《乳腺癌的分子靶向治疗课件.ppt》由会员分享，可在线阅读，更多相关《乳腺癌的分子靶向治疗课件.ppt（62页珍藏版）》请在三一办公上搜索。
1、乳腺癌的分子靶向治疗,恶性肿瘤的发生发展,侵袭转移和肿瘤血管生成，是多数肿瘤共同的生物学过程,其间涉及许多细胞和分子学机制.对恶性肿瘤的细胞和分子生物学机制的研究，推动乳腺癌的基础和临床研究以及分子靶向药物研发.分子靶向药物已经成为抗肿瘤药物的新兴门类，已经并进一步对肿瘤治疗产生日益重要的影响。,恶性肿瘤发生的细胞和分子学机制,自我生长促进对生长抑制信号敏感性下降逃避凋亡和死亡侵袭和转移肿瘤血管生长,分子靶向药物的研究,抗HER2的研究抗肿瘤血管生成研究PARP 抑制剂抗骨转移的研究M-TOR三阴乳腺癌中抗EGFR,HER2阳性乳腺癌,Her2/neu是4个表皮生长因子受体家族成员之一，与细胞
2、的生长，分化生存重要相关。Her2蛋白的过渡表达或基因扩增的乳腺癌约占1/4,是肿瘤恶性程度高，预后差 的标志。Trastuzumab(Herceptin,赫赛汀)是人源化单克隆抗体，针对Her2受体细胞外功能簇。单药或者与化疗联合应用，治疗Her2阳性MBC改善疗效。1998年FDA批准治疗Her2阳性MBC，与紫杉类联合成为标准一线方案。辅助性治疗的 临床研究也已经完成，并在2006年获得FDA批准。NCCN 和 St.gallen 2007 HER2成为风险分级和治疗分组的指标。,曲妥珠单抗治疗HER2阳性乳腺癌,MBC1st lineHO648gM77001 US OncologyBC
3、IRG 007CHATTAnDEMRHEA,2nd+linesGBG-26BO17929EGF104900Numerous Phase II studies,曲妥珠单抗治疗HER2阳性乳腺癌,EBCAdjuvant:HERANSABP B-31NCCTG N9831BCIRG 006PACS 04Neo Adjuvant:NOAHMDACCGeparQuattro,曲妥珠单抗 in EBC Trial,无病生存期(ITT分析):4-年中位随访时间,100,80,60,40,20,0,0,6,12,18,24,30,48,36,42,随机分组后月,16981703,15641619,144015
4、52,13631485,12971414,12401352,712854,11801280,9921020,No.at risk,事件数458369,4-年DFS72.278.6,风险系数0.76,95%可信区间0.66,0.87,p 值0.0001,1-年赫赛汀组,观察组,6.4%,患者(%),新辅助治疗显著提高病理完全缓解率(pCR),MDACC:PCR:H+(P FEC)vs P+FEC alone(65.2%vs 26.3%)NOAHPCR:43%vs 23%tPCR:38%VS 20%,MDACC研究：2/3的患者获病理学完全缓解解,26.3%n=19,65.2%n=23,95%CI
5、(4384%)p=0.016,(n=42),pCR(%),Buzdar A,et al.Proc ASCO 2007,NOAH:更高临床缓解率,ORR,%CR,%PR,%SD,%PD,%,+H(n=115)80.960.020.90.94.3,-H(n=113)73.451.322.15.36.2,65.725.240.410.110.1,HER2 positive,HER2 negative(n=99),Gianni et al ASCO 2007,poster 532,ORR,overall response rate;CR,complete response;PR,partial res
6、ponse;SD,stable disease;PD,progressive disease,NOAH：显著提高病理学完全缓解率(pCR),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 re
7、sponse in breast and nodes,Gianni et al ASCO 2007,poster 532,NOAH:tumour response,赫赛汀联合化疗:新辅助治疗的pCR率,pCR(%),P,D,P,AC P,V,D+cisplatin,D+H,D+V,X+D,AC P CMF,D,P FEC-75,P FEC,Study,Herceptin,Lapatinib,pCR,pathological complete response;AC,doxorubicin,cyclophosphamide;E,epirubicin;L,lapatinib;V,vinorelbi
