HER2阳性EBC的应对策略

1、整理课件,HER2阳性EBC的应对策略,整理课件,Adjuvant CMF,Risk of recurrence,Bonadonna et al. BMJ 2005; 330: 217,1976,The CMF programme,CMF vs observation,C, cyclophosphamide; M, methotrexate; F, 5-fluorouracil,First publication: Bonadonna et al. N Engl J Med 1976; 294: 405-410,Latest data,Risk of death,1976,整理课件,Adjuv

2、ant tamoxifen,36%,Risk of recurrence,Risk of death,First publication: Lancet 1983; 1: 257-261,Br J Cancer 1988; 57: 608-611,Latest data,1983,NATO trial,Tamoxifen vs observation,整理课件,Adjuvant anthracyclines,Risk of recurrence,First publication: Levine et al. J Clin Oncol 1998; 16: 2651-2658,Latest da

3、ta,Levine et al. J Clin Oncol 2005; 23: 5166-5170,1998,NCIC MA.5,CEF vs CMF,C, cyclophosphamide; E, epirubicin; F, fluorouracil; M, methotrexate,整理课件,Adjuvant taxanes,Risk of recurrence,Risk of death,1998,First publication: Henderson et al. Proc Am Soc Clin Oncol 1998; 17: 101a, abs 390A,CALGB 9344,

4、ACP vs AC,17%,A, doxorubicin; C, cyclophosphamide; P, paclitaxel,Latest data,Henderson et al. J Clin Oncol 2003; 21: 976-983,整理课件,Adjuvant aromatase inhibitors,Risk of recurrence,First publication: Baum et al. Breast Cancer Res Treat 2001; 69: 210, abs 8,2001,ATAC,Anastrozole vs tamoxifen,Howell et

5、al. Lancet 2005; 365: 60-62,Latest data,整理课件,Adjuvant Herceptin,36%,34%,Risk of recurrence,Risk of death,First presentation: Piccart-Gebhart et al. ASCO 2005,Smith et al. Lancet 2007; 369: 29-36,Latest data,3 further large studies have also demonstrated similar significant reductions in risk of rela

6、pse and risk of death,Romond et al. N Engl J Med 2005; 353: 1673-1684; Slamon et al. SABCS 2006; abs 52,2005,HERA,1-year Herceptin vs observation after chemotherapy,整理课件,HER2: role in breast cancer,Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and part of the HER family

7、of 4 growth factor receptors (HER1 to HER4)1 Overexpression of HER2 and / or amplification of the HER2 gene occurs in up to 30% of breast cancers1-3 HER2 positivity is associated with2-4 aggressive disease a high risk of relapse poor survival HER2 is the only member of the HER family acknowledged in

8、 guidelines for its prognostic and predictive value in breast cancer5 HER2 is an important therapeutic target,Slamon DJ, et al. Science 1989; 244: 707712 Slamon DJ, et al. Science 1987; 235: 177182 Penault-Llorca F, et al. J Clin Oncol (Meeting Abstracts) 2005; 23: 69s, abs 764 Press MF, et al. J Cl

9、in Oncol 1997; 15: 28942904 Goldhirsch A, et al. Ann Oncol 2006; 17: 17221776,整理课件,Inhibition of HER2-mediated signalling,Activation of antibody-dependent cellular cytotoxicity (ADCC),Herceptin is effective across all stages of disease by activating the immune system and suppressing HER2,Additional

10、mechanisms Prevents formation of truncated HER2 (p95) Inhibition of HER2-regulated angiogenesis,Slamon DJ, et al. N Engl J Med 2001; 344: 783-792 Marty M, et al. J Clin Oncol 2005; 23: 4265-4274 Baselga J. Oncology 2001; 61 (Suppl 2): 14-21 Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353: 16591672

11、 Romond EH, et al. N Engl J Med 2005; 353: 16731684 Slamon D, et al. Breast Cancer Res Treat 2005; 94 (Suppl 1): S5, abs 1 Slamon D, et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, 14-17 December 2006 Smith I, et al. Lancet 2007; 369: 29-36,整理课件,The fascinating history of He

12、rceptin,Phase I IND for rhuMAb HER2,Murine HER2 / neu gene cloned,Human HER2 gene cloned,muMAb 4D5,Association of HER2 with poor clinical outcome,Paclitaxel + H and H mono US approval,Paclitaxel + H and H mono EU approval,1st IA of HERA,1992,1985,1990,1981,1987,2000,1998,2005,2006,HERA recruitment o

