HER2阳性EBC的应对策略课件.ppt

1、HER2阳性EBC的应对策略Adjuvant CMF21%Risk of recurrenceBonadonna et al.BMJ 2019;330:2171976The CMF programmeCMF vs observationC,cyclophosphamide;M,methotrexate;F,5-fluorouracilFirst publication:Bonadonna et al.N Engl J Med 1976;294:405-410Latest data29%Risk of death1976Adjuvant tamoxifen36%29%Risk of recurr

2、enceRisk of deathFirst publication:Lancet 1983;1:257-261Br J Cancer 1988;57:608-611Latest data1983NATO trialTamoxifen vs observationAdjuvant anthracyclinesRisk of recurrenceFirst publication:Levine et al.J Clin Oncol 2019;16:2651-2658Latest dataLevine et al.J Clin Oncol 2019;23:5166-51702019NCIC MA.

3、5CEF vs CMF24%C,cyclophosphamide;E,epirubicin;F,fluorouracil;M,methotrexateAdjuvant taxanes18%Risk of recurrenceRisk of death2019First publication:Henderson et al.Proc Am Soc Clin Oncol 2019;17:101a,abs 390ACALGB 9344ACP vs AC 17%A,doxorubicin;C,cyclophosphamide;P,paclitaxelLatest dataHenderson et a

4、l.J Clin Oncol 2019;21:976-983Adjuvant aromatase inhibitors13%Risk of recurrenceFirst publication:Baum et al.Breast Cancer Res Treat 2019;69:210,abs 82019ATACAnastrozole vs tamoxifenHowell et al.Lancet 2019;365:60-62Latest dataAdjuvant Herceptin36%34%Risk of recurrenceRisk of deathFirst presentation

5、:Piccart-Gebhart et al.ASCO 2019Smith et al.Lancet 2019;369:29-36Latest data3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death Romond et al.N Engl J Med 2019;353:1673-1684;Slamon et al.SABCS 2019;abs 522019HERA1-year Herceptin vs observ

6、ation after chemotherapyHER2:role in breast cancerHuman epidermal growth factor receptor 2(HER2)is a transmembrane protein and part of the HER family of 4 growth factor receptors(HER1 to HER4)1Overexpression of HER2 and/or amplification of the HER2 gene occurs in up to 30%of breast cancers1-3HER2 po

7、sitivity is associated with2-4aggressive diseasea high risk of relapsepoor survivalHER2 is the only member of the HER family acknowledged in guidelines for its prognostic and predictive value in breast cancer5HER2 is an important therapeutic targetSlamon DJ,et al.Science 1989;244:707712Slamon DJ,et

8、al.Science 1987;235:177182Penault-Llorca F,et al.J Clin Oncol(Meeting Abstracts)2019;23:69s,abs 764 Press MF,et al.J Clin Oncol 2019;15:28942904 Goldhirsch A,et al.Ann Oncol 2019;17:17221776Inhibition of HER2-mediated signallingActivation of antibody-dependent cellular cytotoxicity(ADCC)Herceptin is

9、 effective across all stages of disease by activating the immune system and suppressing HER2Additional mechanismsPrevents formation of truncated HER2(p95)Inhibition of HER2-regulated angiogenesisSlamon DJ,et al.N Engl J Med 2019;344:783-792 Marty M,et al.J Clin Oncol 2019;23:4265-4274Baselga J.Oncol

10、ogy 2019;61(Suppl 2):14-21 Piccart-Gebhart MJ,et al.N Engl J Med 2019;353:16591672Romond EH,et al.N Engl J Med 2019;353:16731684Slamon D,et al.Breast Cancer Res Treat 2019;94(Suppl 1):S5,abs 1Slamon D,et al.Abstract 52 presented at the 29th SABCS,San Antonio,Texas,USA,14-17 December 2019Smith I,et a

11、l.Lancet 2019;369:29-36The fascinating history of HerceptinPhase I IND for rhuMAb HER2Murine HER2/neu gene clonedHuman HER2 gene clonedmuMAb 4D5Association of HER2 with poor clinical outcomePaclitaxel+H and H mono US approvalPaclitaxel+H and H mono EU approval1st IA of HERA19921985199019811987200020

