乳腺癌分子靶向药物治疗进展

乳腺癌分子靶向药物治疗进展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哈尔滨医科大学附属肿瘤医院ChemotherapyEndocrine therapyTargeted therapiesTreatmentofBCHIGHLIGHTS IN BREAST CANCER DISEASE BIOLOGYu针对针对HER2受体的靶向药物受体的靶向药物u针对表皮生长因子受体针对表皮生长因子受体(EGFR)的靶向治疗的靶向治疗u针对肿瘤血管生成的分子靶向药物针对肿瘤血管生成的分子靶向药物u其他信号通路抑制剂其他信号通路抑制剂mTOR，Ras，MEK等等乳腺癌分子靶向药物治疗乳腺癌分子靶向药物治疗中位生存期的缩短HER2 扩增/过度表达3 年HER2 正常表达6-7 年HER2 原癌基因扩增原癌基因扩增HER2在约在约20%30%的乳腺癌组织中过度表达的乳腺癌组织中过度表达Slamon DJ et al.Science 1987;235:17782HER2阳性与内分泌治疗及部分化疗耐药密切相关，是重要的预后指标阳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l全球第一种治疗实体瘤的单克隆抗体全球第一种治疗实体瘤的单克隆抗体Inhibition of HER2-mediated signallingActivation of ADCC赫赛汀的作用机制赫赛汀的作用机制Additional mechanismsu Prevents formation of truncated HER2(p95)u Inhibition of HER2-regulated angiogenesisADCC,antibody-dependent cellular cytotoxicity赫赛汀已成为赫赛汀已成为HER2阳性乳腺癌的基础治疗阳性乳腺癌的基础治疗1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeoEBCHER2,human epidermal growth factor receptor 2 EBC,early breast cancer;MBC,metastatic breast cancer13,000 13,000 患者入组的赫赛汀四大辅助临床研究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 2006NCCTG N9831(USA)HERA(ex-USA)BCIRG 006(global)NSABP B-31(USA)IHC/FISH(n=5,090)Observation1 year2 yearsIHC/FISH(n=3,505)1 year1 yearFISH(n=3,222)1 year1 yearIHC/FISH(n=2,030)1 yearDocetaxelDocetaxel+carboplatinDoxorubicin+cyclophosphamideHerceptinStandard CTxPaclitaxelIHC,immunohistochemistry FISH,fluorescence in situ hybridisation CTx,chemotherapy赫赛汀可减少三分之一的死亡风险赫赛汀可减少三分之一的死亡风险012B-31/N9831 ACPH 3HERA CTxH 1 year2Median follow-up,yearsOverall survival benefitBCIRG 006 ACDH3BCIRG 006 DCarboH3FavoursHerceptinFavours noHerceptinHRSlamon et al 2006 Perez et al 2007;Smith et al 2007H,Herceptin;AC,doxorubicin,cyclophosphamide P,paclitaxel;D,docetaxel;Carbo,carboplatin HR,hazard ratioSize of square represents sample size;horizontal bars indicate 95%confidence intervals无论肿瘤大小，赫赛汀均显示无论肿瘤大小，赫赛汀均显示DFS获益获益Slamon et al 2006 Perez et al 2007;Smith et al 20072-5 cmBCIRG 0062-5 cm5 cm0.00.52.51.01.52.00-2 cmN9831/B-310-2 cm5 cmACDH2 cmDCarboH10+nodesDCarboHN-N+N+BCIRG 006N-ACDHN-HERAHRSlamon et al 2006 Perez et al 2007;Smith et al 2007无论年龄大小，赫赛汀均显示无论年龄大小，赫赛汀均显示DFS获益获益35-49 years0.00.52.51.01.52.0HERA35 years50-59 years60 yearsN9831/B-3140 years60 years40-49 years50-59 yearsFavours HerceptinFavours no HerceptinHRPerez et al 2007;Smith et al 2007赫赛汀的新辅助治疗研究进展赫赛汀的新辅助治疗研究进展1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeoEBCNOAH study:neoadjuvant Herceptin for LABCaHormone receptor-positive 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,every 4 weeksHER2-positive LABC(IHC 3+and/or FISH+)n=113H+APq3w x 3H+Pq3w x 4H q3w x 4+CMF q4w x 3Surgery followed