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1、乳腺癌分子靶向药物治疗进展,张清媛 哈尔滨医科大学附属肿瘤医院,Chemotherapy,Endocrine therapy,Targeted therapies,Treatment of BC,HIGHLIGHTS IN BREAST CANCER,DISEASE BIOLOGY,针对HER2受体的靶向药物 针对表皮生长因子受体(EGFR)的靶向治疗 针对肿瘤血管生成的分子靶向药物 其他信号通路抑制剂mTOR，Ras， MEK等,乳腺癌分子靶向药物治疗,HER2在约20% 30%的乳腺癌组织中过度表达,Slamon DJ et al. Science 1987;235:17782,HER2阳
2、性与内分泌治疗及部分化疗耐药密切相关，是重要的预后指标 HER2成为乳腺癌治疗的理想靶点，是预测赫赛汀疗效的重要指标,赫赛汀(曲妥珠单抗): 人源化抗HER2单克隆抗体,高度亲和性 (Kd=0.1nM) 和特异性 95% 人源化, 5% 鼠抗，显著降低免疫原性(HAMA),全球第一种治疗实体瘤的单克隆抗体,Inhibition of HER2-mediated signalling,Activation of ADCC,赫赛汀的作用机制,Additional mechanisms Prevents formation of truncated HER2 (p95) Inhibition of
3、HER2-regulated angiogenesis,ADCC, antibody-dependent cellular cytotoxicity,赫赛汀已成为HER2阳性乳腺癌的基础治疗,1st line,HO648g M77001 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GBG-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDAC
4、C GeparQuattro Numerous Phase II studies,Neo,EBC,HER2, human epidermal growth factor receptor 2 EBC, early breast cancer; MBC, metastatic breast cancer,13,000 患者入组的赫赛汀四大辅助临床研究,Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006,NCCTG N9831 (USA),HERA (ex-USA),BCIRG 006 (global),NSABP B-3
5、1 (USA),IHC / FISH (n=5,090),Observation,1 year,2 years,IHC / FISH (n=3,505),1 year,1 year,FISH (n=3,222),1 year,1 year,IHC / FISH (n=2,030),1 year,Doxorubicin + cyclophosphamide,IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy,赫赛汀可减少三分之一的死亡风险,0,1,2,B-31 / N9831 A
6、CPH,3,HERA CTxH 1 year,2,Median follow-up, years,Overall survival benefit,BCIRG 006 ACDH,3,BCIRG 006 DCarboH,3,Favours Herceptin,Favours no Herceptin,HR,Slamon et al 2006 Perez et al 2007; Smith et al 2007,H, Herceptin; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplati
7、n HR, hazard ratio,Size of square represents sample size; horizontal bars indicate 95% confidence intervals,无论肿瘤大小，赫赛汀均显示DFS获益,Slamon et al 2006 Perez et al 2007; Smith et al 2007,2-5 cm,BCIRG 006,2-5 cm,5 cm,0.0,0.5,2.5,1.0,1.5,2.0,0-2 cm,N9831 / B-31,0-2 cm,5 cm,ACDH,2 cm,DCarboH,2 cm,2 cm,2 cm,Fa
8、vours Herceptin,Favours no Herceptin,HR,HERA,DFS, disease-free survival,无论淋巴结情况，赫赛汀均显示DFS获益,N, node,1-3+ nodes,Favours Herceptin,Favours no Herceptin,0.0,0.5,2.5,1.0,1.5,2.0,1-3+ nodes,4+ nodes,Not assessed,N9831 / B-31,N-,4-9+ nodes,10+ nodes,DCarboH,N-,N+,N+,BCIRG 006,N-,ACDH,N-,HERA,HR,Slamon et
9、al 2006 Perez et al 2007; Smith et al 2007,无论年龄大小，赫赛汀均显示DFS获益,35-49 years,0.0,0.5,2.5,1.0,1.5,2.0,HERA,35 years,50-59 years,60 years,N9831 / B-31,40 years,60 years,40-49 years,50-59 years,Favours Herceptin,Favours no Herceptin,HR,Perez et al 2007; Smith et al 2007,赫赛汀的新辅助治疗研究进展,1st line,HO648g M7700