8、ne;X,Xeloda;FEC,5-fluorouracil,epirubicin,cyclophosphamide;CMF,cyclophosphamide,methotrexate,5-fluorouracil;D,docetaxel,拉帕替尼（Lapatinib）,酪氨酸激酶抑制剂有效的选择性ErbB1(EGFR)和ErbB2(HER2)的双重抑制剂2007年3月13日FDA批准上市与卡培他滨联合，用于既往曾接受过蒽环类、紫杉醇类和曲妥珠单抗治疗的ErbB2过表达的转移性乳腺癌,Akt,Lapatinib 作用机制,Ras,Raf,MAPK,P,Sos,Shc,Grb2,ATP,Akt,
9、MAPK,PI3K,Lapatinib,增生通路,生存通路,通过ATP的正常活化,Lapatinib阻断其活化,生存通路,增生通路,Xia W,et al.Oncogene 2002;21:6255-63.Rusnak DW,et al.Mol Cancer Ther 2001;1:85-94.,单克隆抗体与小分子TKI的比较,抑制激酶的胞内区对突变的ErbB-1 和顶端缺失的 ErbB-2有活性配体的浓度不会影响其抑制活性,与受体的胞外区结合不能与突变和顶端缺失的受体结合-无活性配体的饱和会影响其疗效,小分子酪氨酸激酶抑制剂,单克隆抗体,MBC单药疗效5.1%，(SD 40%)难治性MBC单
10、药疗效1.4%，(SD 33%),难治性晚期或转移性乳腺癌应用Lapatinib 卡培他滨 VS 卡培他滨单药治疗的随机、III期研究,进展、HER2+转移性乳腺癌或LABC 曾接受过蒽环类、紫杉类和曲妥珠单抗治疗*未接受过卡培他滨治疗,患者接受治疗直至疾病进展或出现不可耐受的毒性并进行生存期随访,N=528,卡培他滨2500 mg/m2/d po days 1-14 q 3 wk,Lapatinib 1250 mg po qd+卡培他滨2000 mg/m2/d po days 1-14 q 3 wk,*Trastuzumab must have been administered for m
11、etastatic disease Presented by C.E.Geyer et al,ASCO 2006,Lapatinib+Capecitabine vs CapecitabinePhase III 复治的MBC（ITT）,Time(weeks),0,10,20,30,40,50,60,70,Cumulative Progression-Free Survival,%,0,10,20,30,40,50,60,70,80,90,100,0.001,P-value(log-rank,1-sided),73(45%),45(28%),Progressed or died,0.49(0.34
12、,0.71),Hazard ratio(95%CI),4.4,8.4,Median PFS,mos,161,160,No.of pts,Capecitabine,Lapatinib+capecitabine,Geyer et al,NEJM 2006;355:2733-43,Lapatinib在难治性晚期/转移性乳腺癌,HER2阳性乳腺癌脑转移,Lapatinib单药治疗脑转移有效，51例Lapatinib治疗脑放疗后进展，并且已经用过Lapatinib治疗的患者，联合Capecitabin肿瘤缩小20%，占37%肿瘤缩小50%，占20%5例单药Lapatinib达到PR,1例联合Capeci
13、tabin又达到PR.20例单药Lapa达SD,加上Capecitabin3例PR,10例SD.,辅助治疗临床研究,EGF105485 III期 Lapa vs PlaceboALLTO Study III期 4组 随机对照试验,52WEEKS,Lapatinib Lapatinib+曲妥珠单抗每3周方案共40周,Lapatinib+曲妥珠单抗每周方案共12周,曲妥珠单抗每周方案共12周,Lapatinib52周,曲妥珠单抗每3周方案共40周,Lapatinib34 周,6周清洗期,曲妥珠单抗每周方案共12周,在完成任何蒽环类为主的（新-）辅助化疗后，计划靶向治疗与紫杉醇联合使用,手术、完成（
14、新）辅助化疗(在批准的用药列表中选择),LVEF 50%,Max 6 w,当地实验室确定的 HER2阳性浸润性乳腺癌,中心实验室确定 HER2+;ER and PgR,ALLTO Study,Lapatinib 腹泻,8个临床试验中1126名使用lapatinib的患者：50%出现腹泻 分级54%为1级(轻度)30%为2级(中度)15%为3级(重度)1%为4级(威胁生命)发作及周期44%的患者在最初6天内出现22%的患者在开始治疗28天后出现每次发作平均持续5天,Data on File,GlaxoSmithKline.,Lapatinib皮肤事件,8个临床试验中1126名使用lapatini