byradiotherapyaH continued q3wto Week 52n=115Pq3w x 4CMFq4w x 3Surgery followed byradiotherapyaAPq3w x 3APq3w x 3Pq3w x 4CMFq4w x 3Surgery followed byradiotherapyan=99HER2-negative LABC(IHC 0/1+)p=0.002p=0.004pCR(%)Baselga et al 2007;Gianni et al 2007HER2 positive(n=228)HER2 positive(n=62)NOAH研究中赫赛汀新辅助显著提高了研究中赫赛汀新辅助显著提高了pCR率率Without HerceptinWith Herceptin9080706050403020100HER2 negative(n=99)HER2 negative(n=14)234317195529Total populationIBC populationpCR,pathological complete response in the breastIBC,inflammatory breast cancer新辅助化疗中加入赫赛汀新辅助化疗中加入赫赛汀 明显提高疗效明显提高疗效(16(16个相关研究个相关研究,1,226,1,226例患者入组例患者入组)aX was given either concurrently or sequentially with D+HEC,epirubicin,cyclophosphamide;FEC,5-fluorouracil,epirubicin,cyclophosphamide My,Myocet;X,Xeloda0102030405060708090100pCR(%)Antn et al 2007,n=26My+P+HaUntch et al 2008,n=452EC+H D+H X HCoudert et al 2007,n=70D+HMarty et al 2007,n=30EC D+HLimentani et al 2007,n=31D+V+H(including IBC)Bines et al 2003,n=32D+HBurstein et al 2003,n=40P+H(including IBC)Kelly et al 2006,n=37AC P+H(including IBC)Harris et al 2003,n=40V+H(including IBC)Hurley et al 2002,n=48D+cisplatin+H(including IBC)Tripathy et al 2007,n=28P+X+HLybaert et al 2006,n=25X+D+HBuzdar et al 2007,n=45P FEC+HPernas et al 2007,n=33P FEC+HGianni et al 2007,n=115AP P CMF+H(including IBC)Untch et al 2005,n=174EC P+H赫赛汀已成为赫赛汀已成为HER2阳性乳腺癌的基础治疗阳性乳腺癌的基础治疗1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionHER2,human epidermal growth factor receptor 2 EBC,early breast cancer;MBC,metastatic breast cancer EBCHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeo一线赫赛汀治疗显著延长患者的生存时间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,carboplatinH0648g(IHC 3+)M77001BCIRG 007US Oncology(IHC 3+)Smith et al 2001;Marty et al 2005 Robert et al 2006;Pegram et al 2007TAnDEMTAnDEM-赫赛汀联合阿那曲唑治疗赫赛汀联合阿那曲唑治疗HER-2(+HER-2(+）激素敏感性转移性乳腺癌激素敏感性转移性乳腺癌u临床研究结果（2006年圣安东尼奥）H+AIAIORR20.3%6.8%CBR42.7%27.9%PFS4.8 月2.4月TTP4.8 月2.4月OS28.5月23.9月 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疾病进展后如何合理选择赫赛汀个体化治疗方案选择赫赛汀个体化治疗方案1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionEBCHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeoHerceptin improves OS if continued beyond progressionOS(months)Continued HerceptinDiscontinued HerceptinExtra et al 2006Jackisch et al 2007;Menard et al 2008p0.0001p50(5.1%-5.4%)Use of hypertensive medications(6.8%)Baseline LVEF 50-54(12.9%)Rastogi et al.Abstract LBA513 ASCO 2007u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。uTrastuzumab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。u目前Trastuzumab治疗疗程为1年，建议每三个月一次进行心功检查。