乳腺癌分子靶向藥物治療進(jìn)展課件

乳腺癌分子靶向藥物治療進(jìn)展

張清媛哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院乳腺癌分子靶向藥物治療進(jìn)展張清媛1ChemotherapyEndocrinetherapyTargetedtherapiesTreatmentofBCHIGHLIGHTSINBREASTCANCER

DISEASEBIOLOGYChemotherapyEndocrineTreatmen2針對(duì)HER2受體的靶向藥物針對(duì)表皮生長(zhǎng)因子受體(EGFR)的靶向治療針對(duì)腫瘤血管生成的分子靶向藥物其他信號(hào)通路抑制劑——mTOR，Ras，MEK等乳腺癌分子靶向藥物治療針對(duì)HER2受體的靶向藥物乳腺癌分子靶向藥物治療3中位生存期的縮短HER2擴(kuò)增/過(guò)度表達(dá) 3年

HER2正常表達(dá) 6-7年HER2受體過(guò)度表達(dá)HER2原癌基因擴(kuò)增HER2在約20%～30%的乳腺癌組織中過(guò)度表達(dá)SlamonDJetal.Science1987;235:177–82HER2陽(yáng)性與內(nèi)分泌治療及部分化療耐藥密切相關(guān)，是重要的預(yù)后指標(biāo)HER2成為乳腺癌治療的理想靶點(diǎn)，是預(yù)測(cè)赫賽汀療效的重要指標(biāo)中位生存期的縮短HER2受體過(guò)度表達(dá)HER2原癌基因擴(kuò)增4赫賽汀(曲妥珠單抗):

人源化抗HER2單克隆抗體高度親和性(Kd=0.1nM)和特異性95%人源化,5%鼠抗，顯著降低免疫原性(HAMA)全球第一種治療實(shí)體瘤的單克隆抗體赫賽汀(曲妥珠單抗):

人源化抗HER2單克隆抗體高度親和5Inhibitionof

HER2-mediatedsignallingActivationofADCC赫賽汀的作用機(jī)制AdditionalmechanismsPreventsformationoftruncatedHER2(p95)InhibitionofHER2-regulatedangiogenesisADCC,antibody-dependentcellularcytotoxicityInhibitionof

HER2-mediateds6赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeoEBCHER2,humanepidermalgrowthfactorreceptor2

EBC,earlybreastcancer;MBC,metastaticbreastcancer赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO7>13,000患者入組的赫賽汀四大輔助臨床研究Piccart-Gebhartetal2005

Romondetal2005;Slamonetal2006NCCTGN9831(USA)HERA(ex-USA)BCIRG006(global)NSABPB-31(USA)IHC/FISH(n=5,090)Observation1year2yearsIHC/FISH(n=3,505)1year1yearFISH

(n=3,222)1year1yearIHC/FISH(n=2,030)1yearDocetaxelDocetaxel+carboplatinDoxorubicin+cyclophosphamideHerceptinStandardCTxPaclitaxelIHC,immunohistochemistry

FISH,fluorescenceinsituhybridisationCTx,chemotherapy>13,000患者入組的赫賽汀四大輔助臨床研究Piccar8赫賽汀可減少三分之一的死亡風(fēng)險(xiǎn)012B-31/N9831ACPH

3HERACTxH1year2Medianfollow-up,yearsOverallsurvivalbenefitBCIRG006ACDH3BCIRG006DCarboH3Favours

HerceptinFavoursno

HerceptinHRSlamonetal2006

Perezetal2007;Smithetal2007H,Herceptin;AC,doxorubicin,cyclophosphamide

P,paclitaxel;D,docetaxel;Carbo,carboplatin

HR,hazardratioSizeofsquarerepresentssamplesize;horizontalbarsindicate95%confidenceintervals赫賽汀可減少三分之一的死亡風(fēng)險(xiǎn)012B-31/N98319無(wú)論腫瘤大小，赫賽汀均顯示DFS獲益Slamonetal2006

Perezetal2007;Smithetal2007>2-5cmBCIRG006>2-5cm>5cm0.01.52.00-2cmN9831/B-310-2cm>5cmACDH<2cmDCarboH<2cm≥2cm≥2cmFavoursHerceptinFavoursnoHerceptinHRHERADFS,disease-freesurvival無(wú)論腫瘤大小，赫賽汀均顯示DFS獲益Slamonetal10無(wú)論淋巴結(jié)情況，赫賽汀均顯示DFS獲益N,node1-3+nodesFavoursHerceptinFavoursnoHerceptin0.01.52.01-3+nodes≥4+nodesNotassessedN9831/B-31N-4-9+nodes>10+nodesDCarboHN-N+N+BCIRG006N-ACDHN-HERAHRSlamonetal2006