10、1 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GBG-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDACC GeparQuattro Numerous Phase II studies,Neo,EBC,NOAH study: neoadjuvant Herceptin for LABC,aHormone receptor-positiv
11、e patients receive adjuvant tamoxifen AP, doxorubicin 60 mg/m2, paclitaxel 150 mg/m2; H, Herceptin 8 mg/kg loading then 6 mg/kg P, paclitaxel 175 mg/m2; CMF, cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2 LABC, locally advanced breast cancer; q3w, every 3 weeks; q4w, eve
12、ry 4 weeks,HER2-positive LABC (IHC 3+ and/or FISH+),n=113,H + AP q3w x 3,H + P q3w x 4,H q3w x 4 + CMF q4w x 3,Surgery followed by radiotherapya,H continued q3w to Week 52,n=115,P q3w x 4,CMF q4w x 3,Surgery followed by radiotherapya,AP q3w x 3,AP q3w x 3,P q3w x 4,CMF q4w x 3,Surgery followed by ra
13、diotherapya,n=99,HER2-negative LABC (IHC 0/1+),p=0.002,p=0.004,pCR (%),Baselga et al 2007; Gianni et al 2007,HER2 positive (n=228),HER2 positive (n=62),NOAH研究中赫赛汀新辅助显著提高了pCR率,Without Herceptin With Herceptin,90,80,70,60,50,40,30,20,10,0,HER2 negative (n=99),HER2 negative (n=14),23,43,17,19,55,29,Tot
14、al population,IBC population,pCR, pathological complete response in the breast IBC, inflammatory breast cancer,新辅助化疗中加入赫赛汀明显提高疗效(16个相关研究, 1,226例患者入组),aX was given either concurrently or sequentially with D + H EC, epirubicin, cyclophosphamide; FEC, 5-fluorouracil, epirubicin, cyclophosphamide My, My
15、ocet; X, Xeloda,0,10,20,30,40,50,60,70,80,90,100,pCR (%),赫赛汀已成为HER2阳性乳腺癌的基础治疗,1st line,HO648g M77001 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GBG-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,HER2, human epidermal growth factor receptor 2 EBC, early breast cancer; M
16、BC, metastatic breast cancer,EBC,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDACC GeparQuattro Numerous Phase II studies,Neo,一线赫赛汀治疗显著延长患者的生存时间,Median survival (months),IHC, immunohistochemistry; P, paclitaxel H, Herceptin; D, docetaxel; Carbo, carboplatin,H0648g (IHC 3+),M77001,BCIRG 007,U
17、S Oncology (IHC 3+),Smith et al 2001; Marty et al 2005 Robert et al 2006; Pegram et al 2007,TAnDEM-赫赛汀联合阿那曲唑治疗HER-2 ( + ）激素敏感性转移性乳腺癌,临床研究结果（2006年圣安东尼奥）,2007年3月欧洲推荐 赫赛汀联合芳香化酶抑制剂治疗HER2与激素受体阳性转移性乳癌,疾病进展后如何合理选择赫赛汀个体化治疗方案,1st line,HO648g M77001 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GB
18、G-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,EBC,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDACC GeparQuattro Numerous Phase II studies,Neo,Herceptin improves OS if continued beyond progression,OS (months),Continued Herceptin Discontinued Herceptin,Extra et al 2006 Jack
