ASCO乳腺癌内分泌治疗与骨保护进展

.,乳腺癌内分泌治疗与骨保护进展,浙江省肿瘤医院乳腺肿瘤内科陈占红2015.6.21,.,6月1日9个口头大会报告,LBA500：NSABPB-35关于绝经后DCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择TAM和阿那曲唑何者更优？A501：CALGB40503关于绝经后激素受体阳性乳腺癌一线选择来曲唑单药或联合贝伐单抗的期临床研究；LBA502：PALOMA3是最为关注的期临床研究，对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);A505：Her-2阳性乳腺癌“多西他赛和/或曲妥珠单抗和/或pertuzumab”新辅助治疗期临床研究(NeoSphere)5年随访结果；A506：ER+/PR+/HER-2+早期乳腺癌新辅助治疗T-DM1基础上加或不加内分泌治疗期临床研究；A507：Her-2阳性乳腺癌一线选择T-DM1pertuzumab对曲妥珠单抗紫杉类随机期临床研究(MARIANNE研究);A508：Her-2阳性早期乳腺癌曲妥珠单抗辅助治疗基础上序贯Neratinib安慰剂对照、随机期临床研究（NxteNET）,HER-2/ER专场,.,内容,LBA502：PALOMA3是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);,.,Slide35,PresentedByEricWinerat2015ASCOAnnualMeeting,.,Slide37,PresentedByEricWinerat2015ASCOAnnualMeeting,主要研究终点：BCFI,.,Slide38,PresentedByEricWinerat2015ASCOAnnualMeeting,分层分析,.,Slide39,PresentedByEricWinerat2015ASCOAnnualMeeting,次要研究终点：OS,.,SeriousComplications,PresentedByEricWinerat2015ASCOAnnualMeeting,.,NSABPB-35Summary,PresentedByEricWinerat2015ASCOAnnualMeeting,.,内容,LBA502：PALOMA3是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);,.,CALGB40503(Alliance)/CTSU40503/NCT00601900PhaseIIITrialEvaluatingtheAdditionofBevacizumabtoLetrozoleAsFirst-lineEndocrineTherapyforTreatmentofHormone-receptorPositive(HR+)AdvancedBreastCancer,PresentedByMauraDicklerat2015ASCOAnnualMeeting,.,Bevacizumabpluschemotherapyasfirst-linetherapyinHER2-negativemetastaticbreastcancer,PresentedByJosephSparanoat2015ASCOAnnualMeeting,.,研究设计,分层：1.可测量病灶（有/无）2.无病间隔（24月/24月）主要研究终点：PFS次要研究终点：OS，ORR，CBR，治疗相关毒性事件,随机，开放，多中心，III期临床评估晚期一线乳腺癌使用来曲唑+/-贝伐单抗,.,入组条件,绝经后女性患者（允许使用LHRH激动剂）局部进展或晚期转移性乳腺癌ER和/或PR+（1%），不论HER2状态一线针对晚期乳腺癌的化疗方案允许辅助或新辅助化疗或包含AI或Tam的辅助内分泌治疗良好的骨髓和脏器功能没有已知的脑转移ECOGPS0或1,.,BaselinePatientCharacteristics(1),PresentedByMauraDicklerat2015ASCOAnnualMeeting,基线特征（1）,.,BaselinePatientCharacteristics(2),PresentedByMauraDicklerat2015ASCOAnnualMeeting,基线特征（2）,.,Progression-FreeSurvivalCALGB(Alliance)40503,PresentedByMauraDicklerat2015ASCOAnnualMeeting,PFS：从入组研究至首次疾病进展或任何原因的死亡,主要研究终点：PFS,中位随访时间：39月（范围0.8-70月）,.,Progression-FreeSurvivalBySubgroupAnalysis,PresentedByMauraDicklerat2015ASCOAnnualMeeting,亚组分析,.,OverallSurvivalCALGB(Alliance)40503,PresentedByMauraDicklerat2015ASCOAnnualMeeting,次要研究终点：OS,.,TumorResponse,PresentedByMauraDicklerat2015ASCOAnnualMeeting,.,PatientDisposition,PresentedByMauraDicklerat2015ASCOAnnualMeeting,.,AdverseEventsGrade3*WithTreatmentAttributionMaximumGradeByPatient,PresentedByMauraDicklerat2015ASCOAnnualMeeting,.,Treatment-relatedToxicityGrade3*EventsofSpecialInterest,PresentedByMauraDicklerat2015ASCOAnnualMeeting,.,结论,在晚期乳腺癌一线来曲唑治疗方案中加入贝伐单抗：1.延长PFS4月（HR=0.75，p=0.016），改善ORR及CBR2.截止目前未获得OS获益(HR0.87,p=0.188)3.3级不良事件明显升高，尤其是高血压和蛋白尿对照组来曲唑单药较以往期临床试验显示了更长的PFS时间，达到16月1,2PFS获益而OS未获益与既往贝伐单抗在晚期乳腺癌的临床试验结果相一致，但这种PFS获益需要权衡药物的费用及毒性作用下一步工作需要研究可识别治疗是否有效及耐药的潜在生物标志物，包括PIK3CA突变、CTC、luminal亚型的分析等，同样也等待CALGB40503与LEA研究（来曲唑/氟维斯群联合贝伐单抗研究）的联合分析,.,内容,LBA502：PALOMA3是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);,.,AbstractLBA502ADoubleBlindPhase3TrialofFulvestrantWithorWithoutPalbociclibinPre-andPost-menopausalWomenWithHormoneReceptor-positive,HER2-negativeAdvancedBreastCancerThatProgressedonPriorEndocrineTherapy(PALOMA3Study),PresentedByNicholasTurnerat2015ASCOAnnualMeeting,.,Slide2,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,内分泌耐药问题仍然是临床难题及挑战HR+乳腺癌的生长依赖细胞周期蛋白D1，它是ER的直接转录靶点细胞周期蛋白D1激活CDK4/6，导致G1期向S期转化，进入细胞周期内分泌耐药的细胞系模型生长仍然依赖细胞周期蛋白D1和CDK4/6,.,Palbociclib,Palbociclib是一种口服CDK4/6抑制剂，作用是通过阻止细胞周期G1期向S期转化而抑制细胞增殖和DNA合成。