Perezetal2007;Smithetal2007無(wú)論淋巴結(jié)情況，赫賽汀均顯示DFS獲益N,node1-3+11無(wú)論年齡大小，赫賽汀均顯示DFS獲益35-49years0.01.52.0HERA<35years50-59years≥60yearsN9831/B-31<40years≥60years40-49years50-59yearsFavoursHerceptinFavoursnoHerceptinHRPerezetal2007;Smithetal2007無(wú)論年齡大小，赫賽汀均顯示DFS獲益35-49years012赫賽汀的新輔助治療研究進(jìn)展1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeoEBC赫賽汀的新輔助治療研究進(jìn)展1stlineHO648gRel13NOAHstudy:

neoadjuvantHerceptinforLABCaHormonereceptor-positivepatientsreceiveadjuvanttamoxifen

AP,doxorubicin60mg/m2,paclitaxel150mg/m2;H,Herceptin8mg/kgloadingthen6mg/kg

P,paclitaxel175mg/m2;CMF,cyclophosphamide600mg/m2,methotrexate40mg/m2,5-fluorouracil600mg/m2

LABC,locallyadvancedbreastcancer;q3w,every3weeks;q4w,every4weeksHER2-positiveLABC

(IHC3+and/orFISH+)n=113H+APq3wx3H+P

q3wx4Hq3wx4

+CMFq4wx3SurgeryfollowedbyradiotherapyaHcontinuedq3wtoWeek52n=115P

q3wx4CMF

q4wx3SurgeryfollowedbyradiotherapyaAP

q3wx3AP

q3wx3P

q3wx4CMF

q4wx3Surgeryfollowedbyradiotherapyan=99HER2-negativeLABC

(IHC0/1+)NOAHstudy:

neoadjuvantHerce14p=0.002p=0.004pCR(%)Baselgaetal2007;Giannietal2007HER2positive(n=228)HER2positive(n=62)NOAH研究中赫賽汀新輔助顯著提高了pCR率WithoutHerceptinWithHerceptin9080706050403020100HER2negative

(n=99)HER2negative

(n=14)234317195529TotalpopulationIBCpopulationpCR,pathologicalcompleteresponseinthebreast

IBC,inflammatorybreastcancerp=0.002p=0.004pCR(%)Baselgae15新輔助化療中參加赫賽汀明顯提高療效(16個(gè)相關(guān)研究,1,226例患者入組)aXwasgiveneitherconcurrentlyorsequentiallywithD+H

EC,epirubicin,cyclophosphamide;FEC,5-fluorouracil,epirubicin,cyclophosphamide

My,Myocet;X,Xeloda0102030405060708090100pCR(%)Antónetal2007,n=26My+P+HaUntchetal2008,n=452EC+HD+H±XHCoudertetal2007,n=70D+HMartyetal2007,n=30ECD+HLimentanietal2007,n=31D+V+H

(includingIBC)Binesetal2003,n=32D+HBursteinetal2003,n=40P+H

(includingIBC)Kellyetal2006,n=37ACP+H

(includingIBC)Harrisetal2003,n=40V+H

(includingIBC)Hurleyetal2002,n=48D+cisplatin+H

(includingIBC)Tripathyetal2007,n=28P+X+HLybaertetal2006,n=25X+D+HBuzdaretal2007,n=45PFEC+HPernasetal2007,n=33PFEC+HGiannietal2007,n=115APPCMF+H

(includingIBC)Untchetal2005,n=174ECP+H新輔助化療中參加赫賽汀明顯提高療效(16個(gè)相關(guān)研究,1,16赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionHER2,humanepidermalgrowthfactorreceptor2

EBC,earlybreastcancer;MBC,metastaticbreastcancerEBCHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeo赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO17一線赫賽汀治療顯著延長(zhǎng)患者的生存時(shí)間Mediansurvival(months)IHC,immunohistochemistry;P,paclitaxel

H,Herceptin;D,docetaxel;Carbo,carboplatinH0648g(IHC3+)M77001BCIRG007USOncology(IHC3+)Smithetal2001;Martyetal2005

