Biomarkers-in-Prostate-Cancer在前列腺癌生物標(biāo)記課件

WhyareBiomarkersImportantProstateCancerdiagnosedin200,000menannuallyintheunitedstates30,000cancerspecificdeathsperyearYet,asubstantialportionofcancersdiagnosedthroughPSAscreeningdonotprogresstoclinicallysignificantdisease.ProblemwithPSAscreeningItisnotspecific,resultinginanegativebiopsyrateofupto70%insomeseriesEuropeanrandomizedtrial:1410menscreenedand48treatedtoprevent1deathfromprostatecancerSweedishRandomizedtrialofwatchfulwaiting:Relativeriskforsurgery:0.62(0.44-0.87)NNT15overalland7formenyoungerthan65yHowdoweimprovescreeningandtreatmentdecisions?ClinicalnomogramsIncludeGleasonScore,positivecores,percentinvolvementofcores,andPSAOtherriskfactors:familyhistory,age,raceBiomarkersSupplementknownclinicalinformationClinicalNomogram:KattanNomogramStephensonetal,JnatlCI,2006Howcanbiomarkersimprovemanagement?CategoriesofbiomarkersUrineBasedBloodBasedTissuBasedUrineBasedBiomarkersProteinsUrinary/serumpsaratioAnnexinA3MMP9ProteomicsDNAGlutathione-S-transferaseP1Othermethylation-specificPCRassaysRNAPCA3TMPRSS2-ERGgenefusionRooboletal,Actaoncologica,2011UrinaryPCA3DevelopedfromdifferentialexpressionofnoncodingRNA’sinprostatecancerversusotherprostateconditionsCommerciallyavailable,approveddiagnostictestCollectedfromurinesamplefollowingafirmDRECouldfunctionasafirstlinescreenorprognosticindicatorUrinaryPCA3: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,2010PCA3andTMPRSS2-ERGfusionFusionofastrongandrogenpromoter(transmembraneserineprotease)andanoncogeneFurtherimproveddiagnosticaccuracy(AUC)PCA3:0.65PCA3+Fusion:0.77PCA3+gene-fusion+PSA:0.80Aubinetal,JUrol,2008PCA3:prognosticindicatorConflictingstudiesshowapositiverelationship1withcanceraggressivenessornorelationship2ReduceTrial-chemopreventionofCaPwithDutasteride3:WeakassociationofPCA3withGl7orhighercancerOR:1.017(CI95%:1.01-1.03)Thoughlownumbersofhighgradeprostatecancerweakenstheanalysis1.Hesselsetal,Prostate,20102.Whitmanetal,JUrol,20083.Aubinetal,Urology,2011BloodBasedbiomarkersDiagnosisPSAPSAvelocityFreePSAPro-PSABPH-associatedPSAPrognosisHumanKallikrein2Urokinase

plasminogenactivatorTransformingGrowthfactorβ1Interleukin-6EndoglinLimitationsofTotalPSANeoplasticcellsproducevaryinglevelsofPSABiologicvariation:OscillationsofPSAupto30%inrangeof0.1-20ng/mlDifferentAssays(WHOstandard)Sensitivity:52%Specificity:63%WhatCut-off?PSA(ng/ml)PercentCaP(%)<-1.010.11.1-2.017.02.1-3.023.93.1-4.026.9PCPTThompsonetal,NEJM,2004PSA: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,2008PSAVelocityMeasurementofchangeintotalPSAovertimeTwolargeprospectivetrialsfoundnoindependentpredictivevaluebeyondtotalPSAandotherstandardvariables(PCPTandERSPC)1.Shariatetal,ActaOnc,20112.D’amicoetal,NEJM,20043.Carteretal,JNCI,2006DiagnosisIncreaseriskofdeathdeterminedatPSAvlevelsgreaterthan0.35–2.0ng/mlperyearMaynotpredictearlyprogressionbutanindicationofaggressivediseasebeyondtreatmentwindowPrognosisPercentFreePSAIsoformofPSAthatremainsunboundinplasmaPercentfreePSArelativetothetotalPSAisFDAapprovedasanadjuncttototalPSAbetween4-10ng/mlfPSA<25%usedasatriggerforbiopsyMulticenter,prospectivetrialSpecificity:95%,Sensitivity:20%overPSAAUC:%fPSA=0.72 PSA:0.53Whenuse10-12corebiopsy:efficiencydecreasesCatalonaetal,JAMA,1998Cantoetal,JUrol,2004CombinedpanelofPSAisoformsERSPC:Forevery1,000unscreenedmen,themodel,ifusedtodeterminebiopsy:Reducebiopsyratesby573Miss31/152lowgradeCaP3/40highgradeCaPVickersetal,BMCMed,2008Endoglin:CD105,acellsurfaceco-receptorforTGFβ1and3Foundonimmaturebloodvessels:AngiogenesisPre-prostatectomylevelsmaypredicthighergleasonscoreandPSArecurrenceSvateketal,CCR2008CombiningPanelofMarkersandNomogramBiomarkersusedtosupplementnotreplaceclinicaldatatoimproveaccuracyofprognosisKattannomogram+biomarkerpanel:TGF-β1,IL-6R,IL-6,endoglin,VEGF,VCAM-1PredictiveaccuracyoftheKattannomogramimprovedby15%71.6%versus86.6%Shariatetal,ActaOnc,2011TissueBasedBiomarkersDiagnosticHighmolecularweightcytokeratinp63AMACRPrognosticHumankallikreintype2ProstatespecificmembraneantigenKi-67AndrogenreceptorGenefusionsPTENP53SPINK1/TATIMSMBEZH2HeatshockproteinsDNAmethylationHER2ProstateSpecificMembraneAntigenTransmembraneglycoproteinnegativelyregulatedbyandrogensandoverexpressedinandrogenindependentCaPIncreasedexpressionassociatedwithhighergrade