13、pens,HERA 2-year follow-up,Adjuvant H approval,2008,HERA 4-year follow-up and 1-year H vs 2-year H IA,2011,HERA final analysis 1-year H vs 2-year H,HER2, human epidermal growth factor receptor 2; H, Herceptin; IA, interim analysis,整理课件,Adjuvant Chemotherapy,整理课件,HERA study design,Herceptin q3w x 1 y

14、ear,Observation,HER2-positive early breast cancer(IHC 3+ and / or FISH+)n=5102,Herceptin q3w x 2 years,Option to cross over to Herceptin (after IA 2005),Surgery + (neo)adjuvant chemotherapy + radiotherapy,IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation,整理课件,End points of the HERA

15、 trial,Primary end point DFS 1-year Herceptin vs observation 2-year Herceptin vs observation Secondary end points OS, RFS, distant DFS, safety 1-year Herceptin vs observation 2-year Herceptin vs observation compare DFS, OS, RFS, distant DFS and safety 1-year Herceptin vs 2-year Herceptin,DFS, diseas

16、e-free survival; OS, overall survival; RFS, relapse-free survival,整理课件,HERA 2008 interim analysis: 2-year vs 1-year Herceptin,Statistical assumptions HR 0.80 DFS 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 results,Final analysis

17、triggered by 725 events (2011),Trial continues as planned,No data release,HR, hazard ratio; IDMC, Independent Data Monitoring Committee,整理课件,HERA: IDMC recommendations October 2008,Do not release information on the 2-year Herceptin arm Continue the 1-year Herceptin vs 2-year Herceptin comparison Rel

18、ease updated information on 1-year Herceptin vs observation,No conclusions can be drawn regarding the efficacy of Herceptin therapy for 2 years vs 1 year,整理课件,HERA study design,HER2-positive early breast cancer(IHC 3+ and / or FISH+)n=5102,Surgery + (neo)adjuvant chemotherapy + radiotherapy,Hercepti

19、n q3w x 1 year,Observation,整理课件,HERA: DFS and OS over time 1 and 2 years follow-up,No. of deathsH 1 year vs observation,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,OS benefit,29 vs 37p=0.26,200511 year(0%),59 vs 90p=0.0115,Median follow-up (% follow-up time after selective crossover),200622 years(

20、4.1%),200511 year (0%),Median follow-up (% follow-up time after selective crossover),200622 years (4.3%),No. of DFS eventsH 1 year vs observation,127 vs 220p0.0001,218 vs 321p0.0001,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,DFS benefit,1Piccart-Gebhart et al 2005; 2Smith et al 2007,整理课件,DFS : 4-

21、year median follow-up,100,80,60,40,20,0,0,6,12,18,24,30,48,36,42,Months from randomisation,16981703,15641619,14401552,13631485,12971414,12401352,712854,11801280,9921020,No. at risk,Events 458369,4-yearDFS 72.278.6,HR 0.76,95% CI 0.66, 0.87,p value 0.0001,1-year Herceptin,Observation,6.4%,Patients (%

22、),整理课件,OS : 4-year median follow-up,0,6,12,18,24,30,48,36,42,Months from randomisation,16981703,16421660,16011640,15561615,15191577,14711524,828953,13981447,11751149,Events 213182,4-yearDFS 87.789.3,HR 0.85,95% CI 0.70, 1.04,p value 0.1087,1.6%,1-year Herceptin,Observation,100,80,60,40,20,0,Patients

23、 (%),No. at risk,整理课件,HERA: DFS and OS over time,No. of deathsH 1 year vs observation,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,OS benefit,29 vs 37p=0.26,200511 year(0%),59 vs 90p=0.0115,182 vs 213p=0.1087,Median follow-up (% follow-up time after selective crossover),200622 years(4.1%),20084 yea

24、rs(30.9%),200511 year (0%),Median follow-up (% follow-up time after selective crossover),200622 years (4.3%),20084 years (33.8%),No. of DFS eventsH 1 year vs observation,127 vs 220p0.0001,218 vs 321p0.0001,369 vs 458p0.0001,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,DFS benefit,1Piccart-Gebhart e