12、1920192019HERA recruitment opensHERA 2-year follow-upAdjuvant H approval2019HERA 4-year follow-up and 1-year H vs 2-year H IA2019HERA final analysis 1-year H vs 2-year HHER2,human epidermal growth factor receptor 2;H,Herceptin;IA,interim analysisAdjuvant ChemotherapyHERA study designHerceptin q3w x

13、1 yearObservationHER2-positive early breast cancer(IHC 3+and/or FISH+)n=5102Herceptin q3w x 2 yearsOption to cross over to Herceptin(after IA 2019)Surgery+(neo)adjuvant chemotherapy+radiotherapyIHC,immunohistochemistry;FISH,fluorescence in situ hybridisationEnd points of the HERA trialPrimary end po

14、intDFS 1-year Herceptin vs observation 2-year Herceptin vs observationSecondary end pointsOS,RFS,distant DFS,safety 1-year Herceptin vs observation 2-year Herceptin vs observationcompare DFS,OS,RFS,distant DFS and safety 1-year Herceptin vs 2-year HerceptinDFS,disease-free survival;OS,overall surviv

15、al;RFS,relapse-free survivalHERA 2019 interim analysis:2-year vs 1-year HerceptinStatistical assumptionsHR 0.80DFS absolute reduction 4.9%5-year DFS 1-year arm:70%5-year DFS 2-year arm:74.9%p value 0.014 for early release of resultsFinal analysis triggered by 725 events(2019)Trial continues as plann

16、ed2019 interim analysis 500 events reached June 2019October 2019IDMC advises Executive CommitteeData release at SABCSInterim analysis positiveDatabase cleaningNo data releaseHR,hazard ratio;IDMC,Independent Data Monitoring CommitteeHERA:IDMC recommendations October 2019lDo not release information on

17、 the 2-year Herceptin armlContinue the 1-year Herceptin vs 2-year Herceptin comparisonlRelease updated information on 1-year Herceptin vs observationNo conclusions can be drawn regarding the efficacy of Herceptin therapy for 2 years vs 1 yearOption to cross over to Herceptin(after IA 2019)HERA study

18、 designHER2-positive early breast cancer(IHC 3+and/or FISH+)n=5102Surgery+(neo)adjuvant chemotherapy+radiotherapyHerceptin q3w x 1 yearObservationHerceptin q3w x 2 yearsHERA:DFS and OS over time 1 and 2 years follow-upNo.of deathsH 1 year vs observation012FavoursHerceptinFavours noHerceptinHROS bene

19、fit29 vs 37p=0.26201911 year(0%)59 vs 90p=0.0115Median follow-up(%follow-up time after selective crossover)201922 years(4.1%)201911 year(0%)Median follow-up(%follow-up time after selective crossover)201922 years(4.3%)No.of DFS eventsH 1 year vs observation127 vs 220p0.0001218 vs 321p0.0001012Favours

20、HerceptinFavours noHerceptinHRDFS benefit 1Piccart-Gebhart et al 2019;2Smith et al 2019DFS:4-year median follow-up1008060402000612182430483642Months from randomisation169817031564161914401552136314851297141412401352712854118012809921020No.at riskEvents4583694-yearDFS72.278.6HR0.7695%CI0.66,0.87p val

21、ue0.00011-year HerceptinObservation6.4%Patients(%)OS:4-year median follow-up0612182430483642Months from randomisation1698170316421660160116401556161515191577147115248289531398144711751149Events2131824-yearDFS87.789.3HR0.8595%CI0.70,1.04p value0.10871.6%1-year HerceptinObservation100806040200Patients

22、(%)No.at riskHERA:DFS and OS over timeNo.of deathsH 1 year vs observation012FavoursHerceptinFavours noHerceptinHROS benefit29 vs 37p=0.26201911 year(0%)59 vs 90p=0.0115182 vs 213p=0.1087Median follow-up(%follow-up time after selective crossover)201922 years(4.1%)20194 years(30.9%)201911 year(0%)Medi

23、an follow-up(%follow-up time after selective crossover)201922 years(4.3%)20194 years(33.8%)No.of DFS eventsH 1 year vs observation127 vs 220p0.0001218 vs 321p0.0001369 vs 458p0.0001012FavoursHerceptinFavours noHerceptinHRDFS benefit 1Piccart-Gebhart et al 2019;2Smith et al 20194 year DFS：78.6%vs.72.