心功能监测心功能监测LVEF低于低于50%恢复至恢复至50%以上以上不恢复、或继续恶化不恢复、或继续恶化终止终止Herceptin治疗治疗继续用药继续用药暂停暂停Herceptin治疗，观察或对症处理治疗，观察或对症处理 赫赛汀临床应用赫赛汀临床应用2008年年NCCN复发或复发或IV期乳腺癌指南期乳腺癌指南HR阴性，HER2阳性具有内脏危象复发或IV期乳腺癌u曲妥珠单抗曲妥珠单抗化疗化疗赫赛汀联合辅助化疗方案赫赛汀联合辅助化疗方案uAC THuAC DHuTCHu化疗HuDH 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帕妥珠单抗帕妥珠单抗Pertuzumab(2C4):anti HER2 agent u以HER-2为靶位的人源化单克隆抗体u与HER-2 受体胞外结构域区结合，抑制二聚体的形成u抑制HER2 与 EGFR 和 HER3形成二聚体。Herceptin+pertuzumab provides clinical benefit to patients progressing on HerceptinGelmon et al 2008ResponseCRPRORRSD for 6 months(Cycle 8)CBRPDMedian PFSn(%)n=665(7.6)11(16.7)16(24.2)17(25.8)33(50.0)33(50.0)24 weeksHerceptin+pertuzumab is a well-tolerated combinationPatients(%)Adverse events,all gradesAdverse events,grades 3/4Gelmon et al 2008u针对针对HER2受体的靶向药物受体的靶向药物u针对表皮生长因子受体针对表皮生长因子受体(EGFR)的靶向治疗的靶向治疗u针对肿瘤血管生成的分子靶向药物针对肿瘤血管生成的分子靶向药物u其他信号通路抑制剂其他信号通路抑制剂mTOR，Ras，MEK等等针对针对EGFR的靶向治疗的靶向治疗u小分子酪氨酸激酶抑制剂(SMTKIs)uEGFR单克隆抗体(MAbs)u多靶点抗肿瘤抑制剂酪氨酸激酶抑制剂酪氨酸激酶抑制剂u拉帕替尼（拉帕替尼（Lapatinib，Tykerb）u吉非替尼（吉非替尼（ZD1839，Iressa，Gefitinib，易瑞沙），易瑞沙）u埃罗替尼（埃罗替尼（Tarceva，erlotinib）Lapatinib(Tykerb)u 口服的TKIu 双重抑制剂:EGFR 和HER-2 Geyer CE,et al.ASCO 2006.Clinical Science Symposium.EGF100151:Lapatinib+Capecitabine in Advanced Breast CancerRefractory,progressive metastatic or locally advanced HER2+breast cancer previously treated with anthracycline,taxane,or trastuzumab(N=528 planned*)Lapatinib 1250 mg daily+Capecitabine 2000 mg/m2 dailyfor Days 1-14,3-week cycles(n=160)Capecitabine 2500 mg/m2 dailyfor Days 1-14,3-week cycles(n=161)Follow-up:until progressionor unacceptabletoxicity*Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint.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 review)Overall:22.5%vs 14.3%(P=.113)Geyer CE,et al.ASCO 2006.Clinical Science Symposium.Progression-Free Survival(%)Time(Wks)2040608001001020304050CapecitabineLapatinib+capecitabineITT population 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 u39 patients(38 patients progression after radiothrapy)New/progressive measurable(1 cm)brain metastasesuTreatment:Lapatinib 750 mg po BIDuResult1.2 patients PR 158d and 347d2.5 patients SD 16 weeks Median TTP 3.2 months MST 6.57 months3.1 patient had response,but did not meet RECISTLapatinib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 trialLapatinib+Trastuzumab for Trastuzumab progressing on Her2+Cancer ASCO 2008Progression-Free SurvivalOverall Survival in ITT Population0200DaysGefitinib-表皮生长因子受体酪氨酸激酶抑制剂表皮生长因子受体酪氨酸激酶抑制剂1306090120150400600800100012001400Tumour volume(mm3)Massarweh et al.Breast Cancer Res Treat 2002FulvestrantFulvestrant+gefitinibOestradiolFulvestrant plus gefitinib delays resistance in MCF-7/HER2 tumours in vivo Phase II Trial of Gefitinib in Advanced Breast Cancer Partial responseStable