Robertetal2006;Pegrametal2007一線赫賽汀治療顯著延長(zhǎng)患者的生存時(shí)間Mediansurvi18TAnDEM--赫賽汀聯(lián)合阿那曲唑治療HER-2(+〕激素敏感性轉(zhuǎn)移性乳腺癌臨床研究結(jié)果〔2006年圣安東尼奧〕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月歐洲推薦赫賽汀聯(lián)合芳香化酶抑制劑治療HER2與激素受體陽(yáng)性轉(zhuǎn)移性乳癌TAnDEM--赫賽汀聯(lián)合阿那曲唑治療HER-2(+〕19疾病進(jìn)展后如何合理選擇赫賽汀個(gè)體化治療方案1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionEBCHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeo疾病進(jìn)展后如何合理選擇赫賽汀個(gè)體化治療方案1stlineH20HerceptinimprovesOSifcontinuedbeyondprogressionOS(months)ContinuedHerceptinDiscontinuedHerceptinExtraetal2006Jackischetal2007;Menardetal2008p<0.0001p<0.0001p=0.0014(n=118)(n=154)(n=81)(n=112)(n=70)(n=107)ProspectiveHerminestudyGermanobservationalstudyDemetrastudyOS,overallsurvivalHerceptinimprovesOSifconti21赫賽汀在多線治療中的作用赫賽汀治療的最大獲益是持續(xù)治療臨床證據(jù)提示含赫賽汀方案治療中進(jìn)展并不等于赫賽汀耐藥,調(diào)整化療藥并繼續(xù)赫賽汀治療仍可獲益.赫賽汀通過(guò)持續(xù)抑制HER2

,在多線治療中病人仍可獲益赫賽汀在多線治療中的作用赫賽汀治療的最大獲益是持續(xù)治療22Slamonetal2006

Rastogietal2007

Suteretal2007

Perezetal2008赫賽汀輔助治療的心臟平安性aDatanotcomparableduetodifferentassessmentcriteria

CHF,congestiveheartfailure;cum,cumulativeincidence

LVEF,leftventricularejectionfraction;NR,notreported3.0NRNR18.08.6Asymptomatic

LVEFdecline,%aH1yearACPHACPHACDHDCarboHArmHERANSABPB-31NCCTGN9831BCIRG0061,6789475701,0681,056nSevereCHF,%0.63.8cum(5yr)3.3cum(3yr)1.90.4Cardiacdeath,n00000Slamonetal2006

Rastogiet23Age>50(5.1%-5.4%)Useofhypertensivemedications(6.8%)BaselineLVEF50-54(12.9%)Rastogietal.

AbstractLBA513

ASCO2007Rastogietal.AbstractLBA51324考慮到心臟不良反響事件，臨床上不建議Trastuzumab與蒽環(huán)類(lèi)藥物聯(lián)合。Trastuzumab可以在AC方案后與紫杉醇聯(lián)合使用或者在化療完成后序貫使用。目前Trastuzumab治療療程為1年，建議每三個(gè)月一次進(jìn)展心功檢查?？紤]到心臟不良反響事件，臨床上不建議Trastuzumab與25心功能監(jiān)測(cè)LVEF低于50%恢復(fù)至50%以上不恢復(fù)、或繼續(xù)惡化終止Herceptin治療繼續(xù)用藥暫停Herceptin治療，觀察或?qū)ΠY處理心功能監(jiān)測(cè)LVEF低于50%恢復(fù)至50%以上不恢復(fù)、或繼續(xù)惡26

赫賽汀臨床應(yīng)用

2021年NCCN復(fù)發(fā)或IV期乳腺癌指南HR陰性，HER2陽(yáng)性具有內(nèi)臟危象復(fù)發(fā)或IV期乳腺癌曲妥珠單抗±化療赫賽汀聯(lián)合輔助化療方案AC→THAC→DHTCH化療→HDH→FEC用法：每周方案首劑4mg/kg，維持2mg/kg

三周方案首劑8mg/kg，維持6mg/kg

赫賽汀臨床應(yīng)用

2021年NCCN復(fù)發(fā)或IV期27帕妥珠單抗Pertuzumab(2C4):antiHER2agent

以HER-2為靶位的人源化單克隆抗體與HER-2受體胞外構(gòu)造域Ⅱ區(qū)結(jié)合，抑制二聚體的形成抑制HER2與EGFR和HER3形成二聚體。

帕妥珠單抗Pertuzumab(2C4):antiHE28Herceptin+pertuzumabprovidesclinicalbenefittopatientsprogressingonHerceptinGelmonetal2008ResponseCRPRORRSDfor6months(≥Cycle8)CBRPDMedianPFSn(%)

n=665(7.6)11(16.7)

