妇科肿瘤学和mbcp内文乌斯鲁汶大学课件

P NevenGYNONCOL MBC UZ KULeuven OngoingClinicalResearch TrialsMultidisciplinaryBreastCentre May2007 TenmostfrequentlyoccuringtumoursinFlanders 2000 2001 Source VlaamsKankerregistratienetwerk VLK Age specificincidenceofbreastcancerinwomen Flanders 1997 2001 Source VlaamsKankerregistratienetwerk VLK SABCS2006 2003 Adecreaseinbreastcancerincidence Maybetheincidencewillcomedown I OngoingClinicalTrials May2007 II OngoingMBCResearchProjects Prevention Adjuvant Metastatic I ClinicalTrials May2007 Completed Recruiting FutureTrials EndocrineTherapy Chemotherapy TargetedTherapy RecentlyClosedClinicalTrials May2007 Adjuvant BIG 1 98 TEAM E ZOFASTTACT FEC TXT dd Caelyx EndoxanHERA AC AT Metastatic Lapatinibtrials Tam Iressa EFECT Lapatinib Zarnestra Radiotherapy MSP trial RecruitingClinicalTrials May2007 Prevention IBIS 2 DCIS HighRiskNeo Adjuvant Taxotere Xeloda HerceptinAdjuvant SOFT TEXT TAGAS Pregnancy pharmacokinetics outcome Metastatic MoAbIGF 1R FINDER 2 Vinflunin OralNavelbine Xeloda Sutent BIBW HKIEyetrial MaxidexvsLacrystatTaxotererelateddacrocystostenosis FutureClinicalTrials May2007 Neo Adjuvant Neo AlltoNeoadjuvantPaclitaxel Herceptin PertuzumabAdjuvant Fertilitytrial SOLE ALTTOMINDACT CASAMetastatic Lapatanib Pazopanib RecruitingClinicalTrials IBIS 2 DCIS tamoxifenstandard HighRisk placebostandard 0 10 20 30 40 50 21 T n 3116 A n 3125 48 Numberofcases 12 T n 2372 E n 2352 26 T n 2575 L n 2582 26 14 ATACIESMA17BIG1 98 T n 4007 L n 4003 28 16 IncidenceofContralateralBreastCancers AromataseInhibitorsversusTamoxifen WhyIBIS II Prevention BreastCancerPreventionPostmenopausalWomen OngoingClinicalTrials May2007 IBIS 2 20countriesrecruitingPrevention PlacebovsAnastrozole36 1516ER DCIS TamoxifenvsAnastrozole63 1014 Lateage1stpregnancy parity agemenopause breastdensity familialhistory LCIS ADH Subprotocol Bone Lipid Cognitivefunction IBIS 2RecruitingCentres St LucBrusselSt PierreBrusselVUBBrusselVirgaJesseHasseltSt ElisabethNamenSt AugustinusWilrijkErasmusBrusselBordetBrusselHeiligHartLeuvenOLVrouwZHAalstZOLGenkCliniqueSt PierreOttigniesCHRCitadelleLuikBrugmannBrusselCentreHospitalierdel Ardenne IfyouhavesmallcellLCIS NSABP P1included850suchpatients7 yearsoffollow upTamoxifenversusPlaceboEvents 13 Tam vs38 Placebo Ifplacebo incidenceofeventis1 2 RecruitingClinicalTrials FINDER II2ndlineMetastaticEndocrine FirstLine TTPBenefitofFulvestrantoverTamoifeninER PgR Patients Howelletal JCO2004 22 1605 13 Proportionnotprogressed TTP days Hazardratio 0 85CI 0 63 1 15 p 0 31 MedianTTP Fulvestrant 11 4monthsTamoxifen 8 5months Retrospectiveanalysis ORRF44 3 vsT29 8 p 0 02 Fulvestrant250mg monthProvidesLong termDownregulationofERLevels Gutteridgeetal SABCS2004 MeanERH score Timeontreatment Pre treatment n 29 300 250 200 150 100 50 0 4 6weeks n 26 6months n 20 PD n 8 p 0 01 p 0 001 Fulvestrantinducesdose relatedERdownregulation PgRandKi67 Robertsonetal CancerRes2001 61 6739 6746 Placebo n 29 Fulvestrant50mg n 31 Fulvestrant125mg n 32 Fulvestrant250mg n 32 13 39 50 59 Changefrombaseline 125 136 124 113 Pre treatmentmeanH score