25、t al 2005; 2Smith et al 2007,4 year DFS： 78.6% vs. 72.2%,4年OS：89.3% vs.87.7%,整理课件,Crossover to Herceptin of 65% of the patients originally allocated to observation disrupted the randomised comparison between 1-year Herceptin and observation Question: To what extent might crossover have biased the IT

26、T analysis?,Specific question 1,整理课件,Flow chart of observation patients:by status on 16 May 2005,1698 patients originally randomised to observation,1354 patients alive and disease-free,16 May,2005,344 patients DFS event or lost to follow-up198 alive post DFS event,整理课件,Time to selective crossover by

27、 calendar date (n=885),0.6,0.5,0.4,0.3,0.2,0.0,16 May 2005,22 Aug 2005,28 Nov 2005,6 Mar 2006,12 Jun 2006,18 Sep 2006,25 Dec 2006,1354,1193,596,209,116,71,30,0.1,Switched to Herceptin,No. at riskObservation,Proportion,Randomisation to 1st dose Diagnosis to 1st dose Follow-up from 1st dose,Median tim

28、e (range), months 22.8 (1-52.7) 30.9 (9.1-58.3) 29.1 (0.8-34.5),整理课件,Baseline characteristics of observation patients alive and disease free on 16 May 2005,Compared to patients who did not selectively cross over to Herceptin, those who did were more likely to: be younger have received anthracyclines

29、 and anthracyclines plus taxanes be diagnosed with node-positive disease have hormone receptor-positive tumours,整理课件,885 of 1354 patients (65%) in the observation group who were alive and disease free on May 16 2005 crossed over and received Herceptin Questions: What was the course of disease in the

30、 subgroups of observation patients who did or did not cross over to active therapy? Is there any effect of the late introduction of Herceptin?,Specific question 2,整理课件,Landmark of 16 May 2005,The landmark analysis considers only patients who were alive and disease free on 16 May 2005,整理课件,0,Hercepti

31、n: Alive and disease free on 16 May 2005,6,12,18,24,30,36,42,48,1481,1480,1473,1447,1399,1351,1280,1020,854,100,80,60,40,20,0,No. at risk,Patients alive and disease free (%),DFS (landmark analysis): Herceptin vs observation,Observation: Alive and disease free on 16 May 2005,Months from randomisation

32、,1354,1353,1339,1316,1278,1239,1180,992,712,整理课件,DFS (landmark analysis): observation (alive, no DFS event), selective crossover and no crossover,100,80,60,40,20,0,0,Patients alive and disease free (%),6,12,18,24,30,36,42,48,No. at risk,整理课件,0,Months from randomisation,6,12,18,24,30,36,42,48,1354148

33、1,13541481,13501481,13441474,13321461,13161438,12701378,10651094,759910,100,80,60,40,20,0,OS (landmark analysis): Herceptin vs observation,No. at risk,Patients alive and disease free (%),Herceptin: Alive and disease free on 16 May 2005,Observation: Alive and disease free on 16 May 2005,整理课件,Observat

34、ion: Alive and disease free on 16 May 2005,0,Months from randomisation,6,12,18,24,30,36,42,48,100,80,60,40,20,0,No. at risk,Patients alive (%),OS (landmark analysis): crossover vs no-crossover,1354,1354,1350,1344,1332,1316,1270,1065,759,整理课件,Cardiac safety,Cardiac death Severe CHF (NYHA III and IV)

35、Symptomatic CHF (II, III and IV) Confirmed significant LVEF drop,1 (0.1) 0 (0.0) 3 (0.2) 13 (0.8),0 (0.0) 13 (0.8) 33 (2.0) 62 (3.7) 87 (5.2),No. patients (%),Observationa n=1719,1-year Herceptinn=1682,Herceptin discontinued due to cardiac problems,aPatients who crossed over are censored from the da

36、te of starting Herceptin treatment,CHF, congestive heart failure; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction,整理课件,Cardiac safety: observation group,Cardiac death Severe CHF (NYHA III and IV) Symptomatic CHF (II, III and IV) Confirmed significant LVEF drop,0 (0.0) 0 (0

37、.0) 1 (0.2) 5a (1.1),0 (0.0) 0 (0.0) 9 (1.0) 26 (2.9) 43 (4.9),Crossover n=885,Herceptin discontinued due to cardiac problems,aFor 3 of the patients, the LVEF drop occurred between 16 May 05 and the date of the patient decision and may have influenced the patient decision,No crossover after 16 May 0