16(24.2)17(25.8)33(50.0)33(50.0)24weeksHerceptin+pertuzumabprovide29Herceptin+pertuzumabisawell-toleratedcombinationPatients(%)Adverseevents,allgradesAdverseevents,grades3/4Gelmonetal2008Herceptin+pertuzumabisawe30針對(duì)HER2受體的靶向藥物針對(duì)表皮生長(zhǎng)因子受體(EGFR)的靶向治療針對(duì)腫瘤血管生成的分子靶向藥物其他信號(hào)通路抑制劑——mTOR，Ras，MEK等針對(duì)HER2受體的靶向藥物31針對(duì)EGFR的靶向治療小分子酪氨酸激酶抑制劑(SMTKIs)EGFR單克隆抗體(MAbs)多靶點(diǎn)抗腫瘤抑制劑針對(duì)EGFR的靶向治療小分子酪氨酸激酶抑制劑(SMTKIs32酪氨酸激酶抑制劑拉帕替尼〔Lapatinib，Tykerb〕吉非替尼〔ZD1839，Iressa，Gefitinib，易瑞沙〕埃羅替尼〔Tarceva，erlotinib〕酪氨酸激酶抑制劑拉帕替尼〔Lapatinib，Tykerb〕33Lapatinib(Tykerb)口服的TKI雙重抑制劑:EGFR和HER-2Lapatinib(Tykerb)口服的TKI34GeyerCE,etal.ASCO2006.ClinicalScienceSymposium.EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancerRefractory,progressivemetastaticorlocallyadvancedHER2+breastcancerpreviouslytreatedwithanthracycline,

taxane,ortrastuzumab(N=528planned*)Lapatinib1250mgdaily+

Capecitabine2000mg/m2daily

forDays1-14,3-weekcycles

(n=160)Capecitabine2500mg/m2daily

forDays1-14,3-weekcycles

(n=161)Follow-up:

untilprogression

orunacceptable

toxicity*StudyenrollmentterminatedearlybyIDMCduetosuperiorityofcombinationarminprimaryendpoint.GeyerCE,etal.ASCO2006.Cl35EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancer(cont’d)Longertimetoprogression36.9vs19.7wks(P=.00016)Longerprogression-freesurvival36.9vs17.9wks(P=.000045)Fewerprogressionsordeaths38%vs48%Response(independentreview)Overall:22.5%vs14.3%(P=.113)GeyerCE,etal.ASCO2006.ClinicalScienceSymposium.Progression-FreeSurvival(%)Time(Wks)2040608001001020304050CapecitabineLapatinib+capecitabineITTpopulationEGF100151:Lapatinib+Capecit362007.3FDA批準(zhǔn)

拉帕替尼聯(lián)合卡培他濱治療HER2過(guò)度表達(dá)且經(jīng)蒽環(huán)類(lèi)、紫杉類(lèi)藥物和曲妥珠單抗治療后復(fù)發(fā)的晚期或者轉(zhuǎn)移性乳腺癌

2007.3FDA批準(zhǔn)3739patients(38patientsprogressionafterradiothrapy)New/progressivemeasurable(>1cm)brainmetastasesTreatment:Lapatinib750mgpoBIDResult2patientsPR158dand347d5patientsSD>16weeksMedianTTP3.2monthsMST6.57months1patienthadresponse,butdidnotmeetRECISTLapatinib成為T(mén)rastuzumab耐藥或腦轉(zhuǎn)移患者新選擇

LapatinibforBrainMetastasesinHer2+Cancer

Linetal.ASCO2006;NCI-CTEP6969trialLapatinibforBrainMetastases38Lapatinib+TrastuzumabforTrastuzumabprogressingonHer2+CancerASCO2021Lapatinib+TrastuzumabforTras39Progression-FreeSurvivalProgression-FreeSurvival40OverallSurvivalinITTPopulationOverallSurvivalinITTPopula410200DaysGefitinib--表皮生長(zhǎng)因子受體酪氨酸激酶抑制劑1306090120150400600800100012001400Tumourvolume(mm3)Massarwehetal.BreastCancerResTreat2002FulvestrantFulvestrant+gefitinibOestradiolFulvestrantplusgefitinibdelaysresistanceinMCF-7/HER2tumoursinvivo0200DaysGefitinib--表皮生長(zhǎng)因子受體酪氨酸42