diseaseClinical benefitProgressive disease15 6(66%)3ER-positive(n=9)ER-negative(n=18)11 2(11%)16Robertson et al.ASCO Proc.2003lAcquired resistance 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 toxicityErlotinib-小分子小分子EGFR EGFR 酪氨酸激酶抑制剂酪氨酸激酶抑制剂 previous therapy with either an anthracycline or a taxane for MBC Erlotinib（150 mg orally daily）+gemcitabine（1000 mg/m2,Days 1、8,3-week cycles）A partial response(PR)rate of 17%has been reported(ASCO 2005)N0234：Erlotinib+GemcitabineN0234：Erlotinib+GemcitabineuResultTNNON-TN PPR25%14%0.30CBR25%22%0.75PFS72d98d0.13OS227d738d0.0002TN*=ER(-)/PR(-)/HER-2(-)三阴 ASCO 2007西妥昔单抗西妥昔单抗(Cetuximab，erbitux，C225，爱必妥，爱必妥)uCetuximab是针对HER-1的特异性单克隆抗体u动物试验显示，Cetuximab可有效抑制乳腺癌细胞增殖和生长，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。泰欣生泰欣生是一个针对是一个针对EGFR的单抗药物，通过的单抗药物，通过与与EGFR胞外区胞外区3A表位结合，竞争性抑制配体表位结合，竞争性抑制配体与与EGFR的结合，使受体失去活性：的结合，使受体失去活性：IgG1型单克隆抗体，分子量为型单克隆抗体，分子量为150KD95人源化人源化激发激发ADCC和和CDC效应抑制肿瘤细胞效应抑制肿瘤细胞比内源性配体亲合力更高（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。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）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 70RANDOMIZATIONSURGERYNimotuzumab AC用药方案J.Soriano,N.Batista,et al.European Journal of Cancer Supplements,Vol 5 No 4,Page 116疾病控制情况疾病控制情况疾病控制情况共有共有13例患者入组，例患者入组，12例患者可评估：例患者可评估：9例例PR，3例例SD。Patients Dose Age RaceTNMStageDiagnoseNGERHER-2015045W T4bN0M0IIIBIDC3NegNeg025040WT3N1M0IIIAILC3Neg3 +035044WT3N1M0IIIAIDC3Pos2+0510059BT4bN1M0IIIBIDC3NegNeg0610063BT4bN1M0IIIBIDC2NegNeg1310046BT3N1M0IIIAIDC1PosNeg0720064W T4bN1M0IIIBIDC3NegNeg0820042WT3N1M0IIIAIDC3PosNeg0920042W T4aN1M0IIIBIDC3Neg3+1040058W T4bN0M0IIIBIDC2PosNeg1140059BT4bN1M0IIIBIDC3Neg3+1240034WT3N1M0IIIAIDC1PosNegJ.Soriano,N.Batista,et al.European Journal of Cancer Supplements,Vol 5 No 4,Page 116安全性：安全性：在在50、100、200和和400mg中，未见剂量限制性毒性中，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，患者耐受临床未见心脏毒性；联合治疗安全性高，患者耐受性良好性良好常见不良反应为：皮疹、皮肤反应、恶心、呕吐；常见不良反应为：皮疹、皮肤反应、恶心、呕吐；红斑红斑,丘疹及色素沉着较常见，通常发生在面部及丘疹及色素沉着较常见，通常发生在面部及上肢上部，能自行缓解上肢上部，能自行缓解初步结论：初步结论：泰欣生治疗乳腺癌有效，泰欣生治疗乳腺癌有效，联合治疗在联合治疗在50，100，200和和400mg 剂量下是安全的，有很好的耐受性剂量下是安全的，有很好的耐受性 结结 论论J.Soriano,N.Batista,et al.European Journal of Cancer Supplements,Vol 5 No 4,Page 116苏尼替尼（苏尼替尼（Sunitinib）-小分子多靶点酪氨酸激酶抑制剂小分子多靶点酪氨酸激酶抑制剂 NHONHH3CCH3NHONCH3CH3 Selective inhibitor of:PDGFR VEGFR2(KDR)KIT FLT32006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 study with 64 patients*One PR not yet confirmed.N=64Partial Response*7(11%)Stable Disease 6 months3(5%)Overall Clinical Benefit10(16%)patients had received 3.5 different chemotherapies（anthracycline or taxane）85%of patients had received adjuvant chemotherapysunitinib 50 mg/d u 多激酶抑制剂：丝氨酸多激酶抑制剂：丝氨酸/苏氨酸：苏氨酸：C-Raf(Raf-1)和和B-Raf1酪氨酸激酶受体：酪氨酸激酶受体：VEGFR-2、VEGFR-3、PDGFR-b、FLT-3和和 c-KIT Wilhelm S et al.Clin Cancer Res.2004;64:7099-7109.