1对内分泌耐药细胞系研究发现，Palbociclib有效并且与氟维司群有协同作用。2在一项II期研究中显示Palbociclib+来曲唑对比来曲唑单药治疗新诊断的晚期HR+乳腺癌能明显提高PFS。3,CDK=cyclin-dependentkinase,.,PALOMA3StudyDesign,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,HR+HER2-晚期乳腺癌绝经前，围绝经*，绝经后之前内分泌治疗进展辅助期间或者结束12个内晚期乳腺癌治疗期间1线的针对晚期肿瘤的化疗*绝经前围绝经均使用戈舍瑞林,内脏转移之前治疗的敏感性绝技前/围绝经vs绝经后,绝经后患者必须是之前AI治疗进展的患者首要终点：PFS次要终点：CBR，ORR，OS，安全性，标记物，QoL,.,DemographicsandBaselineTumorCharacteristics,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,基线肿瘤特征,.,TumorCharacteristicsandPriorTreatment,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,肿瘤特征和前期治疗,.,TreatmentSummary,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,治疗情况汇总,.,PrimaryEndpoint:PFS(ITTPopulation),PresentedByNicholasTurnerat2015ASCOAnnualMeeting,.,Slide16,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,.,SummaryofKeySecondaryEfficacyEndpoints,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,次要疗效终点汇总,.,AdverseEventsAllCause,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,不良反应,.,SummaryofAdverseEvents,PresentedByNicholasTurnerat2015ASCOAnnualMeeting,.,总结,Palbociclib联合氟维司群较安慰剂联合氟维司群治疗能明显提高之前内分泌治疗进展的HR+/HER2-晚期乳腺癌的PFSHR=0.422（95%CI，0.318到0.560；P0.000001）在所有提前预设的亚组均能看到获益安全性能耐受Palbociclib联合氟维司群是治疗之前内分泌治疗进展的患者的有效的治疗方式,.,内容,LBA502：PALOMA3是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);,.,RoleofAdjuvantBisphosphonatesInEarlyBreastCancer,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,AromataseInhibitorsResultInIncreasedBoneLossandPoorerQualityBone,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,AromataseInhibitorsAreAssociatedWithAnIncreasedRateofFractures,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,EBCTCGBisphosphonateMeta-analysisFractureData,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,Outline,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,Slide7,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,ABCSG18StudyDesign,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,Slide13,PresentedByMichaelGnantat2015ASCOAnnualMeeting,.,Slide14,PresentedByMichaelGnantat2015ASCOAnnualMeeting,.,Slide15,PresentedByMichaelGnantat2015ASCOAnnualMeeting,.,RiskofFracturesByBaselineBMD,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,ABCSG18BoneMineralDensityChanges,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,Slide11,PresentedByMichaelGnantat2015ASCOAnnualMeeting,.,PhaseIIItrialofbisphosphonatesasadjuvanttherapyinprimarybreastcancer:SWOG/Alliance/ECOG-ACRIN/NCICClinicalTrialsGroup/NRGOncologystudyS0307,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,S0307:StudyDesign,PresentedByRobertColemanat2015ASCOAnnualMeeting,I-III期乳腺癌,.,S0307PrimaryEndpoint:Disease-FreeSurvival,PresentedByRobertColemanat2015ASCOAnnualMeeting,.,S0307:DFSAnalysisbyTumorSubtype,PresentedByJulieGralowat2015ASCOAnnualMeeting,.,S0307:DFSAnalysisbyAge,PresentedByJulieGralowat2015ASCOAnnualMeeting,.,S0307:OverallSurvival,PresentedByJulieGralowat2015ASCOAnnualMeeting,.,S0307:Grade3,4Toxicities,PresentedByJulieGralowat2015ASCOAnnualMeeting,.,S0307:OsteonecrosisoftheJaw(ONJ),PresentedByJulieGralowat2015ASCOAnnualMeeting,.,S0307:Fractures,PresentedByJulieGralowat2015ASCOAnnualMeeting,.,Co