PhaseIITrialofGefitinibinAdvancedBreastCancerPartialresponseStablediseaseClinicalbenefitProgressivedisease156(66%)3ER-positive

(n=9)ER-negative

(n=18)112(11%)16Robertsonetal.ASCOProc.2003AcquiredresistancetoTAM(n=27)orER-negativetumours(n=27)Gefitinib

LD1000mg(D1)Dailydose

500mg/dayuntildiseaseprogressionorunacceptabletoxicityPhaseIITrialofGefitinib43Erlotinib--小分子EGFR酪氨酸激酶抑制劑

previoustherapywitheitherananthracyclineorataxaneforMBC

Erlotinib（150mgorallydaily）+gemcitabine（1000mg/m2,Days1、8,3-weekcycles）Apartialresponse(PR)rateof17%hasbeenreported(ASCO2005)N0234：Erlotinib+GemcitabineErlotinib--小分子EGFR酪氨酸激酶抑制劑

p44N0234

：Erlotinib+GemcitabineResultTNNON-TNPPR25%14%0.30CBR25%22%0.75PFS72d98d0.13OS227d738d0.0002TN*=ER(-)/PR(-)/HER-2(-)三陰

ASCO2007N0234：Erlotinib+Gemcitabine45西妥昔單抗(Cetuximab，erbitux，C225，愛(ài)必妥)Cetuximab是針對(duì)HER-1的特異性單克隆抗體動(dòng)物試驗(yàn)顯示，Cetuximab可有效抑制乳腺癌細(xì)胞增殖和生長(zhǎng)，現(xiàn)有不少研究機(jī)構(gòu)開(kāi)場(chǎng)應(yīng)用Cetuximab單藥或與化療藥物聯(lián)合治療EGFR陽(yáng)性乳腺癌。西妥昔單抗(Cetuximab，erbitux，C22546泰欣生?是一個(gè)針對(duì)EGFR的單抗藥物，通過(guò)與EGFR胞外區(qū)3A表位結(jié)合，競(jìng)爭(zhēng)性抑制配體與EGFR的結(jié)合，使受體失去活性：IgG1型單克隆抗體，分子量為150KD95％人源化激發(fā)ADCC和CDC效應(yīng)抑制腫瘤細(xì)胞比內(nèi)源性配體親合力更高〔Kd=10-9〕泰欣生（尼妥珠單抗,Nimotuzumab）

泰欣生?是一個(gè)針對(duì)EGFR的單抗藥物，通過(guò)與EGFR胞外區(qū)347古巴：泰欣生?聯(lián)合新輔助化療治療乳腺癌研究終點(diǎn)評(píng)估尼妥珠單抗聯(lián)合化療藥物治療局部晚期乳腺癌患者新輔助化療的平安性、藥代動(dòng)力學(xué)及療效。Ⅲ期初治乳腺癌患者泰欣生（50/100/200/400mg，qw）＋阿霉素（60mg/m2，q3w

）＋環(huán)磷酰胺（600mg/m2，q3w）J.

Soriano,N.

Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116古巴：泰欣生?聯(lián)合新輔助化療治療乳腺癌研究終點(diǎn)Ⅲ期初治乳腺癌481781522282936434950576470RANDOMIZATIONSURGERYNimotuzumabAC用藥方案J.

Soriano,N.

Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116178152249疾病控制情況疾病控制情況共有13例患者入組，12例患者可評(píng)估：9例PR，3例SD。PatientsDoseAgeRaceTNMStageDiagnoseNGERHER-2015045WT4bN0M0IIIBIDC3NegNeg025040WT3N1M0IIIAILC3Neg3+035044WT3N1M0IIIAIDC3Pos2+0510059BT4bN1M0IIIBIDC3NegNeg0610063BT4bN1M0IIIBIDC2NegNeg1310046BT3N1M0IIIAIDC1PosNeg0720064WT4bN1M0IIIBIDC3NegNeg0820042WT3N1M0IIIAIDC3PosNeg0920042WT4aN1M0IIIBIDC3Neg3+1040058WT4bN0M0IIIBIDC2PosNeg1140059BT4bN1M0IIIBIDC3Neg3+1240034WT3N1M0IIIAIDC1PosNegJ.

