1、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)ORRPFSABX 300 mg/m2,Q3W 33ABX 100mg/m2,QW3 58ABX 150 mg/m2,QW3 62多西他赛100 mg/m2,Q3W 361.2 EFECT:Evaluation of Treatment Options Following AI FailureFulvestrant IM injection loading-dose regimen*(n=351)Exemes
2、tane25 mg/day orally (n=342)Postmenopausal women with hormone receptorpositive,progressing/recurring advanced breast cancer after nonsteroidal AI(N=693)Progression,death,or withdrawal*Fulvestrant loading-dose regimen comprised 500 mg on Day 0,250 mg on Days 14 and 28,and 250 mg monthly thereafter.Gr
3、adishar W,et al.SABCS 2006.Abstract 12.EFECT:Similar TTP in Patients Treated With Fulvestrant or ExemestaneGradishar W,et al.SABCS 2006.Abstract 12.00.00.20.40.60.81.034219098412112861Proportion of PatientsProgression Free MonthsNo.at RiskFulvestrantExemestane3691215182124273511959650251242000Exemes
4、taneFulvestrantEFECT:Patient Response and Study Conclusions Median duration of response to treatment with fulvestrant vs exemestane:13.5 vs 9.8 months,respectively Fulvestrant as effective and safe as exemestane in women with hormone receptorpositive breast cancer who have progressed on treatment wi
5、th a nonsteroidal AIOutcome,%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).8534Gradishar W,et al.SABCS 2006.Abstract 12.Anthracyclin-pretreated and taxane resistantN:752RANDOMIZCIIxabepilone 40 mg/m2 d 1 静脉滴注3hCapecitabine 10
6、00 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
7、 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 2.1 Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 Blocks signaling through EGFR and HER2 homodimers and heterodimers May also prevent signaling between ErbB1/ErbB2 and other ErbB family membersPTENLapatinibP13KpAktRasRafpErkShcGrb2So8Phospholip
8、id cell membraneTreatment Efficacy:Lapatinib Vs Lapatinib+Trastuzumab*Confirmed CR+PR CR+PR+SD 6 mo Clinical Response LN=145L+TN=146Response Rate,%*(95%CI)6.9(3.4,12.3)10.3(5.9,16.4)Odds Ratio(95%CI)1.5(0.6,3.9)p=0.46Clinical Benefit Rate,%(95%CI)12.4(7.5,18.9)24.7(17.9,32.5)Odds Ratio(95%CI)2.2(1.2
9、,4.5)p=0.01OShaughnessy J,et al.ASCO 2008.Abstract 1015.Progression-Free Survival:L Vs L+TL N=145L+T N=146Progressed or Died,n128127Median,wks8.112.0Hazard ratio(95%CI)0.73(0.57,0.93)P value.008Subjects At Risk148148LL+T53732142132758026 Mo PFSCumulative%Alive Without Progression13%28%02040608010001
10、02030405060Time from Randomization(wks)OShaughnessy J,et al.ASCO 2008.Abstract 1015.Geyer CE,et al.ASCO 2006.Clinical Science Symposium.EGF100151:Lapatinib+Capecitabine in Advanced Breast CancerRefractory,progressive metastatic or locally advanced HER2+breast cancer previously treated with anthracyc
11、line,taxane,or trastuzumab(N=528 planned*)Lapatinib 1250 mg daily+Capecitabine 2000 mg/m2 dailyfor Days 1-14,3-week cycles(n=160)Capecitabine 2500 mg/m2 dailyfor Days 1-14,3-week cycles(n=161)Follow-up:until progressionor unacceptabletoxicity*Study enrollment terminated early by IDMC due to superior
12、ity of combination arm in primary endpoint.EGF100151:Lapatinib+Capecitabine in Advanced Breast Cancer(contd)Addition of lapatinib to capecitabine in women with treatment-refractory,advanced metastatic breast cancer associated with Longer time to progression 36.9 vs 19.7 wks(P=.00016)Longer progressi
13、on-free survival 36.9 vs 17.9 wks(P=.000045)Fewer progressions or deaths 38%vs 48%Response(independent review)Overall:22.5%vs 14.3%(P=.113)Geyer CE,et al.ASCO 2006.Clinical Science Symposium.Progression-Free Survival(%)Time(Wks)2040608001001020304050CapecitabineLapatinib+capecitabineITT populationDo
14、cetaxel+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
15、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)Bev 7.5+Docetaxel(n=248)MosAVADO Trial Progression-Free
16、Survival:By Bevacizumab Dose*Data censored for non-protocol therapy prior to PD mg/kg Q3WHR+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)Bev 15+Docetaxel
17、(n=247)Placebo+Docetaxel(n=241)PFS estimate00.20.40.60.81.0061218MosPFS estimate00.20.40.60.81.0061218Miles D,et al.ASCO 2008.Abstract LBA1011.Miller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab 10 mg/kg Days 1,15+Paclitaxel
18、 90 mg/m2 Days 1,8,15(n=365)Paclitaxel 90 mg/m2 Days 1,8,15(n=350)Patients with locally recurrent or metastatic breast cancer,ECOG performance status score 0-1(N=715)Stratified by disease-free interval,number of metastatic sites,adjuvant chemotherapy,andestrogen receptor statusBevacizumab Paclitaxel
