复旦大学附属肿瘤医院乳腺癌内科治疗新进展乳腺癌内科治疗新进展胡夕春新药新药新方案新方案 新理念新理念 新药不良反应及处理新药不良反应及处理 1.1白蛋白结合紫杉醇白蛋白结合紫杉醇 (ABX) ORRPFSABX300mg/m2,Q3W33ABX100mg/m2,QW358ABX150mg/m2,QW362多西他赛100mg/m2,Q3W361.2 EFECT: Evaluation of Treatment Options Following AI FailureFulvestrant IMinjectionloading-doseregimen*(n=351)Exemestane25mg/dayorally(n=342)Postmenopausal women with hormone receptorpositive, progressing/recurring advanced breast cancer after nonsteroidal AI(N = 693)Progression, death, or withdrawal*Fulvestrantloading-doseregimencomprised 500mgonDay0,250mgonDays14and28,and250mgmonthlythereafter.GradisharW,etal.SABCS2006.Abstract12.EFECT: Similar TTP in Patients Treated With Fulvestrant or ExemestaneGradisharW,etal.SABCS2006.Abstract12.00.00.20.40.60.81.034219098412112861Proportion of PatientsProgression Free MonthsNo. at RiskFulvestrantExemestane3691215182124273511959650251242000ExemestaneFulvestrantEFECT: Patient Response and Study ConclusionsMediandurationofresponsetotreatmentwithfulvestrantvsexemestane:13.5vs9.8months,respectivelyFulvestrantaseffectiveandsafeasexemestaneinwomenwithhormonereceptorpositivebreastcancerwhohaveprogressedontreatmentwithanonsteroidalAIOutcome, %Exemestane (n = 342)Fulvestrant (n = 351)Odds Ratio (95% CI)P ValueORR6.77.41.120(0.578-2.186).7364CBR31.532.21.035(0.720-1.487).8534GradisharW,etal.SABCS2006.Abstract12.Anthracyclin-pretreated and taxane resistantN: 752RANDOMIZCIIxabepilone 40 mg/m2 d 1 静脉滴注3hCapecitabine 1000 mg/m2 po. BID x 14Capecitabine 1250 mg/m2 po. BID x 141.3 Ixabepilone+Capecitabine vs CapecitabineL.T. Vahdat et al. Proc ASCO 2007. Abstr 1006Ixabepilone+Capecitabine vs CapecitabineL.T. Vahdat et al. Proc ASCO 2007. Abstr 1006Ixabepilone+Capecitabine vs CapecitabineL.T. Vahdat et al. Proc ASCO 2007. Abstr 1006新药新药新方案新方案 新理念新理念 新药不良反应及处理新药不良反应及处理 2.1LapatiniboraltyrosinekinaseinhibitorofErbB1andErbB2BlockssignalingthroughEGFRandHER2homodimersandheterodimersMayalsopreventsignalingbetweenErbB1/ErbB2andotherErbBfamilymembersPTENLapatinibP13KpAktRasRafpErkShcGrb2So8PhospholipidcellmembraneTreatment Efficacy: Lapatinib Vs Lapatinib + Trastuzumab*ConfirmedCR+PRCR+PR+SD6mo Clinical Response LN=145L + TN=146ResponseRate,%*(95%CI)6.9(3.4,12.3)10.3(5.9,16.4)OddsRatio(95%CI)1.5(0.6,3.9)p=0.46ClinicalBenefitRate,%(95%CI)12.4(7.5,18.9)24.7(17.9,32.5)OddsRatio(95%CI)2.2(1.2,4.5)p=0.01OShaughnessyJ,etal.ASCO2008.Abstract1015.Progression-Free Survival: L Vs L+TL N = 145L+T N = 146ProgressedorDied,n128127Median,wks8.112.0Hazardratio(95%CI)0.73(0.57,0.93)Pvalue.008Subjects At Risk148148LL+T53732142132758026MoPFSCumulative % Alive Without Progression13%28%0204060801000102030405060Time from Randomization (wks)OShaughnessyJ,etal.ASCO2008.Abstract1015.GeyerCE,etal.ASCO2006.ClinicalScienceSymposium.EGF100151: Lapatinib + Capecitabine in Advanced Breast