Soriano,N.

Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116疾病控制情況疾病控制情況PatientsDoseAgeRac50平安性：在50、100、200和400mg中，未見(jiàn)劑量限制性毒性臨床未見(jiàn)心臟毒性；聯(lián)合治療平安性高，患者耐受性良好常見(jiàn)不良反響為：皮疹、皮膚反響、惡心、嘔吐；紅斑,丘疹及色素沉著較常見(jiàn)，通常發(fā)生在面部及上肢上部，能自行緩解初步結(jié)論：泰欣生治療乳腺癌有效，聯(lián)合治療在50，100，200和400mg劑量下是平安的，有很好的耐受性結(jié)論J.

Soriano,N.

Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116平安性：結(jié)論J.

Sor51蘇尼替尼（Sunitinib）--小分子多靶點(diǎn)酪氨酸激酶抑制劑

NHONHH3CCH3NHONCH3CH3Selectiveinhibitorof:PDGFRVEGFR2(KDR)KITFLT32006年1月美國(guó)FDA批準(zhǔn)上市,用于治療晚期腎細(xì)胞癌和胃腸道間質(zhì)瘤。蘇尼替尼（Sunitinib）--小分子多靶點(diǎn)酪氨酸激酶抑制52SunitinibinBreastCancerPatients

multicentricphaseIIstudywith64patients*OnePRnotyetconfirmed.N=64PartialResponse*7(11%)StableDisease>6months3(5%)OverallClinicalBenefit10(16%)patientshadreceived3.5differentchemotherapies（anthracyclineortaxane）85%ofpatientshadreceivedadjuvantchemotherapysunitinib50mg/dSunitinibinBreastCancerPat53多激酶抑制劑：絲氨酸/蘇氨酸：C-Raf(Raf-1)和B-Raf1

酪氨酸激酶受體：VEGFR-2、VEGFR-3、PDGFR-b、FLT-3和c-KIT

WilhelmSetal.ClinCancerRes.2004;64:7099-7109.索拉非尼(sorafenib)：口服信號(hào)轉(zhuǎn)導(dǎo)抑制劑,在Raf激酶水平和受體酪氨酸激酶VEGFR-2和PDGFR-β阻斷Raf/MEK/ERK途徑,抗腫瘤血管生成及腫瘤細(xì)胞增殖多激酶抑制劑：絲氨酸/蘇氨酸：C-Raf(Raf-1)和B54SofitinibphaseIIinMBCSofitinibphaseIIinMBC55針對(duì)HER2受體的靶向藥物針對(duì)表皮生長(zhǎng)因子受體(EGFR)的靶向治療針對(duì)腫瘤血管生成的分子靶向藥物其他信號(hào)通路抑制劑——mTOR，Ras，MEK等針對(duì)HER2受體的靶向藥物56Angiogenesisisinvolvedthroughouttumourformation,growthandmetastasisAdaptedfromPoonRT,etal.JClinOncol2001;19:1207–25StagesatwhichangiogenesisplaysaroleintumourprogressionPremalignantstageMalignanttumourTumour

growthVascular

invasionDormant

micrometastasisOvert

metastasis(Avasculartumour)(Angiogenic

switch)(Vascularised

tumour)(Tumourcell

intravasation)(Seedingin

distantorgans)(Secondaryangiogenesis)Angiogenesisisinvolvedthrou57血管生成的雙向調(diào)節(jié)機(jī)制ActivatorInhibitorAngiostatinEndostatinThrombospondin-1VEGFbFGFPDGF血管生成的雙向調(diào)節(jié)機(jī)制ActivatorInhibitorA58Bevacizumab(MonoclonalAntibodytoVEGF)Humanizedtoavoidimmunogenicity(93%human,7%murine)Recognizesallisoformsofvascularendothelialgrowthfactor,Kd=8x10-10MTerminalhalflife17-21daysBevacizumab(MonoclonalAntibo59715casesStratify:DFI<24mos.vs.>24os.<3vs.>3metastaticsitesAdjuvantchemotherapyyesvs.noER+vs.ER-vs.ERunknownageRANDOMIZE