19、isch et al 2007; Menard et al 2008,p0.0001,p0.0001,p=0.0014,(n=118),(n=154),(n=81),(n=112),(n=70),(n=107),Prospective Hermine study,German observational study,Demetra study,OS, overall survival,赫赛汀在多线治疗中的作用,赫赛汀治疗的最大获益是持续治疗 临床证据提示含赫赛汀方案治疗中进展并不等于赫赛汀耐药,调整化疗药并继续赫赛汀治疗仍可获益. 赫赛汀通过持续抑制HER2 ,在多线治疗中病人仍可获益,Sla
20、mon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008,赫赛汀辅助治疗的心脏安全性,aData not comparable due to different assessment criteria CHF, congestive heart failure; cum, cumulative incidence LVEF, left ventricular ejection fraction; NR, not reported,3.0 NR NR 18.0 8.6,Asymptomatic LVEF decline
21、, %a,H 1 year ACPH ACPH ACDH DCarboH,Arm,HERA NSABP B-31 NCCTG N9831 BCIRG 006,1,678 947 570 1,068 1,056,n,Severe CHF, %,0.6 3.8cum (5 yr) 3.3cum (3 yr) 1.9 0.4,Cardiac death, n,0 0 0 0 0,Age 50 (5.1%-5.4%) Use of hypertensive medications (6.8%) Baseline LVEF 50-54 (12.9%),Rastogi et al. Abstract LB
22、A513 ASCO 2007,考虑到心脏不良反应事件，临床上不建议Trastuzumab与蒽环类药物联合。 Trastuzumab可以在AC方案后与紫杉醇联合使用或者在化疗完成后序贯使用。 目前Trastuzumab治疗疗程为1年，建议每三个月一次进行心功检查。,心功能监测,LVEF低于50%,恢复至50%以上,不恢复、或继续恶化,终止Herceptin治疗,继续用药,暂停Herceptin治疗，观察或对症处理,赫赛汀临床应用,2008年NCCN复发或IV期乳腺癌指南 HR阴性，HER2阳性具有内脏危象复发或IV期乳腺癌 曲妥珠单抗化疗 赫赛汀联合辅助化疗方案 AC TH AC DH TCH
23、化疗H DH FEC,用法： 每周方案 首剂4mg/kg，维持2mg/kg 三周方案 首剂8mg/kg，维持6mg/kg,帕妥珠单抗Pertuzumab(2C4): anti HER2 agent,以HER-2为靶位的人源化单克隆抗体 与HER-2 受体胞外结构域区结合，抑制二聚体的形成 抑制HER2 与 EGFR 和 HER3形成二聚体。,Herceptin + pertuzumab provides clinical benefit to patients progressing on Herceptin,Gelmon et al 2008,Response CR PR ORR SD fo
24、r 6 months ( Cycle 8) CBR PD Median PFS,n (%) n=66 5 (7.6) 11 (16.7) 16 (24.2) 17 (25.8) 33 (50.0) 33 (50.0) 24 weeks,Herceptin + pertuzumab is a well-tolerated combination,Patients (%),Adverse events, all grades Adverse events, grades 3/4,Gelmon et al 2008,针对HER2受体的靶向药物 针对表皮生长因子受体(EGFR)的靶向治疗 针对肿瘤血管
25、生成的分子靶向药物 其他信号通路抑制剂mTOR，Ras， MEK等,针对EGFR的靶向治疗,小分子酪氨酸激酶抑制剂 (SMTKIs) EGFR单克隆抗体(MAbs) 多靶点抗肿瘤抑制剂,酪氨酸激酶抑制剂,拉帕替尼（Lapatinib，Tykerb） 吉非替尼（ZD1839，Iressa，Gefitinib，易瑞沙） 埃罗替尼（Tarceva，erlotinib）,Lapatinib (Tykerb),口服的TKI 双重抑制剂:EGFR 和HER-2,Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,EGF100151: Lapati
26、nib + Capecitabine in Advanced Breast Cancer,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd),Longer time to progression 36.9 vs 19.7 wks (P = .00016) Longer progression-free survival 36.9 vs 17.9 wks (P = .000045) Fewer progressions or deaths 38% vs 48% Response (independent re
27、view) Overall: 22.5% vs 14.3% (P = .113),Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,2007.3 FDA批准 拉帕替尼联合卡培他滨治疗HER2过度表达且经蒽环类、紫杉类药物和曲妥珠单抗治疗后复发的晚期或者转移性乳腺癌,39 patients (38 patients progression after radiothrapy) New/progressive measurable ( 1 cm) brain metastases Treatment: Lapatinib 750 mg