38、5 n=469,整理课件,HERA 4-year follow-up data: summary (1),The updated analysis at 4 years was limited to 1-year Herceptin vs observation as recommended by IDMC Extensive selective crossover of observation patients to active therapy biased the ITT comparison Landmark analysis of observation patients who w

39、ere disease free on 16 May 2005 explored the effects of later introduction of Herceptin Lack of randomisation limits the interpretation of the landmark analysis different outcome due to drug effect or patient characteristics?,整理课件,HERA 4-year follow-up data: summary (2),In HERA, the DFS benefit asso

40、ciated with Herceptin is maintained at 4-year median follow-up 50% of patients in the observation arm crossed over to Herceptin treatment, therefore the OS benefit is no longer statistically significant Patients crossing over at a later date appear to benefit from 1 year of Herceptin,整理课件,HERA: conc

41、lusions and next steps,4-year follow-up data support the hypothesis that the risk of relapse in HER2-positive early breast cancer persists over time Prolonged exposure to the Herceptin antibody may improve efficacy This is being tested in the comparison of the 1-year and 2-year groups in the HERA st

42、udy,整理课件,aBased on small subgroups of patients with HER2-positive breast cancer; bDDFS; CTx, chemotherapy; AC, doxorubicin, cyclophosphamide; P, paclitaxel; T, docetaxel; Carbo, carboplatin; V, vinorelbine; CEF, cyclophosphamide, epirubicin, 5-fluorouracil,Additional studies demonstrate consistent D

43、FS benefit for Herceptin,3,4,5,4,Gianni et al 2008; Gianni et al 2009; Joensuu et al 2009; Slamon et al 2006; Perez et al 2007;Smith et al 2007; Spielmann et al 2007,3,3,Median follow-up, years,DFS benefit,B-31 / N9831 ACPH,HERA CTxH 1 year,FinHera VH / THCEFb,PACS-04a CTxH 1 year,BCIRG 006 ACTH,TCa

44、rboH,n=231,n=528,NOAH CTx / HH 1 year,3,0,1,2,Favours Herceptin,Favours no Herceptin,HR,整理课件,1-year Herceptin treatment consistently reduces the risk of death by one-third,0,1,2,B-31 / N9831 ACPH,3,HERA CTxH 1 year,4,OS benefit,BCIRG 006 ACTH,3,TCarboH,3,Favours Herceptin,Favours no Herceptin,HR,5,F

45、inHer VH / THCEF,n=231,Median follow-up, years,Gianni et al 2009; Joensuu et al 2009; Slamon et al 2006; Perez et al 2007; Smith et al 2007,整理课件,HER2-positive breast cancer: outstanding questions,Concurrent or sequential Herceptin therapy? Herceptin efficacy in lower-risk patients? Optimal treatment

46、 duration? Translational research? New combinations? ALTTO (Herceptin + lapatinib) BETH (Herceptin + Avastin),整理课件,Ld qd + Hc q3w for 52 weeks,Lb qd for 52 weeks,ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/ Herceptin,Surgery and completion of (neo)adjuvant anthracycli

47、ne-based chemotherapy,Concurrent taxanese for 12 weeks,aHerceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; bLapatinib 1500 mg; cHerceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; dLapatinib 1000 mg; ePaclitaxel 80 mg/m2 qw or docetaxel q3w,No taxane,Hc qw for 12 weeks,Ha q3w for 52 we

48、eks,6-week washout,Lb qd for 34 weeks,HER2-positive early breast cancer(n=8000),Ld qd + Hc q3w for 52 weeks,Lb qd for 52 weeks,Hc qw for 12 weeks,Ha q3w for 52 weeks,6-week washout,Lb qd for 34 weeks,整理课件,BETH: Phase III randomised trial comparing Herceptin-containing adjuvant regimens +/ Avastin,aA

49、ctual recruitment to date 300; bDocetaxel 75 mg/m2 q3w + carboplatin AUC 6 q3w or docetaxel 100 mg/m2 FEC; CTx, chemotherapy; q3w, three weekly,CTxb + Herceptin + Avastin,Resected node-positive or high-risk node-negative HER2-positive early breast cancer n3600 (maximum)a,Herceptin continued q3w unti

