乳腺癌的化疗及靶向治疗课件

乳腺癌的化疗及靶向治疗 解放军总医院肿瘤中心,乳腺癌 每年新发病例：20万 ，发病率18.7/10万，死亡率5.5/10万 高发人群：4550岁， 城市农村 乳腺癌术后约80%的患者需辅助治疗。 约30%的患者会出现肿瘤复发和远出转移。其中90%的复发转移是在 5年内出现。,乳腺癌,手术,放疗,化疗,内分泌,靶向治疗,免疫及中药,术后辅助化疗,晚期或复发转移后化疗,乳腺癌化疗药物的进展,非蒽环类单药 PR，TTP较短（3-6月) 非蒽环类联合化疗 CMF, CMFVP 缓解率明显提高（CR），TTP延长(8-10月) 与非蒽环类单药比较，总生存无明显改善 蒽环类单药(阿霉素、表阿霉素) 疗效与非蒽环类联合化疗相似 蒽环类联合化疗 联合方案: AC, FAC, AVCMF, FEC, CEF ORR、CR提高，TTP（8-12月） meta-analysis证实：边缘性生存优势 紫杉类（紫杉醇/多西紫杉醇） 紫杉醇疗效与阿霉素相似 多西紫杉醇疗效优于阿霉素和非蒽环类联合化疗 紫杉类/蒽环类联合 生物反应调节剂 (Herceptin) 与化疗策略结合,1980s,1960s,1970s,1990s,2000s,1976,1990,1998,1999,1997,2000,2005,2002,1995,1996,乳腺癌辅助化疗进展,Bonadonna et al1. 进行了第一个比较CMF方案与最佳支持治疗辅助治疗淋巴结阳性乳腺癌的随机临床试验 与对照相比，CMF辅助化疗使得疾病复发风险下降了23.5，疾病死亡风险下降了 15%2,G Bonadonna et al. NEJM 1976, updated: NEJM 1995,1976,1998,1999,1997,2000,2005,2002,1995,1996,乳腺癌辅助化疗进展,NSABP B15 试验比较了AC 方案4个周期与CMF方案6个周期辅助治疗淋巴结阳性乳腺癌的疗效和安全性 无病生存率 (DFS): 43% vs 42% 总生存 (OS): 56% vs 56% 由于较短的治疗周期及方便性，在美国AC 成为辅助化疗的首选方案,Fisher et al. J Clin Oncol. 1990;8:1483-1496.,1990,含蒽环类方案 VS CMF,对于高危病人（N4）ACCMF6,1976,1990,1999,1997,2000,2005,2002,1995,1996,乳腺癌辅助化疗进展,MA.5 试验比较了CMF方案与CEF-120方案6个周期辅助治疗淋巴结阳性乳腺癌的疗效和安全性 与CMF相比，CEF辅助化疗使得疾病复发风险下降了29，疾病死亡风险下降了 19%,1998,第一代随机临床试验: 比较紫杉类/蒽环类与非紫杉类/蒽环类的疗效 序贯治疗 联合化疗 CALGB 9344 ：AC vs AC-T 复发危险减少17，死亡危险减少18%。 NSABP B-28： AC vs AC-T： 减少无病生存事件相对危险17% ECTO: ATCMF vs ACMF: 明显改善了患者的无进展生存，降低34的复发风险 BCIRG 001 : TAC vs FAC DFS: 相对降低28%复发风险OS: 相对降低30%死亡风险 NSABP B27 ：ACx4 vs ACx4-Tx4: 病理完全缓解率：12.8% 、26.1% PACS 01: FEC vs FEC-T DFS: 相对降低17%复发风险OS: 相对降低23%死亡风险,1976,1990,1999,1997,2000,2005,2003,1995,1996,乳腺癌辅助化疗进展,1998,紫杉类乳腺癌辅助化疗第一代随机临床试验：总结,(AC-P),(AC-P),(AP CMF),(TAC),(AC-T),CALGB 9344,NSABP B 28,DFS (复发风险/年),-10%,-20%,-30%,-40%,ECTO,-17%,-17%,-34%,BCIRG 001,-28%,(FEC T),PACS 01,-17%,NSABP B 27,-14%,ECOG 2197,AT,P=泰素 T=多西他赛,阳性试验,阴性试验,(FEC P),GEICAM 9906,-37%,US Oncology: Are Anthracyclines Essential?,Jones, SABCS 2005,紫杉类乳腺癌辅助化疗,第二代随机临床试验: 确立最佳的紫杉类给药方案和比较两个方案中紫杉类的疗效 序贯治疗/联合化疗 剂量密度/剂量强度 紫杉醇(泰素) vs. 