Datanotshown Finder II FulvestrantHD 135postmenopausalwomenwithHR ABCafterfailureononepriorendocrinetherapy Progression 3 monthlyfollow up EndpointsTTP primary ORRCBSafety FulvestrantLD HD high dose 500mgIMonDay0 500mgonDays14and28and500mgevery28 3daysthereafter LD high dose 500mgIMonDay0 250mgonDays14and28andevery28 3daysthereafter AD approveddose 250mgIMevery28 3days Randomisation1 1 FulvestrantAD FinderII OverviewofEligibility 2ndlineBreastCancerTreatment 12Monthgap Yes Yes No KEYAdjuvantTreatmentEligible randomisedintostudy NotEligibleFirstLineTreatmentR RecurrenceP Progression Patientswhopreviouslyreceivedadjuvanttreatment Yes PatientswhowerediagnosedwithAdvancedBreastCancer Eligible R R R R P Yes P EBC ABC RegulatoryDefinitionof2ndlineBreastCancer Current FutureClinicalTrials TargetedTherapies ALTTOAdjuvant TwoTargets OneDrugLapatinibProfile Lapatinibisanoveloraldual tyrosinekinaseinhibitorwithspecificityfortheErbB 1andErbB 2receptorsBelongstothe4 anilinoquinazolineclassoftyrosinekinaseinhibitorsBindsreversiblytothecytoplasmicATP bindingsiteofthekinase therebypreventingreceptorphosphorylationandactivation N 3 Chloro 4 3 fluorobenzyl oxy phenyl 6 5 2 methylsulfonyl ethyl amino methyl 2 furyl 4 quinazolinamine Lapatinib ALTTOSTUDYDESIGN Four arm randomised open labelandmulticentrestudyinwomenwithprimarybreastcancerthatoverexpressesoramplifiesHER2 SampleSize8000patientsPrimaryEndpoint DFSSecondaryEndpointsOSTTR timetorecurrence TTDR Timetodistantrecurrence SafetyandtolerabilityProposedstart2Q07Studyduration 5years 4yearsforenrolmentand1yearasfollow up 2Interimanalyses at600and1000DFSevents approximately ALTTOSTUDYDESIGN 4Arms Trastuzumabfor52wksLapatinibfor52wksTrastuzumab Lapatinibfor52wksTrastuzumabfor12wks 6wkwashout Lapatinibfor34wksTreatmentSchema1 all neo adjuvantchemotherapycompletedpriortoadministeringtargetedtherapyTreatmentSchema2 targetedtherapyisinitiatedafter neo adjuvantanthracycline basedchemotherapyandgivenconcurrentlywithweeklypaclitaxel BASELINE Lapatinib1500mg day radiotherapywhenindicated Trastuzumab3 weekly8mg kgthen6mg kg radiotherapywhenindicated Lapatinib1500mg dayfor34wks Trastuzumab4mg kgthen2mg kgweeklyfor12wks 52Weeks CentralDeterminedHER2positive Lapatinib1000mg day Trastuzumab3 weekly8mg kgthen6mg kg radiotherapywhenindicated 6weeksWashout RANDOMISATION Surgery completeNeo adjuvantChemotherapy LVEF 50 PatientswithERorPgR positivetumoursreceiveendocrinetherapyselectedaccordingtomenopausalstatus endocrinetherapywillbestartedaftertheendofthechemotherapy willbeadministeredconcurrentlywithtargetedtherapiesandwillbeplannedforatleast5years radiotherapywhenindicated LocalDeterminedHER2positive NEO ALTTOSTUDYDESIGN T 2cm Nx M0 FISH IHC3 6weeks12weeks9weeks34weeks TumorbiopsyPET Tumorbiopsy NewdrugsfortargettingHER 1 HER 2 Dual TargetHER 1DrugsinthePipeline LapatinibHER 1 HER 2GSKPhaseIIIbreastHKI 272HER 1 HER 2WyethPhaseIIbreastBIBW 2992HER 1 HER 2BoehringerPhaseIIbreastAEE788HER 1 HER 2 VEGFNovartisSolidtumoursBMS 599626HER 1 HER 2BMSSolidTumoursCI 1033HER 1 HER 2 HER 4PfizerPhaseIIbreast Metastatic