudy462CaPmedianf/u18ymatchedto1,222controlsTotalPSAatage44-50wascomparedTotalPSAatage44-50y(ng/ml)OddsRatioofCaP≤0.501.000.51-1.02.511.01-2.07.022.01-3.019.01Ulmertetal,BMCMed,2008现在是14页\一共有23页\编辑于星期日PSAVelocityMeasurementofchangeintotalPSAovertimeTwolargeprospectivetrialsfoundnoindependentpredictivevaluebeyondtotalPSAandotherstandardvariables(PCPTandERSPC)1.Shariatetal,ActaOnc,20112.D’amicoetal,NEJM,20043.Carteretal,JNCI,2006DiagnosisIncreaseriskofdeathdeterminedatPSAvlevelsgreaterthan0.35–2.0ng/mlperyearMaynotpredictearlyprogressionbutanindicationofaggressivediseasebeyondtreatmentwindowPrognosis现在是15页\一共有23页\编辑于星期日PercentFreePSAIsoformofPSAthatremainsunboundinplasmaPercentfreePSArelativetothetotalPSAisFDAapprovedasanadjuncttototalPSAbetween4-10ng/mlfPSA<25%usedasatriggerforbiopsyMulticenter,prospectivetrialSpecificity:95%,Sensitivity:20%overPSAAUC:%fPSA=0.72 PSA:0.53Whenuse10-12corebiopsy:efficiencydecreasesCatalonaetal,JAMA,1998Cantoetal,JUrol,2004现在是16页\一共有23页\编辑于星期日CombinedpanelofPSAisoformsERSPC:Forevery1,000unscreenedmen,themodel,ifusedtodeterminebiopsy:Reducebiopsyratesby573Miss31/152lowgradeCaP3/40highgradeCaPVickersetal,BMCMed,2008现在是17页\一共有23页\编辑于星期日Endoglin:CD105,acellsurfaceco-receptorforTGFβ1and3Foundonimmaturebloodvessels:AngiogenesisPre-prostatectomylevelsmaypredicthighergleasonscoreandPSArecurrenceSvateketal,CCR2008现在是18页\一共有23页\编辑于星期日CombiningPanelofMarkersandNomogramBiomarkersusedtosupplementnotreplaceclinicaldatatoimproveaccuracyofprognosisKattannomogram+biomarkerpanel:TGF-β1,IL-6R,IL-6,endoglin,VEGF,VCAM-1PredictiveaccuracyoftheKattannomogramimprovedby15%71.6%versus86.6%Shariatetal,ActaOnc,2011现在是19页\一共有23页\编辑于星期日TissueBasedBiomarkersDiagnosticHighmolecularweightcytokeratinp63AMACRPrognosticHumankallikreintype2ProstatespecificmembraneantigenKi-67AndrogenreceptorGenefusionsPTENP53SPINK1/TATIMSMBEZH2HeatshockproteinsDNAmethylationHER2现在是20页\一共有23页\编辑于星期日ProstateSpecificMembraneAntigenTransmembraneglycoproteinnegativelyregulatedbyandrogensandoverexpressedinandrogenindependentCaPIncreasedexpressionassociatedwithhighergradeandbiochemicalr