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1、 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ChemotherapyChemotherapyEndocrine Endocrine therapytherapyT Targeted argeted therapiestherapiesTreatmentTreatmentof ofBCBCHIGHLIGHTS IN BREAST CANCERHIGHLIGHTS IN BREAST CANCER DISEASE BIOLOGYDISEASE BIOLOGYu针对针对HER2H
2、ER2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)(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mTORmTOR，RasRas，MEK 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 HER2 受体过度表达受体过度表达受体过度表达受体过度表达HER2 原癌基因扩增原癌基因扩增HER2HER2HER2HER2在约在约在约在约20%20%20%20%30%30%30%30%的乳腺癌组织中
3、过度表达的乳腺癌组织中过度表达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;235:17782Slamon DJ et al.Science 1987;235:17782HER2HER2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HER2HER2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赫赛汀赫赛汀(曲妥珠单抗曲妥珠单抗):):人源化抗人源化抗HER2HER2单克隆抗体单克隆抗体l l高度亲和性高度亲和性(K(
4、Kd d=0.1nM)=0.1nM)和和特异性特异性l l95%95%人源化人源化,5%,5%鼠抗，显鼠抗，显著降低免疫原性著降低免疫原性(HAMA)HAMA)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 Inhibition of HER2-mediated signallingHER2-mediated signallingActivation of ADCCActivation of ADCC赫赛汀的作用机制赫赛汀的作用机制Additional mechanismsuPrevents formation of truncated HER2(
5、p95)uInhibition of HER2-regulated angiogenesisADCC,antibody-dependent cellular cytotoxicityADCC,antibody-dependent cellular cytotoxicity赫赛汀已成为赫赛汀已成为HER2HER2阳性乳腺癌的基础治疗阳性乳腺癌的基础治疗1st line1st lineHO648gHO648gM77001 M77001 US OncologyUS OncologyBCIRG 007BCIRG 007CHATCHATTAnDEMTAnDEMRHEARHEAR Re el la ap
6、ps se e2nd+lines2nd+linesGBG-26GBG-26BO17929BO17929EGF104900EGF104900Numerous Numerous Phase II studiesPhase II studiesMBCMBCP Pr ro og gr re es ss si io on nHERAHERANSABP B-31NSABP B-31NCCTG N9831NCCTG N9831BCIRG 006BCIRG 006AdjuvantAdjuvantNOAHNOAHMDACCMDACCGeparQuattroGeparQuattroNumerous Phase I
7、I Numerous Phase II studiesstudiesNeoNeoEBCEBCHER2,human epidermal growth factor receptor 2 HER2,human epidermal growth factor receptor 2 EBC,early breast cancer;MBC,metastatic breast cancerEBC,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-Gebh
8、art et al 2005 Piccart-Gebhart et al 2005 Romond et al 2005;Slamon et al 2006Romond et al 2005;Slamon et al 2006NCCTG N9831(USA)NCCTG N9831(USA)HERA(ex-USA)HERA(ex-USA)BCIRG 006(global)BCIRG 006(global)NSABP B-31(USA)NSABP B-31(USA)IHC/FISH IHC/FISH(n=5,090)(n=5,090)ObservationObservation1 year1 yea
9、r2 years2 yearsIHC/FISH IHC/FISH(n=3,505)(n=3,505)1 year1 year1 year1 yearFISHFISH(n=3,222)(n=3,222)1 year1 year1 year1 yearIHC/FISH IHC/FISH(n=2,030)(n=2,030)1 year1 yearDocetaxelDocetaxel+carboplatinDoxorubicin+Doxorubicin+cyclophosphamidecyclophosphamideHerceptinStandard CTxPaclitaxelIHC,immunohi
10、stochemistry IHC,immunohistochemistry FISH,fluorescence FISH,fluorescence in situin situ hybridisation CTx,hybridisation CTx,chemotherapychemotherapy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0 01 12 2B-31/N9831 B-31/N9831 ACACP PH H 3 3HERA CTxHERA CTxH 1 yearH 1 year2 2Median follow-up,yearsMedian follow-up,ye