50、l 1 year total,Herceptin + Avastin continued q3w until 1 year total,Primary endpoint: DFSSecondary endpoints: OS; RFS; distant recurrence-free interval; safety; biomarker analysis,整理课件,St Gallen Treatment Guidelines2007: summary Recommendation: HER2 and Herceptin treatment,Patients with HER2-positiv

51、e disease at high risk of early recurrence gain substantial benefit from treatment with Herceptin Herceptin should be given either with or after CTa for intermediate- or high-risk patients with confirmed HER2 overexpression / amplification, irrespective of endocrine responsiveness,aHerceptin is lice

52、nsed in the EU and Switzerland for the adjuvant treatment of HER2-positive early breast cancer following chemotherapy,整理课件,根据左心室射血分数(LVEF)的 赫赛汀辅助治疗方案选择指定原则,LVEF 检查时间表 - 赫赛汀治疗前 - 治疗4-8个月期间 - 治疗12个月时 - 有临床需要时,对化疗方案选择方面无明显限制 赫赛汀不宜同蒽环类药物同时使用,LVEF 检查时间表 - 赫赛汀治疗前 - 每三个月一次 - 有临床需要时,化疗后使用赫赛汀单药序贯治疗 赫赛汀可联合不含蒽

53、环类的化疗药物,临床慎用,LVEF 50%,LVEF 40-50%,LVEF 40%,左室射血分数(LVEF) 基线值评估 首选：心超 亦可选用：MUGA扫描,准确的 HER2 评估,HER2 阳性,整理课件,赫赛汀辅助治疗心脏不良事件的建议,HER2 +患者从赫赛汀辅助治疗的获益远大于心脏不良事件的风险 赫赛汀辅助治疗相关心脏事件是可逆性， 发生后2-4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保证治疗中的心脏安全性 接受赫赛汀辅助治疗的患者： LVEF 40%大多数患者可以继续接受赫赛汀治疗，建议每3个月检测LVEF LVEF 40%建议停赫赛汀治疗，心内科

54、随访并每月进行一次LVEF检测,整理课件,2007 St Gallen 共识： 赫赛汀辅助方案,整理课件,Neoadjuvant Chemotherapy,整理课件,赫赛汀新辅助治疗 ：NOAH 研究设计,HER2, human epidermal growth factor receptor 2; LABC, locally advanced breast cancer; IHC, immunohistochemistry;FISH, fluorescence in situ hybridisation; H, Herceptin (8 mg/kg loading then 6 mg/kg)

55、; 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 patients receive adjuvant tamoxifen,Gianni et al ASCO 2007, poster 532,HER2-negative LABC(IHC 0/1+),ATq3w x 3,Tq3w x 4,CMFDays 1, 8

56、q4w x 3,Surgery,n=99,Tq3w x 4,CMFDays 1, 8 q4w x 3,Surgery,HER2-positive LABC(IHC 3+ or FISH+),n=113,n=115,H + ATq3w x 3,H + Tq3w x 4,H q3w x 4 + CMF Days 1, 8 q4w x 3,Surgery,H continued q3w x 7 Radiotherapya,ATq3w x 3,Radiotherapya,Radiotherapya,整理课件,NOAH: 临床缓解率,ORR, % CR, % PR, % SD, % PD, %,+ H(

57、n=115) 80.9 60.0 20.9 0.9 4.3,- H(n=113) 73.4 51.3 22.1 5.3 6.2,65.7 25.2 40.4 10.1 10.1,HER2 positive,HER2 negative (n=99),Gianni et al ASCO 2007, poster 532,ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease,整理课件,NOAH：赫赛汀+化疗新辅助化疗可显著

58、提高病理学缓解率,0,10,20,30,40,50,+ H,- H,HER2 negative,+ H,- H,HER2 negative,Patients(%),HER2 positive,HER2 positive,pCR,tpCR,43%,23%,17%,38%,20%,16%,p=0.29,p=0.002,p=0.003,p=0.43,pCR, pathological complete response; tpCR, total pathological complete response in breast and nodes,Gianni et al ASCO 2007, poster 532,Superior pCR in Herceptin patients,NOAH: tumour response,整理课件,EFS: HER2-positive population,1.00,0.75,0.50,0.25,0.00,0,6,12,18,24,30,36,42,Probability, EFS,Months,H + CTCT,Events 3652,HRa 0.56,pa 0.006,Patients 115112,Median follow-up is 3 years aUnadjusted for stratificatio