19、 for Locally Recurrent or Metastatic DiseaseEastern Cooperative Oncology Group(ECOG)2100 trial First planned interim analysis of randomized,first-line,phase 3 trialMiller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab Paclitax
20、el for Locally Recurrent or Metastatic DiseasePFS significantly longer with combination therapy 10.97 months vs 6.11 months HR=0.498(95%CI,0.401-0.618),P .001Overall survival significantly higher for patients receiving bevacizumab+paclitaxel vs paclitaxel alone HR=0.674(95%CI,0.495-0.917),P=.01Overa
21、ll response significantly better for patients treated with bevacizumab+paclitaxel 28.2%vs 14.2%for paclitaxel alone cohort(P .0001)Xe 1000 mg/m2 BIDPTX 175 mg/m2(n=431)EPI 60 mg/m2PTX 175 mg/m2(n=431)Patients with locally recurrent or metastatic breast cancer2.2 Phase III study of Paclitaxel+Xeloda(
22、XP)vs Paclitaxel+EPI(EP)advanced breast cancer,lueck et alPhase III study of Paclitaxel+Xeloda(XP)vs Paclitaxel+EPI(EP)EP vs XP Time to progression 11.8 m vs 12.3 m Response 41.0 vs 41.5 Opened to Accrual:May 20012.4 TAnDEM 研究设计研究设计Crossover to receive trastuzumab was actively offered to all patient
23、s who progressed on anastrozole aloneHER2-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 surviva
24、l103483117141311941100A+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 progres
25、sion101885757363222171496756341100Probability1.00.00.20.40.60.813.818.2HTXHT55680.6970.0450.488,0.995 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
26、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 TransATAC central laboratory analysis indicates benefit of anastrozole over tamoxifen similar for ER-positive patients with or without being PR positive,according to central analysis All patients HR:0.72 ER-positive/PR-positive patients HR:0.
27、72 ER-positive/PR-negative patients HR:0.66Dowsett M,et al.SABCS 2006.Abstract 48.3.2 TransATAC Central Laboratory Analysis:A vs T for ER and PR Status Benefit of anastrozole over tamoxifen better for patients with no HER2 expression,but confidence intervals of relative benefits with 2 treatments ov
28、erlapped All patients HR:0.72 HER2-negative patients HR:0.66 HER2-positive patients HR:0.92Dowsett M,et al.SABCS 2006.Abstract 48.TransATAC Central Laboratory Analysis:A vs T for HER2 Status HR+patients Recruitment period:Latest follow-up:Median follow-up:Mean age:3.3 LHRHa疗效:Meta-analysisChemothera
29、py(tam)LHRH(n=2741)01020304050Death after recurrence(%)012345678910Years since randomisationHR=0.85,95%CI=0.73-0.99,p=0.04Chemotherapy tamoxifenLHRH addition13.2%vs.10.9%2.3%reduction01020304050Recurrence(%)012345678910Years since randomisationHR=0.88,95%CI=0.77-0.99,p=0.04Chemotherapy tamoxifenLHRH
30、 addition29.6%vs.25.2%4.4%reduction3.4CALGB9840English每周方案80 mg/m2 三周方案175 mg/m2三周方案175 mg/m2 x 6每周方案90 mg/m2 QW x 12ORR40%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 Oncotype 21基因芯片 Dutch 70-Gene基因芯片(mammaprint)Oncotype DXThe 21-Gene Recurrence Score(Oncotype DX)is an RT-PCR based gene
31、 expression profiling assay that includes 16 cancer genes and 5 reference genes.Predicting Tamoxifen Benefit With Recurrence Score(RS)AssayNSABP B-14:estrogen receptorpositive,nodenegative breast cancer Treated with tamoxifen(n=290)Treated with placebo(n=355)RS assay:21-gene assay including 16 cance
32、r genes 9 proliferative genes 7 estrogen genesRS assay assigned predictive categories according to recurrence risk Low risk:RS 18 Intermediate risk:RS 18,31 High risk:RS 31Paik et al.ASCO 2005.Abstract 510.Prognostic Value of Recurrence Score AssayRS genes correlate with increased recurrence risk in
33、 placebo arm 10-year distant recurrence-free survival lower in higher-risk groups(P=.0001)Proliferation genes associated with recurrence in untreated patients CCNB1:HR=1.55;P=.001 SURV:HR=1.33;P=.001 MYBL2:HR=1.28;P=.003 Ki-67:HR=1.27;P=.020 STK15:HR=1.42;P=.008Paik et al.ASCO 2005.Abstract 510.Prog
34、nostic Value of RS Assay in Tamoxifen-Treated PatientsDistant recurrence-free survival following tamoxifen treatment greater in lower RS risk category(P=.060)Greater quantitative ER gene expression predicts better response to tamoxifen(P 65 YrsCALGB 49907 Relapse-Free Survival:Multivariate AnalysisM
35、uss HB,et al.ASCO 2008.Abstract 507.VariableComparisonWorse:BetterHazardRatio(HR)95%CIFor HRP ValueTreatmentX/Std2.091.4-3.2.0006Size(cm)5:21.471.0-2.2.048#Positive lymph nodes4:11.351.1-1.7.0044ReceptorsNeg:Pos3.042.0-4.6.0001N=622;15%eventsStd,standard chemotherapy(CMF or AC);X,capecitabineThe future of breast cancer managementPreventionNovel therapiesDetectionBreast cancer in the 21st centuryImproving use of current treatmentsTailored therapiesMultidisciplinary approach