11、arsOverall survival benefitOverall survival benefitBCIRG 006 ACBCIRG 006 ACD DH H3 3BCIRG 006 DCarboHBCIRG 006 DCarboH3 3FavoursFavoursHerceptinHerceptinFavours noFavours noHerceptinHerceptinHRHRSlamon et al 2006 Slamon et al 2006 Perez et al 2007;Smith et al 2007Perez et al 2007;Smith et al 2007H,H
12、erceptin;AC,doxorubicin,cyclophosphamide H,Herceptin;AC,doxorubicin,cyclophosphamide P,paclitaxel;D,docetaxel;Carbo,carboplatin P,paclitaxel;D,docetaxel;Carbo,carboplatin HR,hazard ratioHR,hazard ratioSize of square represents sample size;horizontal bars indicate 95%confidence intervalsSize of squar
13、e 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DFSDFS获益获益Slamon et al 2006 Slamon et al 2006 Perez et al 2007;Smith et al 2007Perez et al 2007;Smith et al 20072-5 cm2-5 cmBCIRG 006BCIRG 0062-5 cm2-5 cm5 cm5 cm0.00.00.50.52.52.51.01.01.51.52.02.00-2
14、 cm0-2 cmN9831/B-31N9831/B-310-2 cm0-2 cm5 cm5 cmACACDHDH2 cm2 cmDCarboHDCarboH2 cm10+nodes10+nodesDCarboHDCarboHN-N-N+N+N+N+BCIRG 006BCIRG 006N-N-ACACDHDHN-N-HERAHERAHRHRSlamon et al 2006 Slamon et al 2006 Perez et al 2007;Smith et al 2007Perez 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D
15、FSDFS获益获益35-49 years35-49 years0.00.00.50.52.52.51.01.01.51.52.02.0HERAHERA35 years35 years50-59 years50-59 years60 years60 yearsN9831/B-31N9831/B-3140 years40 years60 years60 years40-49 years40-49 years50-59 years50-59 yearsFavours HerceptinFavours HerceptinFavours no HerceptinFavours no HerceptinH
16、RHRPerez et al 2007;Smith et al 2007Perez 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 line1st lineHO648gHO648gM77001 M77001 US OncologyUS OncologyBCIRG 007BCIRG 007CHATCHATTAnDEMTAnDEMRHEARHEAR Re el la ap ps se e2nd+lines2nd+linesGBG-26GBG-26BO17929BO17929EGF104900EGF104900Numerous Num
17、erous Phase II studiesPhase II studiesMBCMBCP Pr ro og gr re es ss si io on nHERAHERANSABP B-31NSABP B-31NCCTG N9831NCCTG N9831BCIRG 006BCIRG 006AdjuvantAdjuvantNOAHNOAHMDACCMDACCGeparQuattroGeparQuattroNumerous Phase II Numerous Phase II studiesstudiesNeoNeoEBCEBCNOAH study:NOAH study:neoadjuvant H
18、erceptin for LABCneoadjuvant Herceptin for LABCa aHormone receptor-positive patients receive adjuvant tamoxifen Hormone receptor-positive patients receive adjuvant tamoxifen AP,doxorubicin 60 mg/mAP,doxorubicin 60 mg/m2 2,paclitaxel 150 mg/m,paclitaxel 150 mg/m2 2;H,Herceptin 8 mg/kg loading then 6
19、mg/kg;H,Herceptin 8 mg/kg loading then 6 mg/kg P,paclitaxel 175 mg/mP,paclitaxel 175 mg/m2 2;CMF,cyclophosphamide 600 mg/mCMF,cyclophosphamide 600 mg/m2 2,methotrexate 40 mg/m,methotrexate 40 mg/m2 2,5-fluorouracil 600 mg/m,5-fluorouracil 600 mg/m2 2 LABC,locally advanced breast cancer;LABC,locally
20、advanced breast cancer;q3w,every 3 weeks;q4w,every 4 weeksq3w,every 3 weeks;q4w,every 4 weeksHER2-positive LABCHER2-positive LABC(IHC 3+and/or FISH+)(IHC 3+and/or FISH+)n=113n=113H+APH+APq3w x 3q3w x 3H+PH+Pq3w x 4q3w x 4H q3w x 4 H q3w x 4+CMF q4w x 3+CMF q4w x 3Surgery followed bySurgery followed