24、2%4年年OS：89.3%vs.87.7%Crossover to Herceptin of 65%of the patients originally allocated to observation disrupted the randomised comparison between 1-year Herceptin and observationQuestion:To what extent might crossover have biased the ITT analysis?Specific question 1Flow chart of observation patients

25、:by status on 16 May 20191698 patients originally randomised to observation1354 patients alive and disease-free 16 May2019344 patients DFS event or lost to follow-up198 alive post DFS event469 patients remained on observation344 patients ineligible for crossoverTime to selective crossover by calenda

26、r date(n=885)0.60.50.40.30.20.016 May 201922 Aug 201928 Nov 20196 Mar 201912 Jun 201918 Sep 201925 Dec 20191354119359620911671300.1Switched to HerceptinNo.at riskObservationProportionRandomisation to 1st doseDiagnosis to 1st doseFollow-up from 1st doseMedian time(range),months22.8(50%50%LVEF 40-50%L

27、VEF 40-50%LVEF 40%LVEF 40%左室射血分数左室射血分数(LVEF)(LVEF)基线值评估基线值评估首选：心超首选：心超 亦可选用：亦可选用：MUGAMUGA扫描扫描准确的准确的 HER2 HER2 评估评估HER2 HER2 阳性阳性赫赛汀辅助治疗心脏不良事件的建议HER2+患者从赫赛汀患者从赫赛汀 辅助治疗的获益远大于心脏辅助治疗的获益远大于心脏不良事件的风险不良事件的风险赫赛汀赫赛汀 辅助治疗相关心脏事件是可逆性，辅助治疗相关心脏事件是可逆性，发生后发生后2-4月内自行恢复的概率高不影响后续的治疗月内自行恢复的概率高不影响后续的治疗治疗前心功能评估及方案选择可以更好的

28、保证治疗治疗前心功能评估及方案选择可以更好的保证治疗中的心脏安全性中的心脏安全性接受赫赛汀接受赫赛汀 辅助治疗的患者：辅助治疗的患者：LVEF 40%大多数患者可以继续接受赫赛汀大多数患者可以继续接受赫赛汀 治治疗，建议每疗，建议每3个月检测个月检测LVEFLVEF 40%建议停赫赛汀建议停赫赛汀 治疗，心内科随访并治疗，心内科随访并每月进行一次每月进行一次LVEF检测检测2019 St Gallen 共识：赫赛汀辅助方案Neoadjuvant Chemotherapy赫赛汀新辅助治疗：NOAH 研究设计HER2,human epidermal growth factor receptor 2

29、;LABC,locally advanced breast cancer;IHC,immunohistochemistry;FISH,fluorescence in situ hybridisation;H,Herceptin(8 mg/kg loading then 6 mg/kg);A,doxorubicin(60 mg/m2);T,paclitaxel(150 mg/m2);CMF,cyclophosphamide(600 mg/m2)/methotrexate(40 mg/m2)/5-fluorouracil(600 mg/m2)aHormone receptor-positive p

30、atients receive adjuvant tamoxifenGianni et al ASCO 2019,poster 532HER2-negative LABC(IHC 0/1+)ATq3w x 3Tq3w x 4CMFDays 1,8 q4w x 3Surgeryn=99Tq3w x 4CMFDays 1,8 q4w x 3SurgeryHER2-positive LABC(IHC 3+or FISH+)n=113n=115H+ATq3w x 3H+Tq3w x 4H q3w x 4+CMFDays 1,8 q4w x 3SurgeryH continued q3w x 7Radi

31、otherapyaATq3w x 3RadiotherapyaRadiotherapyaNOAH:临床缓解率ORR,%CR,%PR,%SD,%PD,%+H(n=115)80.960.020.90.94.3-H(n=113)73.451.322.15.36.265.725.240.410.110.1HER2 positiveHER2 negative(n=99)Gianni et al ASCO 2019,poster 532ORR,overall response rate;CR,complete response;PR,partial response;SD,stable disease;P

32、D,progressive disease NOAH：赫赛汀+化疗新辅助化疗可显著提高病理学缓解率 01020304050+H-HHER2 negative+H-HHER2 negativePatients(%)HER2 positiveHER2 positivepCRtpCR43%23%17%38%20%16%p=0.29p=0.002p=0.003p=0.43pCR,pathological complete response;tpCR,total pathological complete response in breast and nodesGianni et al ASCO 201

