BiomarkersinProstateCancer在前列腺癌生物标记

WhyareBiomarkersImportantProstateCancerdiagnosedin200,000menannuallyintheunitedstates30,000cancerspecificdeathsperyearYet,asubstantialportionofcancersdiagnosedthroughPSAscreeningdonotprogresstoclinicallysignificantdisease.当前1页，总共23页。ProblemwithPSAscreeningItisnotspecific,resultinginanegativebiopsyrateofupto70%insomeseriesEuropeanrandomizedtrial:1410menscreenedand48treatedtoprevent1deathfromprostatecancerSweedishRandomizedtrialofwatchfulwaiting:Relativeriskforsurgery:0.62(0.44-0.87)NNT15overalland7formenyoungerthan65y当前2页，总共23页。Howdoweimprovescreeningandtreatmentdecisions?ClinicalnomogramsIncludeGleasonScore,positivecores,percentinvolvementofcores,andPSAOtherriskfactors:familyhistory,age,raceBiomarkersSupplementknownclinicalinformation当前3页，总共23页。ClinicalNomogram:KattanNomogramStephensonetal,JnatlCI,2006当前4页，总共23页。Howcanbiomarkersimprovemanagement?当前5页，总共23页。CategoriesofbiomarkersUrineBasedBloodBasedTissuBased当前6页，总共23页。UrineBasedBiomarkersProteinsUrinary/serumpsaratioAnnexinA3MMP9ProteomicsDNAGlutathione-S-transferaseP1Othermethylation-specificPCRassaysRNAPCA3TMPRSS2-ERGgenefusionRooboletal,Actaoncologica,2011当前7页，总共23页。UrinaryPCA3DevelopedfromdifferentialexpressionofnoncodingRNA’sinprostatecancerversusotherprostateconditionsCommerciallyavailable,approveddiagnostictestCollectedfromurinesamplefollowingafirmDRECouldfunctionasafirstlinescreenorprognosticindicator当前8页，总共23页。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当前9页，总共23页。PCA3andTMPRSS2-ERGfusionFusionofastrongandrogenpromoter(transmembraneserineprotease)andanoncogeneFurtherimproveddiagnosticaccuracy(AUC)PCA3:0.65PCA3+Fusion:0.77PCA3+gene-fusion+PSA:0.80Aubinetal,JUrol,2008当前10页，总共23页。PCA3:prognosticindicatorConflictingstudiesshowapositiverelationship1withcanceraggressivenessornorelationship2ReduceTrial-chemopreventionofCaPwithDutasteride3:WeakassociationofPCA3withGl7orhighercancerOR:1.017(CI95%:1.01-1.03)Thoughlownumbersofhighgradeprostatecancerweakenstheanalysis1.Hesselsetal,Prostate,20102.Whitmanetal,JUrol,20083.Aubinetal,Urology,2011当前11页，总共23页。BloodBasedbiomarkersDiagnosisPSAPSAvelocityFreePSAPro-PSABPH-associatedPSAPrognosisHumanKallikrein2UrokinaseplasminogenactivatorTransformingGrowthfactorβ1Interleukin-6Endoglin当前12页，总共23页。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当前13页，总共23页。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当前14页，总共23页。PSAVelocityMeasurementofchangeintotalPSAovertimeTwolargeprospectivetrialsfoundnoindependentpredictivevaluebeyondtotalPSAandotherstandardvariables(PCPTandERSPC)1.Shariatetal,ActaOnc,20112.D’amicoetal,NEJM,20043.Carteretal,JNCI,2006DiagnosisIncreaseriskofdeathdeterminedatPSAvlevelsgreaterthan0.35–2.0ng/mlperyearMaynotpredictearlyprogressionbutanindicationofaggressivediseasebeyondtreatmentwindowPrognosis当前15页，总共23页。PercentFreePSAIsoformofPSAthatremainsunboundinplasmaPercentfreePSArelativetothetotalPSAisFDAapprovedasanadjuncttototalPSAbetween4-10ng/mlfPSA<25%usedasatriggerforbiopsyMulticenter,prospectivetrialSpecificity:95%,Sensitivity:20%overPSAAUC:%fPSA=0.72 PSA:0.53Whenuse10-12corebiopsy:efficiencydecreasesCatalonaetal,JAMA,1998Cantoetal,JUrol,2004当前16页，总共23页。CombinedpanelofPSAisoformsERSPC:Forevery1,000unscreenedmen,themodel,ifusedtodeterminebiopsy:Reducebiopsyratesby573Miss31/152lowgradeCaP3/40highgradeCaPVickersetal,BMCMed,2008当前17页，总共23页。Endoglin:CD105,acellsurfaceco-receptorforTGFβ1and3Foundonimmaturebloodvessels:AngiogenesisPre-prostatectomylevelsmaypredicthighergleasonscoreandPSArecurrenceSvateketal,CCR2008当前18页，总共23页。CombiningPanelofMarkersandNomogramBiomarkersusedtosupplementnotreplaceclinicaldatatoimproveaccuracyofprognosisKattannomogram+biomarkerpanel:TGF-β1,IL-6R,IL-6,endoglin,VEGF,VCAM-1PredictiveaccuracyoftheKattannomogramimprovedby15%71.6%versus86.6%Shariatetal,ActaOnc,2011当前19页，总共23页。TissueBasedBiomarkersDiagnosticHighmolecularweightcytokeratinp63AMACRPrognosticHumankallikreintype2ProstatespecificmembraneantigenKi-67AndrogenreceptorGenefusionsPTENP53SPINK1/TATIMSMBEZH2HeatshockproteinsDNAmethylationHER2当前20页，总共23页。ProstateSpecificMembraneAntigenTransmembraneglycoproteinnegativelyregulatedbyandrogensandoverexpressedinandrogenindependentCaPIncreasedexpressionassociatedwithhighergradeandbiochem