多西紫杉醇(泰索帝) 紫杉类联合Herceptin的效益,Ax4Tx4Cx4 3周续贯 36周,Ax4Tx4Cx4 2周续贯 24周,ACx4Tx4 3周联合 24周,ACx4Tx4 2周联合16周,CALGB 9741方案ACX4Tx4 每2周,剂量密集方案（Q2W）可以显著降低复发风险26%（p=0.01）；4年无病生存率为82%，Q3W方案无病生存率为75% 剂量密集方案降低死亡风险31%（p=0.013）；3年OS为92%，Q3W方案为90%,Dose-Dense v Conventional Chemotherapy,Citron M, et al: JCO 2003,Node-Positive (n=2005),DFS,OS,CALGB 9741,ECOG 1199 研究设计,阿霉素 60mg/m2,泰素,多西他赛,175 mg/m2 (P3),环磷酰胺 600mg/m2,80 mg/m2 (P1),100 mg/m2 (D3),35 mg/m2 (D1),JA. Sparano et al., 2005 SABCS; Abs 48,E1199：无病生存,4年无病生存比例（）,1.0,0.0,0.2,0.4,0.6,0.8,0,6,12,18,24,30,36,42,48,60,54,66,泰素三周：80.6,泰素每周：83.5,多西他赛三周：83.1,多西他赛每周：80.5,无病生存比例,周,E1199：总生存曲线,4年总生存比例（）,1.0,0.2,0.4,0.6,0.8,0,6,12,18,24,30,36,42,48,60,54,66,0.0,泰素三周：88.8,多西他赛三周：89.3,泰素每周：91.7,多西他赛每周：88.9,总生存比例,周,紫杉类序贯治疗常见G34毒性反应(5%),BCIRG 001 “TAC (DAC) vs FAC”,Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2,5-FU 500 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2,R,Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14,Every 3 weeks x 6 cycles,NEJM,Primary Endpoint: Disease-Free Survival,Overall Survival (ITT),1.0,0.8,0.6,0.4,0.2,0.0,0,6,12,18,24,30,36,42,48,54,60,66,FAC,TAC (DAC),Cumulative Probability,87%,81%,N Events HR P-value Stratified Log-Rank TAC 745 91 0.70 .0080 FAC 746 130,Survival Time (months),NEJM,Neutropenic Fever With DAC = 25% without G-CSF,FEC vs FEC Paclitaxel,FE90C x 6 q 3 weeks,FE90C x 4 q 3 weeks then paclitaxel weekly x 8,Node positive and high risk node negative,Premenopausal 55% ER+ 80%,N=1248,Martin et al, SABCS 2005,1976,1990,1999,1997,2000,2002,1995,1996,乳腺癌辅助化疗进展,赫赛汀辅助治疗临床观察,NSABP B-31：AC-T vs AC-TH NCCTG N9831:AC-T vs AC-TH vs AC-T-H HERA: 化疗后：H 1年vs 2年vs 观察 BCIRG 006:AC-T vs AC-HT vs TCH,1998,2005,NSABP B-31,NCCTG N9831,Arm 1,Arm 2,Arm A,Arm B,Arm C,AC q 3 wk * 4,= paclitaxel q 3 wk * 4,= paclitaxel q 1 wk * 12,= trastuzumab q 1 w,HERA (Randomization after chemotherapy),Arm A No Herceptin,Arm B,Arm C,(1 yr),(2 yr),= trastuzumab q 3 w,Romond, E. H. et al. N Engl J Med 2005;353:1673-1684,Kaplan-Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B),DISEASE-FREE SURVIVAL,% alive and disease free,4 x AC 60/600 mg/m2,4 x Docetaxel 100 mg/m2,6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6,1 Year Trastuzumab,N=3,222,1 Year Trastuzumab,ACT,ACTH,TCH,Her 2+ (Central FISH) N+ or high risk N- (30%),4 x AC 60/600 mg/m2,4 x Docetaxel 100 mg/m2,Slamon D., SABCS 2006,BCIRG 006 SABCS 2006 F/U 36 months,Stratified by Nodes and Hormonal Receptor Status,Disease Free Survival - 2nd Interim Analysis,Absolute DFS benefits (from years 