Paclitaxel+BevacizumabPaclitaxelE2100:StudyDesign

-線治療晚期乳腺癌的Ⅲ期臨床研究

28-DayCycle:Paclitaxel90mg/m2D1,8and15Bevacizumab10mg/kgD1and15715casesStratify:RANDOMIPac60AllpatientsMeasurableDisease010203040PaclitaxelOverallResponseRatePac+BevE2100:Response31623633025034.3%16.4%28.2%14.2%P<0.0001P<0.0001AllpatientsMeasurableDisease61E2100:ProgressionFreeSurvivalHR=0.498(0.401-0.618)LogRankTestp<0.001Months0.01.0PFSProportion0102030Pac.+Bev.10.97monthsPaclitaxel6.11monthsE2100:ProgressionFreeSurviv62BevacizumabToxicity

NCI-CTCGrades3and4PaclitaxelPac.+Bev.Grade3Grade4Grade3Grade4HTN*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-CTCv3.0,worstperpatient*P<0.0001;**P=0.0004BevacizumabToxicity

NCI-CTCG63NCCN2006年美國(guó)NCCN指南已推薦Bevacizumab聯(lián)合紫杉醇用于晚期乳腺癌的治療。NCCN2006年美國(guó)NCCN指南已推薦Bevacizuma64PhaseIItrialofCapecitabine+Bevacizumab

2007ASCOPhaseIItrialofCapecitabine65ResultResult66乳腺癌分子靶向藥物治療進(jìn)展課件67抗血管生成給藥方式許多化療藥低劑量時(shí)具有抗血管生成作用連續(xù)規(guī)律的低劑量化療〔metronomicchemotherapy〕稱(chēng)為抗血管生成化療(antiangiogenicchemotherapy)低劑量化療的優(yōu)勢(shì)抗血管生成給藥方式許多化療藥低劑量時(shí)具有抗血管生成作用68Metronomicchemotherapy+bevacizumabMetronomicchemotherapy+bevaci69Metronomicchemotherapy+bevacizumabMetronomicchemotherapy+bevaci70Conclusions腫瘤血管的形成是抗腫瘤治療中一個(gè)非常重要的靶抗新生血管治療與其他治療方法可能有協(xié)同效應(yīng)降低毒性，不增加副反響可與放療、化療、生物靶向治療聯(lián)用Conclusions腫瘤血管的形成是抗腫瘤治療中一個(gè)非常重71其他細(xì)胞周期抑制劑－779〔temsirolimus、CCI-779〕法尼基轉(zhuǎn)移酶抑制劑(farnesyltransferaseinhibitors，F(xiàn)TIs)Bcl-2反義核酸G3139其他細(xì)胞周期抑制劑－779〔temsirolimus、C72Sensitivity(+)Sensitivity(-)ResponderSurvivalbenefitNon-RespondersToxicitywithoutsurvivalbenefitDelayineffectivetreatment

TheFuture-TailoredTherapyMolecularprofiling122Righttherapyforrightpatient3Sensitivity(+)Sensitivity(73謝謝！謝謝！74

乳腺癌分子靶向藥物治療進(jìn)展

張清媛哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院乳腺癌分子靶向藥物治療進(jìn)展張清媛75ChemotherapyEndocrinetherapyTargetedtherapiesTreatmentofBCHIGHLIGHTSINBREASTCANCER

DISEASEBIOLOGYChemotherapyEndocrineTreatmen76針對(duì)HER2受體的靶向藥物針對(duì)表皮生長(zhǎng)因子受體(EGFR)的靶向治療針對(duì)腫瘤血管生成的分子靶向藥物其他信號(hào)通路抑制劑——mTOR，Ras，MEK等乳腺癌分子靶向藥物治療針對(duì)HER2受體的靶向藥物乳腺癌分子靶向藥物治療77中位生存期的縮短HER2擴(kuò)增/過(guò)度表達(dá) 3年

HER2正常表達(dá) 6-7年HER2受體過(guò)度表達(dá)HER2原癌基因擴(kuò)增HER2在約20%～30%的乳腺癌組織中過(guò)度表達(dá)SlamonDJetal.Science1987;235:177–82HER2陽(yáng)性與內(nèi)分泌治療及部分化療耐藥密切相關(guān)，是重要的預(yù)后指標(biāo)HER2成為乳腺癌治療的理想靶點(diǎn)，是預(yù)測(cè)赫賽汀療效的重要指標(biāo)中位生存期的縮短HER2受體過(guò)度表達(dá)HER2原癌基因擴(kuò)增78赫賽汀(曲妥珠單抗):