21、byradiotherapyradiotherapya aH continued q3wH continued q3wto Week 52to Week 52n=115n=115P Pq3w x 4q3w x 4CMFCMFq4w x 3q4w x 3Surgery followed bySurgery followed byradiotherapyradiotherapya aAPAPq3w x 3q3w x 3APAPq3w x 3q3w x 3P Pq3w x 4q3w x 4CMFCMFq4w x 3q4w x 3Surgery followed bySurgery followed
22、byradiotherapyradiotherapya an=99n=99HER2-negative LABCHER2-negative LABC(IHC 0/1+)(IHC 0/1+)p=0.002p=0.002p=0.004p=0.004pCR pCR(%)(%)Baselga et al 2007;Gianni et al 2007Baselga et al 2007;Gianni et al 2007HER2 positive HER2 positive(n=228)(n=228)HER2 positiveHER2 positive(n=62)(n=62)NOAHNOAH研究中赫赛汀新
23、辅助显著提高了研究中赫赛汀新辅助显著提高了pCRpCR率率Without HerceptinWithout HerceptinWith HerceptinWith Herceptin9090808070706060505040403030202010100 0HER2 negativeHER2 negative(n=99)(n=99)HER2 negativeHER2 negative(n=14)(n=14)232343431717191955552929Total populationTotal populationIBC populationIBC populationpCR,pathol
24、ogical complete response in the breastpCR,pathological complete response in the breastIBC,inflammatory breast cancerIBC,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)a aX was given either concurrently or sequentially with D+HX was given either co
25、ncurrently or sequentially with D+HEC,epirubicin,cyclophosphamide;EC,epirubicin,cyclophosphamide;FEC,5-fluorouracil,epirubicin,cyclophosphamideFEC,5-fluorouracil,epirubicin,cyclophosphamide My,Myocet;X,XelodaMy,Myocet;X,Xeloda0102030405060708090100pCR(%)Antn et al 2007,n=26My+P+HaUntch et al 2008,n=
26、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(inc
27、luding 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HER2HER2阳性乳腺癌的基础治疗阳性乳腺癌的基础治疗1st line1st lineHO648gHO648gM77001 M77001 US OncologyUS On
28、cologyBCIRG 007BCIRG 007CHATCHATTAnDEMTAnDEMRHEARHEAR Re el la ap ps se e2nd+lines2nd+linesGBG-26GBG-26BO17929BO17929EGF104900EGF104900Numerous Numerous Phase II studiesPhase II studiesMBCMBCP Pr ro og gr re es ss si io on nHER2,human epidermal growth factor receptor 2 HER2,human epidermal growth fa
29、ctor receptor 2 EBC,early breast cancer;MBC,metastatic breast cancer EBC,early breast cancer;MBC,metastatic breast cancer EBCEBCHERAHERANSABP B-31NSABP B-31NCCTG N9831NCCTG N9831BCIRG 006BCIRG 006AdjuvantAdjuvantNOAHNOAHMDACCMDACCGeparQuattroGeparQuattroNumerous Phase II Numerous Phase II studiesstu
30、diesNeoNeo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)Median survival(months)IHC,immunohistochemistry;P,paclitaxel IHC,immunohistochemistry;P,paclitaxel H,Herceptin;D,docetaxel;Carbo,carboplatinH,Herceptin;D,docetaxel;Carbo,carboplatinH0648gH0648g(IHC 3+)(IHC 3+)M77001M77001BCIRG 007B
31、CIRG 007US OncologyUS Oncology(IHC 3+)(IHC 3+)Smith et al 2001;Marty et al 2005 Smith et al 2001;Marty et al 2005 Robert et al 2006;Pegram et al 2007Robert et al 2006;Pegram et al 2007TAnDEM-TAnDEM-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.