2 to 4): ACTH vs ACT: 6% TCH vs ACT: 5%,% Disease Free,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,Patients,Events,1073,192,AC-T,1074,128,AC-TH,1075,142,TCH,81%,87%,86%,77%,83%,82%,87%,93%,92%,HR (AC-TH vs AC-T) = 0.61 0.48;0.76 P0.0001,HR (TCH vs AC-T) = 0.67 0.54;0.83 P=0.0003,Year from randomization,Overall Survival 2nd Interim Analysis,HR (AC-TH vs AC-T) = 0.59 0.42;0.85 P=0.004,HR (TCH vs AC-T) = 0.66 0.47;0.93 P=0.017,% Survival,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,Patients,Events,1073,80,AC-T,1074,49,AC-TH,1075,56,TCH,97%,99%,98%,93%,97%,95%,92%,91%,86%,Year from randomization,Cardiac Deaths and CHF as per Independent Review Panel,first interim analysis,P = 0.0015,倾向 非赫赛汀治疗,0,1,2,HERA DFS,1 年,NSABP B-31/NCCTG N9831综合分析 DFS,2年,HERA OS,1年,北美临床综合分析 OS,2年,中位随访时间,倾向 赫赛汀治疗,HR,BCIRG 006 ACDH DFS,BCIRG 006 DCarboH DFS,2年,2年,赫赛汀辅助治疗疗效汇总,So Is Adjuvant Herceptin Needed For All Breast Cancer Patients? Speculation ! Ravdin,60 Year Old Women. ER +, Her2 +, average comorbidity. Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w. Her2 FISH +. Additional RR conferred by Her2 1.5.,Risk of developing CHF 5%, 2/3 have symptoms resolve in 6 months. Cardiac status at 10 years?,440mg 冻干粉针剂 20ml 无菌注射用水,赫赛汀用法用量,所需溶液的体积 = 体重（Kg）剂量（4mg/Kg负荷量或2mg/Kg维持量） 21（mg/ml，配置好溶液的浓度）,Herceptin 使用方法,HER2 阳性(IHC 3+ or FISH + )，淋巴结阳性的乳腺癌病人都需考虑含赫赛汀的辅助治疗方案 . HER2阳性,淋巴结阴性，肿瘤 =1cm的乳腺癌病人赫赛汀可以在AC序贯紫杉醇的辅助治疗方案中与紫杉醇联合使用或在辅助化疗完成后序贯使用 考虑到心脏不良反应事件，不建议赫赛汀辅助治疗时与AC方案联用 赫赛汀辅助治疗的疗程为一年，建议定期进行心功能检查 赫赛汀辅助治疗可以选用每周治疗或三周治疗方案,乳腺癌辅助治疗的进展,疾病相关复发风险降低百分比,0,10,20,30,40,17%,46%,31%,CEF vs CMF Levine 2005,AC T vs AC Henderson 2003,Piccart 2005,DAC vs FAC Martin 2005,28%,Romond 2005,50,52%,化疗+赫赛汀 vs 化疗,化疗+赫赛汀 vs 化疗,23.5%,CMF vs 不化疗Bonadonna1995,浸润性乳腺癌 常用的术后辅助化疗方案,低危的腋淋巴结阴性： CMF6 (环磷酰胺/氨甲喋呤/氟尿嘧啶) AC 46 (多柔比星/环磷酰胺) 或EC 46 (表柔比星/环磷酰胺) 有高危复发因素的腋淋巴结阴性： CAF6 (环磷酰胺/多柔比星/氟尿嘧啶) 或CEF6 (环磷酰胺/表柔比星/氟尿嘧啶),腋淋巴结阳性： AC 4 T4 (AC序贯紫杉醇) FEC 3 T 3 (FEC序贯多西他赛) TAC 6 (多西他赛/多柔比星/环磷酰胺) 密集化疗(每两周方案，同时非格司亭支持) dd AC4 dd T4，每两周方案 ATC (多柔比星序贯紫杉醇序贯环磷酰胺)，每两周方案,HER-2过表达的患者，考虑采用含曲妥珠单抗的辅助化疗方案： ACT曲妥珠单抗 (多柔比星/环磷酰胺序贯紫杉醇曲妥珠单抗),复发或转移性乳腺癌的化疗 治疗目标：改善生活质量、延长生存,复发转移性乳腺癌的化疗原则, 辅助治疗仅用内分泌治疗而未用化疗的患者可以选择 CMF 或 CAF 方案 辅助治疗未用过蒽环类和紫杉类化疗的患者首选AT方案（蒽环类联合紫杉类），如CMF辅助治疗失败的患者；部分辅助治疗用过蒽环类和/或紫杉类化疗，但临床未判定耐药和治疗失败的患者也可使用AT方案 