CancerRefractory,progressivemetastaticorlocallyadvancedHER2+breastcancerpreviouslytreatedwithanthracycline,taxane,ortrastuzumab(N=528planned*)Lapatinib1250mgdaily+Capecitabine 2000mg/m2dailyforDays1-14,3-weekcycles(n=160)Capecitabine2500mg/m2dailyforDays1-14,3-weekcycles(n=161)Follow-up:until progressionor unacceptabletoxicity*StudyenrollmentterminatedearlybyIDMCduetosuperiorityofcombinationarminprimaryendpoint.EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd)Additionoflapatinibtocapecitabineinwomenwithtreatment-refractory,advancedmetastaticbreastcancerassociatedwithLongertimetoprogression36.9vs19.7wks(P=.00016)Longerprogression-freesurvival36.9vs17.9wks(P=.000045)Fewerprogressionsordeaths38%vs48%Response(independentreview)Overall:22.5%vs14.3%(P=.113)GeyerCE,etal.ASCO2006.ClinicalScienceSymposium.Progression-Free Survival (%)Time (Wks)2040608001001020304050CapecitabineLapatinib+capecitabineITTpopulationDocetaxel + Avastin15mg/kg every3 weeksPhase III trial of Avastin plus docetaxel in first-line MBC (AVADO)lRecruitment commenced March 2006 and completed in March 2007lPrimary endpoint: PFSsecondary endpoints: ORR, OS, safety, QoLlTrial met primary endpoint; data will be presented mid-2008Previously untreated HER2-negative locally recurrent or MBC (n=705)Docetaxel 100mg/m2 every 3 weeks + placeboDocetaxel + Avastin7.5mg/kg every3 weeksPI: David MilesTreat to disease progressionTreat to disease progressionTreat to disease progressionRHR+95%CI(unstratified)Bev7.5+Docetaxel(n=248)MosAVADO Trial Progression-Free Survival: By Bevacizumab Dose*Datacensoredfornon-protocoltherapypriortoPDmg/kgQ3WHR+95%CI(stratified*).69(.54.89)P =.0035.79(.63.98)P =.0318Placebo+Docetaxel(n=241)Median,mos8.78.0HR+95%CI(stratified*).61(.48.78)P .0001Median,mos8.88.0.72(.57.90)P =.0036HR+95%CI(unstratified)Bev15+Docetaxel(n=247)Placebo+Docetaxel(n=241)PFS estimate00.20.40.60.81.0061218MosPFS estimate00.20.40.60.81.0061218MilesD,etal.ASCO2008.AbstractLBA1011.Milleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.Bevacizumab10mg/kgDays1,15+Paclitaxel 90mg/m2Days1,8,15(n=365)Paclitaxel90mg/m2Days1,8,15(n=350)Patientswithlocallyrecurrentormetastaticbreastcancer,ECOGperformancestatusscore0-1(N=715)Stratified by disease-free interval, number of metastatic sites, adjuvant chemotherapy, andestrogen receptor statusBevacizumab Paclitaxel for Locally Recurrent or Metastatic DiseaseEasternCooperativeOncologyGroup(ECOG)2100trialFirstplannedinterimanalysisofrandomized,first-line,phase3trialMilleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.Bevacizumab Paclitaxel for Locally Recurrent or Metastatic