28、po BID Result 2 patients PR 158d and 347d 5 patients SD 16 weeks Median TTP 3.2 months MST 6.57 months 1 patient had response, but did not meet RECIST Lapatinib成为Trastuzumab耐药或脑转移患者新选择,Lapatinib for Brain Metastases in Her2+ Cancer Lin et al. ASCO 2006; NCI-CTEP 6969 trial,Lapatinib+Trastuzumab for
29、Trastuzumab progressing on Her2+ Cancer ASCO 2008,Progression-Free Survival,Overall Survival in ITT Population,0,200,Days,Gefitinib-表皮生长因子受体酪氨酸激酶抑制剂,1,30,60,90,120,150,400,600,800,1000,1200,1400,Tumour volume (mm3),Massarweh et al. Breast Cancer Res Treat 2002,Fulvestrant,Oestradiol,Fulvestrant plus
30、 gefitinib delays resistance in MCF-7 / HER2 tumours in vivo,Phase II Trial of Gefitinib in Advanced Breast Cancer,Partial response Stable disease Clinical benefit Progressive disease,1 5 6 (66%) 3,ER-positive (n=9),ER-negative (n=18),1 1 2 (11%) 16,Robertson et al. ASCO Proc. 2003,Acquired resistan
31、ce to TAM (n=27) or ER-negative tumours (n=27) Gefitinib LD 1000 mg (D1) Daily dose 500 mg/day until disease progression or unacceptable toxicity,Erlotinib-小分子EGFR 酪氨酸激酶抑制剂,previous therapy with either an anthracycline or a taxane for MBC,Erlotinib （150 mg orally daily ） + gemcitabine （ 1000 mg/m2 ,
32、 Days 1、8, 3-week cycles ）,A partial response (PR) rate of 17% has been reported (ASCO 2005),N0234 ：Erlotinib + Gemcitabine,N0234 ：Erlotinib + Gemcitabine,Result,TN*=ER ( - ) /PR( - ) /HER-2 ( - )三阴,ASCO 2007,西妥昔单抗(Cetuximab， erbitux， C225，爱必妥),Cetuximab是针对HER-1的特异性单克隆抗体 动物试验显示，Cetuximab可有效抑制乳腺癌细胞增殖
33、和生长，现有不少研究机构开始应用Cetuximab单药或与化疗药物联合治疗EGFR 阳性乳腺癌。,泰欣生是一个针对EGFR的单抗药物，通过与EGFR胞外区3A表位结合，竞争性抑制配体与EGFR的结合，使受体失去活性： IgG1型单克隆抗体，分子量为150KD 95人源化 激发ADCC和CDC效应抑制肿瘤细胞 比内源性配体亲合力更高（Kd=10-9）,泰欣生（尼妥珠单抗, Nimotuzumab）,古巴：泰欣生联合新辅助化疗治疗乳腺癌,研究终点 评估尼妥珠单抗联合化疗药物治疗局部晚期乳腺癌患者新辅助化疗的安全性、药代动力学及疗效。,期初治乳腺癌患者,泰欣生（50/100/200/400mg，qw
34、） 阿霉素（60mg/m2 ，q3w ） 环磷酰胺（600mg/m2 ，q3w ）,J. Soriano, N. Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116,1 7 8 15 22 28 29 36 43 49 50 57 64 70,RANDOMI ZAT I ON,S U R G E R Y,Nimotuzumab,AC,用药方案,J. Soriano, N. Batista, et al. European Journal of Cancer Supplements, Vol 5
35、 No 4, Page 116,疾病控制情况,疾病控制情况 共有13例患者入组，12例患者可评估：9例PR，3例SD。,J. Soriano, N. Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116,安全性： 在50、100、200和400mg中，未见剂量限制性毒性 临床未见心脏毒性；联合治疗安全性高，患者耐受性良好 常见不良反应为：皮疹、皮肤反应、恶心、呕吐；红斑,丘疹及色素沉着较常见，通常发生在面部及上肢上部，能自行缓解 初步结论： 泰欣生治疗乳腺癌有效，联合治疗在50，100，200和
36、400mg 剂量下是安全的，有很好的耐受性,结 论,J. Soriano, N. Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116,苏尼替尼（Sunitinib）-小分子多靶点酪氨酸激酶抑制剂,Selective inhibitor of: PDGFR VEGFR2 (KDR) KIT FLT3,2006年1 月美国FDA 批准上市, 用于治疗晚期肾细胞癌和胃肠道间质瘤。,Sunitinib in Breast Cancer Patients multicentric phase II st