蒽环类辅助治疗失败的患者，可以选择的方案有： XT（卡培他滨 联合 多西他赛）和 GT（吉西他滨 联合 紫杉醇）方案 紫杉类治疗失败的患者，目前尚无标准方案推荐，可以考虑的药物有： 卡培他滨、长春瑞滨、吉西他滨和铂类，采取单药或联合化疗 曲妥珠单抗+紫杉醇卡铂 曲妥珠单抗多西他赛卡铂 紫杉醇+贝伐单抗,晚期乳腺癌治疗的进展,分层: DFI 24 mos. 3 metastatic sites Adjuvant chemotherapy yes vs. no ER+ vs. ER- vs. ER unknown,RANDOMI ZE,紫杉醇周疗+ Bevacizumab(贝伐单抗),紫杉醇周疗,E2100研究设计,28-day cycle: 紫杉醇90 mg/m2 D1, 8 and 15 Bevacizumab 10 mg/kg D1 and 15,E2100: 缓解率,316,236,330,250,34.3%,16.4%,28.2%,14.2%,所有患者,可测量疾病,0,10,20,30,40,紫杉醇周疗,Overall Response Rate,紫杉醇周疗 + Bev,E2100: 无进展生存,HR = 0.498 (0.401-0.618) Log Rank Test p0.001,Months,PFS Proportion,E2100:总生存,Months,OS Proportion,紫杉醇周疗+ Bev.,紫杉醇周疗,HR = 0.674 (0.495-0.917) Log Rank Test p=0.01,结论,将 bevacizumab (贝伐单抗)加入到紫杉醇周疗中治疗MBC 明显延长了无进展生存 提高了客观缓解率 需要更长的随访以评估对总生存的影响 需要进一步研究以识别最可能从VEGF靶向治疗中获益的患者,Lapatinib,A first dual-tyrosine kinase inhibitor, small molecule, oral agent (BA56%). Blocks signaling through ErbB-1 and ErbB-2 homodimers and heterodimers intracellularly Potentially blocks multiple ErbB signaling pathways more effectively than single-target inhibitors,1+1,2+2,1+2,Lapatinib,Downstream signaling cascade,Lapatinib Monotherapy in Previously Treated Metastatic Breast Cancer,EGF20002 Open-label phase II trial Lapatinib 1500 mg/day p.o. until tumor progression In 2nd or later line MBC patients who failed trastuzumab-based therapies ErbB2 IHC 3+ or FISH+,Efficacy (N=78) ORR*: 8% SD*: 14% 16 wk PFS*: 22%,*ORR = overall response rate *SD = stable disease *PFS = progression free survival,EGF100151 Study Design,Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Measurable disease by RECIST LVEF institution LLN,Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk,Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk,Patients on treatment until progression or unacceptable toxicity, then followed for survival,Stratification: Disease sites Stage of disease,*Trastuzumab must have been administered for metastatic disease,Target N=528,RANDOMI ZAT ION,Time to Progession as Assessed by IRC,0.2,0.4,0.6,0.8,0.0,1.0,0,Cumulative Progression-Free,10,20,30,40,50,60,Time (weeks),70,Response Rate ITT Population,14% (9 - 21),22% (16 - 29),Overall response rate (95%CI),P-value (Fishers exact, 2-sided),17%