RecruitingClinicalTrials Exemestane IGF 1R1stLineMetastaticEndocrine TargettedTherapies IGFanditsreceptor Importantmediatorsofcellgrowth OestrogenReceptor MediatedSignallingPathwaysinBreastCancer IGFregulatesthemalignantphenotypeIGFisastrongbreastcancermitogenThereiscrosstalkbetweenERandIGFsignallingNon genomicorgenomicERIGFisaregulatorofestrogen mediatedgrowthIGFinducesproliferationofER breastcancercellsUpregulationintamoxifen resistantbreastcancercells CombiningEndocrineandBiologicalAgentsinM BreastCancer IGF OestrogenReceptor MediatedSignallingPathwaysinBreastCancer IGFRisTyrosineKinasetype1receptorSmallmoleculesandMoAb MonoclonalAB IGF 1R OestrogenReceptor MediatedSignallingPathwaysinBreastCancerExemestane MoAb IGF 1RvsExemestane ER FirstLineMeasurableMetastaticRandomized 1 1 andOpenLabel150patientsPFSCB Safety PKparameters CTCmarkersforexpressionofIGF 1R HRQoL CP751 871 20mg kg q3wArmAExemestane2 5mg CP Fulvestrant CPq4wArmBExemestane2 5mg CP Pfizer ProphylacticmastectomyandsubclinicalbreastpathologiesHER 2expressionbybodyweightArthralgiaandAIsTheprognosticvalueofPRinbreastcancerLHRH agoniststoprotectovarianfunctioninER posBrCaThecontinuousimportanceoftamoxifenasanadjuvanttherapyEndometrialthicknessonAI switchMMPinbreastcancerAssociationsbetweenER PR HER2expressioninoperableBrCa II OwnClin AndBasicResearchRecentlyPublished leavingoutclin trials May2007 EarlyrelapsebyER PR HER2expression ImprovingNPI HER 1 uPARintriplenegativeandotherbreastcancersPET CTinstaginglargeandlocallyadvancedbreastcancerCorrelationsLN status ER PR HER 2 LN status ageCorrelationsAge ER PR HER 2expressionRetrospectiveandprospectiveregistrationstudy Breastcancers MirenaPostmenopausalbreastcancercharacteristicsbyuseofHRTPaloprai ER PR breastcancers Fulvestrantanduterinevolume OngoingClinical BasicResearch May2007 MoleculargeneticanalysisasanadditiontothemorphologicclassificationofbreastcancersTheclinicalrelevanceofproteaseinbreastcancer matrixmetalloproteinasenandcathepsinesMenopausalsymptomsofbreastcancertherapiesProteonomicsinbreastcancerGeneticsinbreastandovariancancer PhDtopics ER ER basal likeHER 2 luminaltype subtypeA B C DFSin1962operablebreastcancersSubgroupAnalysisbyER PR HER 2 ThesisLicBiomed Sc S Pintens andProjectCo Assist O Brouckaert EarlybreastcancerrelapsebyER PR HER 2 n 1962 UZLeuven2000 2005 OBrouckaert SPintens DFSbyER PR HER 2 AnnualincidenceofrelapseNNN Earlyrelapse CanweimproveNPI Thefuture CyclinEasaprognosticfactor StageI IIbreastcancer TotalcyclinEpredictsSurvival InteractionER statusandagebyHER 2status HER 2negative HER 2positive TheinteractionbetweenERandageisHER 2dependentThenegativeassociationbetweenERandHER 2isagedependent ER PRandHER 2 InteractionPR statusandagebyHER 2status TheinteractionbetweenPRandageisHER 2dependentThenegativeassociationbetweenPRandHER 2isagedependent ER PRandHER 2 HER 2negative HER 2positive InteractionHER statusandagebyER PR TheinteractionbetweenHER 2andageisER PRdependentTheolderoneisthelesslikelyHER 2positiveisonlyifthetumourisER positive ER PRandHER 2 BreastCancer AdjuvantTherapyTreatmentSideEffects Qualityof