37、udy with 64 patients,*One PR not yet confirmed.,patients had received 3.5 different chemotherapies （anthracycline or taxane） 85% of patients had received adjuvant chemotherapy,sunitinib 50 mg/d,多激酶抑制剂：丝氨酸/苏氨酸：C-Raf (Raf-1)和B-Raf1 酪氨酸激酶受体：VEGFR-2、 VEGFR-3、 PDGFR-b、 FLT-3和 c-KIT,Wilhelm S et al. Clin
38、Cancer Res. 2004;64:7099-7109.,索拉非尼( sorafenib)：口服信号转导抑制剂,在Raf激酶水平和受体酪氨酸激酶VEGFR-2和PDGFR-阻断Raf/MEK/ERK途径,抗肿瘤血管生成及肿瘤细胞增殖,Sofitinib phase II in MBC,针对HER2受体的靶向药物 针对表皮生长因子受体(EGFR)的靶向治疗 针对肿瘤血管生成的分子靶向药物 其他信号通路抑制剂mTOR，Ras， MEK等,Angiogenesis is involved throughout tumour formation, growth and metastasis,Ada
39、pted from Poon RT, et al. J Clin Oncol 2001;19:120725,Stages at which angiogenesis plays a role in tumour progression,Premalignant stage,Malignant tumour,Tumour growth,Vascular invasion,Dormant micrometastasis,Overt metastasis,(Avascular tumour),(Angiogenic switch),(Vascularised tumour),(Tumour cell
40、 intravasation),(Seeding in distant organs),(Secondary angiogenesis),血管生成的双向调节机制,Angiostatin Endostatin Thrombospondin-1,VEGF bFGF PDGF,Bevacizumab (Monoclonal Antibody to VEGF),Humanized to avoid immunogenicity (93% human, 7% murine) Recognizes all isoforms of vascular endothelial growth factor, Kd
41、=8 x 10-10M Terminal half life 17-21 days,715 cases Stratify: DFI 24 os. 3 metastatic sites Adjuvant chemotherapy yes vs. no ER+ vs. ER- vs. ER unknown age,RANDOMI ZE,Paclitaxel + Bevacizumab,Paclitaxel,E2100: Study Design -线治疗晚期乳腺癌的期临床研究,28-Day Cycle: Paclitaxel 90 mg/m2 D1, 8 and 15 Bevacizumab 10
42、 mg/kg D1 and 15,All patients,Measurable Disease,0,10,20,30,40,Paclitaxel,Overall Response Rate,Pac + Bev,E2100: Response,316,236,330,250,34.3%,16.4%,28.2%,14.2%,E2100: Progression Free Survival,HR = 0.498 (0.401-0.618) Log Rank Test p0.001,Months,PFS Proportion,Bevacizumab Toxicity NCI-CTC Grades 3
43、 and 4,NCI-CTC v3.0, worst per patient,*P0.0001; *P=0.0004,NCCN,2006年美国NCCN指南已推荐Bevacizumab联合紫杉醇用于晚期乳腺癌的治疗。,Phase II trial of Capecitabine + Bevacizumab 2007 ASCO,Result,抗血管生成给药方式,许多化疗药低剂量时具有抗血管生成作用 连续规律的低剂量化疗（metronomic chemotherapy）称为抗血管生成化疗(antiangiogenic chemotherapy) 低剂量化疗的优势,Metronomic chemoth
44、erapy+bevacizumab,Metronomic chemotherapy+bevacizumab,Conclusions,肿瘤血管的形成是抗肿瘤治疗中一个非常重要的靶 抗新生血管治疗与其他治疗方法可能有协同效应 降低毒性，不增加副反应 可与放疗、化疗、生物靶向治疗联用,其他,细胞周期抑制剂779 （ temsirolimus、CCI-779） 法尼基转移酶抑制剂( farnesyl transferase inhibitors，FTIs) Bcl-2反义核酸G3139,Sensitivity ( + ),Sensitivity ( - ),Responder Survival benefit,Non-Responders Toxicity without survival benefit Delay in effective treatment,The Future - Tailored Therapy,Molecular profiling,1,2,2,Right therapy for right patient,3,谢 谢！,