DiseasePFSsignificantlylongerwithcombinationtherapy10.97monthsvs6.11monthsHR=0.498(95%CI,0.401-0.618),P.001Overallsurvivalsignificantlyhigherforpatientsreceivingbevacizumab+paclitaxelvspaclitaxelaloneHR=0.674(95%CI,0.495-0.917),P=.01Overallresponsesignificantlybetterforpatientstreatedwithbevacizumab+paclitaxel28.2%vs14.2%forpaclitaxelalonecohort(P.0001)Xe1000mg/m2BIDPTX175mg/m2(n=431)EPI60mg/m2PTX175mg/m2(n=431)Patientswithlocallyrecurrentormetastaticbreastcancer2.2 Phase III study of Paclitaxel+Xeloda (XP) vs Paclitaxel+EPI (EP) advancedbreastcancer,luecketalPhase III study of Paclitaxel+Xeloda (XP) vs Paclitaxel+EPI (EP)EPvsXPTimetoprogression11.8mvs12.3mResponse41.0vs41.52.3 NSABP B-33 Stage I-II Breast CancerStage I-II Breast CancerPostmenopausal, ER or Postmenopausal, ER or PgRPgR-Positive-PositiveTamoxifen for 5 YearsTamoxifen for 5 YearsDisease-freeDisease-freeExemestaneExemestaneX 2 yearsX 2 yearsPlaceboPlaceboX 2 yearsX 2 yearsRandomizationRandomizationOpened to Accrual: May 2001ExemestaneExemestaneX 5 yearsX 5 yearsPlaceboPlaceboX 5 yearsX 5 yearsProtocol Amendment in 2002Years After SurgeryYears After Surgery% Event-Free% Event-Free0 01 12 23 34 45 50 02020404060608080100100 Group Group N N EventsEventsPlacebo Placebo 779 779 37 37Exemestane Exemestane 783 783 17 17B-33: Relapse-Free Survival*RR=RR=0.440.44 p= p=0.0040.004 96% 96%94%94%*Eligible pts with follow-up*Eligible pts with follow-up2.4 TAnDEM 研究设计研究设计CrossovertoreceivetrastuzumabwasactivelyofferedtoallpatientswhoprogressedonanastrozolealoneHER2-positive, HR-positive MBC (n=208)RAnastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose 2 mg/kg qw until disease progressionAnastrozole1 mg daily untildisease progressionHR, hormone receptor; MBC, metastatic breast cancer; R, randomisationProgression-free survival103483117141311941100A + HNo. at risk10436229542100000AProbability 1.00.80.60.40.2051015202530354045505560Months95% CI3.7, 7.02.0, 4.6p value0.0016Median PFS4.8 months2.4 monthsEvents8799CI, confidence intervalPFS = time from randomisation to date of progressive disease or death0.02.5 HTX:HT Time to progression101885757363222171496756341100Probability1.00.00.20.40.60.813.818.2HTXHT55680.6970.0450.488, 0.995 ap=0.035 for exploratory analysis correcting for imbalance in ER / PgR status and duration of primary disease p valueaHR95% CIEvents05101520253035404550Months from randomisationNo. at riskHTXHT112110新药新药新方案新方案 新理念新理念 新药不良反应及处理新药不良反应及处理 3.1攻克血脑屏障的新手段攻克血脑屏障的新手段 TransATACcentrallaboratoryanalysisindicatesbenefitofanastrozoleovertamoxifensimilarforER-positivepatientswithorwithoutbeingPRpositive,accordingtocentralanalysisAllpatientsHR:0.72ER-positive/PR-positivepatientsHR:0.72ER-positive/PR-negativepatientsHR:0.66DowsettM,etal.SABCS2006.Abstract48.3.2 TransATAC Central Laboratory Analysis: A vs T for ER and PR StatusBenefitofanastrozoleovertamoxifenbetterforpatientswithnoHER2expression,butconfidenceintervalsofrelativebenefitswith2treatmentsoverlappedAllpatientsHR:0.72HER2-negativepatientsHR:0.66HER2-positivepatientsHR:0.92DowsettM,etal.SABCS2006.Abstract48.TransATAC