索拉非尼索拉非尼(sorafenib)：口服口服信号转导抑制剂信号转导抑制剂,在在Raf激酶水平和受体酪氨酸激激酶水平和受体酪氨酸激酶酶VEGFR-2和和PDGFR-阻断阻断Raf/MEK/ERK途径途径,抗肿瘤血管生成及肿瘤细胞增殖抗肿瘤血管生成及肿瘤细胞增殖Sofitinib phase II in MBCu针对针对HER2受体的靶向药物受体的靶向药物u针对表皮生长因子受体针对表皮生长因子受体(EGFR)的靶向治疗的靶向治疗u针对肿瘤血管生成的分子靶向药物针对肿瘤血管生成的分子靶向药物u其他信号通路抑制剂其他信号通路抑制剂mTOR，Ras，MEK等等Angiogenesis is involved throughout tumour formation,growth and metastasisAdapted from Poon RT,et al.J Clin Oncol 2001;19:120725Stages at which angiogenesis plays a role in tumour progressionPremalignantstageMalignanttumourTumourgrowthVascularinvasionDormantmicrometastasisOvertmetastasis(Avasculartumour)(Angiogenicswitch)(Vascularisedtumour)(Tumour cellintravasation)(Seeding indistant organs)(Secondaryangiogenesis)血管生成的双向调节机制血管生成的双向调节机制AngiostatinEndostatinThrombospondin-1VEGFbFGFPDGFBevacizumab(Monoclonal Antibody to VEGF)Humanized to avoid immunogenicity(93%human,7%murine)Recognizes all isoforms of vascular endothelial growth factor,Kd=8 x 10-10M Terminal half life 17-21 days715 cases Stratify:DFI 24 os.3 metastatic sites Adjuvant chemotherapy yes vs.no ER+vs.ER-vs.ER unknown ageRANDOMIZE Paclitaxel+BevacizumabPaclitaxelE2100:Study Design -线治疗晚期乳腺癌的线治疗晚期乳腺癌的期临床研究期临床研究 28-Day Cycle:Paclitaxel 90 mg/m2 D1,8 and 15Bevacizumab 10 mg/kg D1 and 15All patientsMeasurable Disease010203040PaclitaxelOverall Response RatePac+Bev E2100:Response31623633025034.3%16.4%28.2%14.2%P0.0001P0.0001E2100:Progression Free SurvivalHR=0.498(0.401-0.618)Log Rank Test p0.001Months0.00.10.20.30.40.50.60.70.80.91.0PFS Proportion0102030Pac.+Bev.10.97 monthsPaclitaxel 6.11 monthsBevacizumab ToxicityNCI-CTC Grades 3 and 4PaclitaxelPac.+Bev.Grade 3Grade 4Grade 3Grade 4HTN*0%0%13%0.3%Thromboembolic0.3%0.9%1.2%0%Bleeding0%0%0.6%0.3%Proteinuria*0%0%0.9%1.5%NCI-CTC v3.0,worst per patient*P0.0001;*P=0.0004NCCNu2006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 ASCOResult抗血管生成给药方式u许多化疗药低剂量时具有抗血管生成作用许多化疗药低剂量时具有抗血管生成作用u连续规律的低剂量化疗（连续规律的低剂量化疗（metronomic chemotherapymetronomic chemotherapy）称为抗血管生成化疗称为抗血管生成化疗(antiangiogenic(antiangiogenic chemotherapy)chemotherapy)u低剂量化疗的优势低剂量化疗的优势Metronomic chemotherapy+bevacizumabMetronomic chemotherapy+bevacizumabConclusionsu肿瘤血管的形成是抗肿瘤治疗中一个非常重要的靶u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其他u细胞周期抑制剂779（temsirolimus、CCI-779）u法尼基转移酶抑制剂(farnesyl transferase inhibitors，FTIs)uBcl-2反义核酸G3139Sensitivity(+)Sensitivity(-)ResponderSurvival benefitNon-RespondersToxicity without survival benefitDelay in effectivetreatmentThe Future-Tailored TherapyMolecular profiling 1 2 2Right therapy for right patient 3谢 谢！