32、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选择赫赛汀个体化治疗方案疾病进展后如何合理选择赫赛汀个体化治疗方案1st line1st lineHO648gHO648gM77001 M77001 US OncologyUS OncologyBCIRG 007BCIRG 007CHATCHATTAnDEMTAnDEMRHEARHEAR Re el la ap ps se e2nd+lines2nd+linesGBG-26GBG-26BO17929BO179
33、29EGF104900EGF104900Numerous Numerous Phase II studiesPhase II studiesMBCMBCP Pr ro og gr re es ss si io on nEBCEBCHERAHERANSABP B-31NSABP B-31NCCTG N9831NCCTG N9831BCIRG 006BCIRG 006AdjuvantAdjuvantNOAHNOAHMDACCMDACCGeparQuattroGeparQuattroNumerous Phase II Numerous Phase II studiesstudiesNeoNeoHer
34、ceptin improves OS if continued beyond Herceptin improves OS if continued beyond progressionprogressionOS(months)OS(months)Continued HerceptinContinued HerceptinDiscontinued HerceptinDiscontinued HerceptinExtra et al 2006Extra et al 2006Jackisch et al 2007;Menard et al 2008Jackisch et al 2007;Menard
35、 et al 2008p0.0001p0.0001p0.0001p50(5.1%-5.4%)Use of hypertensive medications(6.8%)Baseline LVEF 50-54(12.9%)Rastogi et al.Rastogi et al.Abstract LBA513Abstract LBA513 ASCO 2007ASCO 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
36、检查。心功能监测心功能监测LVEFLVEF低于低于50%50%恢复至恢复至50%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HerceptinHerceptin治疗治疗继续用药继续用药暂停暂停HerceptinHerceptin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20082008年年NCCNNCCN复发或复发或IVIV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
37、/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)Pertuzumab(2C4):anti HER2 agent: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 Herceptin+pertuzumab provides clinical benefit to patients progressing o
38、n Herceptinto patients progressing on HerceptinGelmon et al 2008Gelmon et al 2008ResponseResponseCRCRPRPRORRORRSD for 6 months(Cycle 8)SD for 6 months(Cycle 8)CBRCBRPDPDMedian PFSMedian PFSn(%)n(%)n=66n=665(7.6)5(7.6)11(16.7)11(16.7)16(24.2)16(24.2)17(25.8)17(25.8)33(50.0)33(50.0)33(50.0)33(50.0)24
39、weeks24 weeksHerceptin+pertuzumab is a well-tolerated Herceptin+pertuzumab is a well-tolerated combinationcombinationPatients(%)Patients(%)Adverse events,all gradesAdverse events,all gradesAdverse events,grades 3/4Adverse events,grades 3/4Gelmon et al 2008Gelmon et al 2008u针对针对HER2HER2受体的靶向药物受体的靶向药物
40、u针对表皮生长因子受体针对表皮生长因子受体(EGFR)(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mTORmTOR，RasRas，MEK MEK等等针对针对EGFREGFR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（LapatinibLapatinib，TykerbTykerb）u吉非替尼（吉非替尼（ZD1839ZD1839，IressaIressa，GefitinibGefitinib
41、，易瑞沙），易瑞沙）u埃罗替尼（埃罗替尼（TarcevaTarceva，erlotiniberlotinib）Lapatinib(Tykerb)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 EGF100151:Lapatinib+Capecitabine in Advanced Breast CancerAdvanced Breast CancerRefractory,progre
42、ssive 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 pro
43、gressionor unacceptabletoxicity*Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint.EGF100151:Lapatinib+Capecitabine in EGF100151:Lapatinib+Capecitabine in Advanced Breast Cancer(contd)Advanced Breast Cancer(contd)Longer time to progression36.9 vs 19.7
44、 wks(P=.00016)Longer progression-free survival36.9 vs 17.9 wks(P=.000045)Fewer progressions or deaths38%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+
45、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 T
46、TP 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+CancerLapatinib for Brain Metastases in Her2+Cancer Lin et al.ASCO 2006;NCI-CTEP 6969 trialLapatinib+Trastuzumab for Trastuzumab Lapatinib+Trastuzumab
47、 for Trastuzumab progressing on Her2+Cancerprogressing on Her2+Cancer ASCO 2008Progression-Free SurvivalProgression-Free SurvivalOverall Survival in ITT PopulationOverall Survival in ITT Population0 0200200DaysDaysGefitinib-Gefitinib-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1 13030606090901201201501504004006
48、00600800800100010001200120014001400Tumour Tumour volumevolume(mm(mm3 3)Massarweh et al.Breast Cancer Res Treat 2002FulvestrantFulvestrantFulvestrant+gefitinibOestradiolOestradiolFulvestrant plus gefitinib delays resistance in MCF-7/HER2 tumours in vivoFulvestrant plus gefitinib delays resistance in
49、MCF-7/HER2 tumours in vivo Phase II Trial of Gefitinib in Advanced Breast Cancer Phase II Trial of Gefitinib in Advanced Breast Cancer Partial responsePartial responseStable diseaseStable diseaseClinical benefitClinical benefitProgressive diseaseProgressive disease1 15 5 6(66%)6(66%)3 3ER-positiveER
50、-positive(n=9)(n=9)ER-negativeER-negative (n=18)(n=18)1 11 1 2(11%)2(11%)1616Robertson et al.ASCO Proc.2003Robertson et al.ASCO Proc.2003lAcquired resistance to TAM(n=27)Acquired resistance to TAM(n=27)or or ER-negative tumours(n=27)ER-negative tumours(n=27)GefitinibGefitinib LD 1000 mg(D1)Daily dos