15、b的患者，46%报告有皮疹(所有级别)*重度皮疹罕见;4%的患者出现3级皮疹，没有4级皮疹的报告多数皮肤事件出现较早，在治疗前14天内出现中位数周期为29天85%的事件无需干预、剂量调整或治疗中断1%由于皮肤事件终止治疗,*Excluding PPE Data on File,GlaxoSmithKline.,其它新的抗HER2药物,Pertuzumab阻断异源性二聚体，效力可能比Herceptin更强。61例三线治疗的安全性报告了该抗体相关的毒性：59%腹泻（G3/4 仅2%），其他G3/4 AE：DV血栓1例，皮疹1例。对心脏功能影响很小，2例33例可评价疗效，ORR 18.2%,CB 3
16、9.4%，进行中研究：联合Herceptin一线MBC.,其他新型抗HER2药物(续),HKI-272,不可逆的全HER2 TKI。N=42 MBCPR 13,SD 20%1例 G3/4腹泻。Trastuzumab-DM1 HER2+MBCN=16 PR26%,贝伐单抗在乳腺癌的临床研究-抗肿瘤血管生成治疗,VEGF 家族和受体,Neufeld G,et al.FASEB J.1999;13:9-22.,VEGFR-3(Flt-4),VEGFR-2(Flk-1/KDR),VEGFR-1(Flt-1),Angiogenesis,Lymphangiogenesis,胎盘生长因子PIGF,VEGF-
17、A,VEGF-B,VEGF-C,VEGF-D,Bevacizumab(重组人抗VEGF单克隆抗体),贝伐单抗:针对VEGF的人源化单克隆抗体(93%human,7%murine),能够识别所有VEGF亚型(Kd=8 x 10-10M),终末半衰期17-21 天.,抗血管生成治疗靶点,贝伐单抗治疗晚期乳腺癌I/II期临床研究,75例化疗过的晚期乳腺癌接受不同剂量贝伐单抗疗效分析:,疗效 3mg/kg(18)10mg/kg(41)20mg/kg(16)CR(%)0 1(2.4)0PR(%)1(5.6)4(9.8)1(6.8)22周临床获益(5)2(11)7(17)3(19)中位有效时间(M)3.1
18、 5.6 8.0,Cobleigh MA,et al.Semin Oncol 2003;30,117-24,1 2.Kabbinavar F,et al.J Clin Oncol.2003;21:60-65.3.Giantonio B,et al.ASCO 2005.Abstract 2.4.Miller KD,et al.J Clin Oncol.2005;23:792-799.5.Miller KD.SABCS 2005.Abstract 3.6.Sandler AB,et al.ASCO 2005.Abstract LBA4.7.Kindler HL,et al.ASCO GI 2007
19、.Abstract 108.8.Available at:http:/www.clinicaltrials.gov.,Bevacizumab Phase III Trials MBC,Capecitabine vs.Capecitabine+Beva 治疗晚期乳腺癌,KD Miller.J Clin Oncol,2005,Capecitabine vs.Capecitabine+Beva 不良反应,KD Miller.J Clin Oncol,2005,No grade 4,Best response(%),Phase III trial of bevacizumab plus paclita
20、xelin first-line mBC(E2100):有效率,All patients,Patients withmeasurable disease,49.2%,25.2%,21.2%,36.9%,Paclitaxel,Bevacizumab+paclitaxel,CR+PRp0.001,CR+PRp0.001,CR=complete responsePR=partial response,Miller,et al.NEJM 2007,6050403020100,11.4,061218243036,PFS estimate,HR=0.48,Paclitaxel(n=354)Bevacizu
21、mab+paclitaxel(n=368),PFS by investigator,5.8,11.3,HR=0.42,PFS by IRF*,5.8,Months,1.00.80.60.40.20,*Scans available for 90%of patients,Phase III trial of bevacizumab plus paclitaxel in first-line mBC(E2100):PFS,Adapted from Cameron.EJC Suppl.2008 withpermission from Elsevier;Avastin SmPC 2008,AVADO:
22、response(patients with measurable disease),%,mg/kg q3w,Miles,et al.ASCO 2008(Abstract LBA1011),Bev 15+docetaxel(n=247),HR+95%CI(unstratified),Bev 7.5+docetaxel(n=248),Months,PFS estimate,1.00.80.60.40.20,061218,AVADO:progression-free survival(ITT population),*Data censored for non-protocol therapy b
23、efore PD;mg/kg q3w,HR+95%CI(stratified*),0.69(0.540.89)p=0.0035,0.79(0.630.98)p=0.0318,Placebo+docetaxel(n=241),Median,8.7,8.0,HR+95%CI(stratified*),0.61(0.480.78)p0.0001,Median,8.8,8.0,0.72(0.570.90)p=0.0099,HR+95%CI(unstratified),Placebo+docetaxel(n=241),Miles,et al.ASCO 2008(Abstract LBA1011),43,
24、RIBBON-1:Study Design,Previously untreated MBC(n=1237)Stratification factors:Disease-free interval Previous adjuvant chemotherapy Number of metastatic sites Cape.,T or Anthra.,Robert et al.ASCO 2009.Abstract 1005.,Primary endpoint:PFS as assessed by investigatorSecondary endpoints:Overall Survival(O
25、S)Safety,Capecitabine(1000 mg/m2 BID x 14d)Taxane(docetaxel or protein-bound paclitaxel)Anthracycline-based chemotherapy(AC,EC,FAC,FEC)Placebo or bevacizumab(15 mg/kg),44,44,RIBBON-1:Patient Characteristics,All data as%,unless otherwise noted.,Robert et al.ASCO 2009.Abstract 1005.,45,RIBBON-1:Object
26、ive Response Rate,PL,BV,PL,BV,23.6,35.4,37.9,51.3,Capecitabinep=0.0097,Taxane/Anthracyclinep=0.0054,%,Measurable*Disease,%,79,80,86,83,*Includes only patients with measurable disease at baseline,CR,PR,Robert et al.ASCO 2009.Abstract 1005.,45th Asco 2009,46,RIBBON-1:Exploratory Secondary Endpoint:PFS
27、 by Chemotherapy Subgroups,All mPFS=median PFS,Robert et al.ASCO 2009.Abstract 1005.,47,RIBBON-1:Overall Survival,Robert et al.ASCO 2009.Abstract 1005.,48,RIBBON-1:Selected Grade 3 AEs,VTE=Venous ThromboEmbolism,Robert et al.ASCO 2009.Abstract 1005.,49,RIBBON-1:Authors Summary,For the pre-specified
28、capecitabine and taxane/anthracycline cohorts,the addition of bevacizumab led to a statistically significant improvement in:PFS(by investigator)PFS(by IRC)ORR No difference was noted in OSSafety:Incidence of bevacizumab-related adverse events consistent with prior studiesNo new bevacizumab-related s