33、9,poster 532Superior pCR in Superior pCR in Herceptin Herceptin patientspatientsNOAH:tumour responseEFS:HER2-positive population1.000.750.500.250.0006121824303642Probability,EFSMonthsH+CTCTEvents3652HRa0.56pa0.006Patients115112Median follow-up is 3 yearsaUnadjusted for stratification variables:adjus

34、ted HR=0.55,p=0.0062HR,hazard ratio;CI,confidence interval;CT,chemotherapy95%CI0.36-0.85From SABCS 2019Overall survival:HER2-positive population06121824303642Probability,overall survivalMonthsEvents1722Patients115112HR0.65p0.18Median follow-up is 3 years95%CI0.34-1.23H+CTCT1.000.750.500.250.00From S

35、ABCS 2019EFS by subgroup analysis of patients with HER2-positive disease:with vs without trastuzumab0.00.51.01.52.0Total seriesNon inflammatoryInflammatoryER and/or PgR positiveER and PgR negativecN0cN 1pCRNon pCRFavoursHFavours no H22716661791483319468159Patients(n)HRMedian follow-up is 3 yearsFrom

36、 SABCS 2019EFS:HER2 positive(without trastuzumab)vs HER2 negative1.000.750.500.250.0006121824303642Probability,EFSMonthsCT,HER2 positiveCT,HER2 negativeEvents5233Patients11299Median follow-up is 3 yearsFrom SABCS 2019MDACC Trial designH qw x 12+P q3w x 4Appropriate endocrine therapy for patients wit

37、h ER+diseaseStage IIIIIA breast cancer;HER2 positiveP q3w x 4FEC q3w x 4H qw x 12+FEC q3w x 4Local therapyRandomisationFEC=fluorouracil,epirubicin,cyclophosphamideH=Herceptin;P=paclitaxelBuzdar A,et al.Clin Cancer Res 2019 13(1):228N=19N=23Cohort 1 Jun.2019 to Oct.2019Cohort 2 Feb.2019 to May.2019Pr

38、otocol AmendmentH qw x 12+P q3w x 4Appropriate endocrine therapy for patients with ER+diseaseStage IIIIIA breast cancer;HER2 positiveH qw x 12+FEC q3w x 4Local therapyN=22MDACC研究：2/3的患者获病理学缓解26.3%n=1965.2%n=2395%CI(4384%)p=0.016(n=42)pCR(%)P+FEC aloneH+(P FEC)Buzdar A,et al.Proc ASCO 2019赫赛汀新辅助治疗 MD

39、ACC研究：随访至今100%的无病生存率Buzdar A,et al.Proc ASCO 2019ASCO 2019,6月月 1日：我们是否可以治愈日：我们是否可以治愈HER2阳性乳腺癌呢？阳性乳腺癌呢？Edward Romond 目前的中位随访时间1年6.3个月.结论：结论：Buzdar新辅助化疗数据新辅助化疗数据提示赫赛汀治疗潜能提示赫赛汀治疗潜能无病生存率无病生存率1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 随访月份随访月份化疗组化疗组化疗化疗+赫赛汀组赫赛汀组HER2阴性的患者接受没有赫赛汀以外同样的化疗。表柔比星环磷酰胺 90/600 mg/m2

40、;多西紫杉醇,100 mg/m2 或75 mg/m2 如加用卡培他滨;赫赛汀,6 mg/kg;卡培他滨,1000 mg/m2 bid d1-14GeparQuattro 研究:新辅助化疗+赫赛汀 表柔比星表柔比星+环磷酰胺环磷酰胺 q3w x 4+赫赛汀赫赛汀q3w x 4手术手术赫赛汀赫赛汀 q3w 至第至第 52周周多西紫杉醇多西紫杉醇 q3w x 4+赫赛汀赫赛汀q3w x 4多西紫杉醇多西紫杉醇 q3w x 4+卡培他滨卡培他滨d1-14 q3w x 4+赫赛汀赫赛汀q3w x 4卡培他滨卡培他滨d1-14q3w x 4+赫赛汀赫赛汀q3w x 4多西紫杉醇多西紫杉醇 q3w x 4+赫赛汀赫赛汀q3w x 4Untch et al 2019Untch et al 2019pCR(%)45.5%20.6%2009 St Gallen experts panel discussion result谢谢！谢谢！