Central Laboratory Analysis: A vs T for HER2 Status9,022HR+patientsRecruitmentperiod:1987-2001Latestfollow-up:2006Medianfollow-up:6.8yearsMeanage:43.6years3.3LHRHa疗效:Meta-analysisChemotherapy(tam)LHRH(n=2741)RECURRENCERECURRENCEDEATH AFTER RECURRENCEDEATH AFTER RECURRENCE01020304050Deathafterrecurrence(%)012345678910YearssincerandomisationHR=0.85,95%CI=0.73-0.99,p=0.04Chemotherapy tamoxifenLHRH addition13.2%vs.10.9%2.3% reduction01020304050Recurrence(%)012345678910YearssincerandomisationHR=0.88,95%CI=0.77-0.99,p=0.04Chemotherapy tamoxifenLHRH addition29.6%vs.25.2%4.4% reduction3.4CALGB9840English每周方案80mg/m2三周方案175mg/m2三周方案175mg/m2x6每周方案90mg/m2QWx12ORR40%28%27%42%TTP9月5月22.0周23.9周OS24月16月3.5 基因芯片基因芯片FDA 批准批准Oncotype21基因芯片Dutch70-Gene基因芯片(mammaprint)Oncotype DXThe21-GeneRecurrenceScore(OncotypeDX)isanRT-PCRbasedgeneexpressionprofilingassaythatincludes16cancergenesand5referencegenes.PROLIFERATIONPROLIFERATIONKi-67Ki-67STK15STK15SurvivinSurvivinCyclinB1CyclinB1MYBL2MYBL2ESTROGENESTROGENERERPRPRBcl2Bcl2SCUBE2SCUBE2INVASIONINVASIONStromelysinStromelysin33CathepsinCathepsinL2L2HER2HER2GRB7GRB7HER2HER2BAG1BAG1GSTM1GSTM1REFERENCE GENESREFERENCE GENESBeta-Beta-actinactin,GAPDH,RPLPO,GAPDH,RPLPOGUS,TFRCGUS,TFRCCD68CD68Predicting Tamoxifen Benefit With Recurrence Score (RS) AssayNSABPB-14:estrogenreceptorpositive,nodenegativebreastcancerTreatedwithtamoxifen(n=290)Treatedwithplacebo(n=355)RSassay:21-geneassayincluding16cancergenes9proliferativegenes7estrogengenesRSassayassignedpredictivecategoriesaccordingtorecurrenceriskLowrisk:RS18Intermediaterisk:RS18,31Highrisk:RS31Paiketal.ASCO2005.Abstract510.Prognostic Value of Recurrence Score AssayRSgenescorrelatewithincreasedrecurrenceriskinplaceboarm10-yeardistantrecurrence-freesurvivallowerinhigher-riskgroups(P=.0001)ProliferationgenesassociatedwithrecurrenceinuntreatedpatientsCCNB1:HR=1.55;P =.001SURV:HR=1.33;P =.001MYBL2:HR=1.28;P =.003Ki-67:HR=1.27;P =.020STK15:HR=1.42;P =.008Paiketal.ASCO2005.Abstract510.Prognostic Value of RS Assay in Tamoxifen-Treated PatientsDistantrecurrence-freesurvivalfollowingtamoxifentreatmentgreaterinlowerRSriskcategory(P=.060)GreaterquantitativeERgeneexpressionpredictsbetterresponsetotamoxifen(P 65 YrsCALGB 49907 Relapse-Free Survival: Multivariate AnalysisMussHB,etal.ASCO2008.Abstract507.VariableComparisonWorse:BetterHazardRatio (HR)95% CIFor HRP ValueTreatmentX/Std2.091.4-3.2.0006Size(cm)5:21.471.0-2.2.048#Positivelymphnodes4:11.351.1-1.7.0044ReceptorsNeg:Pos3.042.0-4.6.0001N=622;15%eventsStd,standardchemotherapy(CMForAC);X,capecitabineThe future of breast cancer managementPreventionNovel therapiesDetectionBreast cancer in the 21st centuryImproving use of current treatmentsTailored therapiesMultidisciplinary approach