29、afety signals in each of the chemotherapy groups,Robert et al.ASCO 2009.Abstract 1005.,贝伐单抗临床研究方向(III期临床试验),转移性乳腺癌:一线RIBBON1:化疗+/-贝伐单抗,(1239例)AVEREL:Docetaxel+Herceptin+/-贝伐单抗(462例)辅助治疗:BEATRICE(三阴):辅化+/-贝伐单抗,(2530例)BETH（NSABP B-44）:HER2+:辅化/Herceptin+/-贝伐单抗(5400例)E5103:AC-T+/-B,BEVA 短程.长程NSABP B-46
30、 1 TAC/TC/TC+B新辅助化疗:NSABP B40:AC/TX/DG+贝伐单抗(1200例),研究中的抗血管生成新靶点治疗药物,抗VEGF 贝伐单抗VEGF Trap（可溶性受体,已经进入3期临床）小分子配体阻断剂TKISutent单药临床获益16%，与Taxan联合进行中。阿那曲唑+/-Sorafenib（ER+和/或PR+MBC）AxitinibPazopanib 选择性更强的VEGF抑制剂。抗VEGFR,Axitinib治疗晚期乳腺癌,Axitinib+Docetaxel vs Docetaxel N=168例M-TTP:8.2m vs 7.0mORR:40%vs 23%AE(G
31、3/4):ADDFN(16%/7%)Stomatitis(13%/2%)Diarrhea(11%/0%)Hypertension(5%/2%),受体酪氨酸激酶抑制剂Sunitinib Phase III Trial,MBCSUN 1064 Doce+/-Sunitinib in her2-MBC(一线)SUN 1094 Pacli+beva vs Pacli+Sunitinib LA/MBCSUN 1099 Xelo+/-Sunitinib in her2+MBC(hercep or lapa treated)EBC HER2阴性乳腺癌新辅助化疗后：SUN vs PLACEBO 1年,其他新型
32、分子靶向治疗以及研究,PARP1 Olaparib AZD2281口服PARP 1 抑制剂 I期 Inhibitor BSI-201 NF-kB受体活化因子的配体（RANKL）抑制剂Denosumab抑制RANKL的活性，减少骨吸收。,Addition of PARP1 Inhibitor BSI-201 to Gemcitabine/Carboplatin Improves Outcomes in Metastatic TNBC,Randomized,multicenter,open-label phase II trial Poly(ADP-ribose)polymerase-1(PARP
33、1)Critical enzyme in DNA repair and cell proliferation Involved in non-BRCAdependent DNA repair pathwaysUpregulated in most TNBCBSI-201 potent PARP1 inhibitor,OShaughnessy J et.al,2009 ASCO,Abs NO.3,Study Design,OShaughnessy J et.al,2009 ASCO,Abs NO.3,Results-ORR/CBR,OShaughnessy J et.al,2009 ASCO,A
34、bs NO.3,Results-PFS/OS,OShaughnessy J et.al,2009 ASCO,Abs NO.3,Results-Safety,OShaughnessy J et.al,2009 ASCO,Abs NO.3,Denosumab对双磷酸盐治疗过的骨转移乳腺癌,随机开放 Phase II 活性对照，N=111研究目的：评估Denosumab在经过8周以上双磷酸盐治疗的骨转移乳腺癌uNTX仍然高的患者，疗效和安全性分析。主要发现：静脉双磷酸盐无反应患者，Denosumab比继续双磷酸盐能降低uNTX(77%vs 34%p0.1)治疗两周后，中位uNTX降低达80，且维持25周。在25周时其他骨标志改变百分比，Denosumab也更大。骨相关事件更少：13 vs 10常见安全性事件：骨痛，恶心，贫血等。,Gralow SABCS 2008 AB 1155,谢谢,