人源化抗HER2單克隆抗體高度親和性(Kd=0.1nM)和特異性95%人源化,5%鼠抗，顯著降低免疫原性(HAMA)全球第一種治療實(shí)體瘤的單克隆抗體赫賽汀(曲妥珠單抗):

人源化抗HER2單克隆抗體高度親和79Inhibitionof

HER2-mediatedsignallingActivationofADCC赫賽汀的作用機(jī)制AdditionalmechanismsPreventsformationoftruncatedHER2(p95)InhibitionofHER2-regulatedangiogenesisADCC,antibody-dependentcellularcytotoxicityInhibitionof

HER2-mediateds80赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeoEBCHER2,humanepidermalgrowthfactorreceptor2

EBC,earlybreastcancer;MBC,metastaticbreastcancer赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO81>13,000患者入組的赫賽汀四大輔助臨床研究Piccart-Gebhartetal2005

Romondetal2005;Slamonetal2006NCCTGN9831(USA)HERA(ex-USA)BCIRG006(global)NSABPB-31(USA)IHC/FISH(n=5,090)Observation1year2yearsIHC/FISH(n=3,505)1year1yearFISH

(n=3,222)1year1yearIHC/FISH(n=2,030)1yearDocetaxelDocetaxel+carboplatinDoxorubicin+cyclophosphamideHerceptinStandardCTxPaclitaxelIHC,immunohistochemistry

FISH,fluorescenceinsituhybridisationCTx,chemotherapy>13,000患者入組的赫賽汀四大輔助臨床研究Piccar82赫賽汀可減少三分之一的死亡風(fēng)險(xiǎn)012B-31/N9831ACPH

3HERACTxH1year2Medianfollow-up,yearsOverallsurvivalbenefitBCIRG006ACDH3BCIRG006DCarboH3Favours

HerceptinFavoursno

HerceptinHRSlamonetal2006

Perezetal2007;Smithetal2007H,Herceptin;AC,doxorubicin,cyclophosphamide

P,paclitaxel;D,docetaxel;Carbo,carboplatin

HR,hazardratioSizeofsquarerepresentssamplesize;horizontalbarsindicate95%confidenceintervals赫賽汀可減少三分之一的死亡風(fēng)險(xiǎn)012B-31/N983183無(wú)論腫瘤大小，赫賽汀均顯示DFS獲益Slamonetal2006

Perezetal2007;Smithetal2007>2-5cmBCIRG006>2-5cm>5cm0.01.52.00-2cmN9831/B-310-2cm>5cmACDH<2cmDCarboH<2cm≥2cm≥2cmFavoursHerceptinFavoursnoHerceptinHRHERADFS,disease-freesurvival無(wú)論腫瘤大小，赫賽汀均顯示DFS獲益Slamonetal84無(wú)論淋巴結(jié)情況，赫賽汀均顯示DFS獲益N,node1-3+nodesFavoursHerceptinFavoursnoHerceptin0.01.52.01-3+nodes≥4+nodesNotassessedN9831/B-31N-4-9+nodes>10+nodesDCarboHN-N+N+BCIRG006N-ACDHN-HERAHRSlamonetal2006

Perezetal2007;Smithetal2007無(wú)論淋巴結(jié)情況，赫賽汀均顯示DFS獲益N,node1-3+85無(wú)論年齡大小，赫賽汀均顯示DFS獲益35-49years0.01.52.0HERA<35years50-59years≥60yearsN9831/B-31<40years≥60years40-49years50-59yearsFavoursHerceptinFavoursnoHerceptinHRPerezetal2007;Smithetal2007無(wú)論年齡大小，赫賽汀均顯示DFS獲益35-49years086赫賽汀的新輔助治療研究進(jìn)展1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeoEBC赫賽汀的新輔助治療研究進(jìn)展1stlineHO648gRel87NOAHstudy:

neoadjuvantHerceptinforLABCaHormonereceptor-positivepatientsreceiveadjuvanttamoxifen

AP,doxorubicin60mg/m2,paclitaxel150mg/m2;H,Herceptin8mg/kgloadingthen6mg/kg

P,paclitaxel175mg/m2;CMF,cyclophosphamide600mg/m2,methotrexate40mg/m2,5-fluorouracil600mg/m2

LABC,locallyadvancedbreastcancer;q3w,every3weeks;q4w,every4weeksHER2-positiveLABC

(IHC3+and/orFISH+)n=113H+APq3wx3H+P

q3wx4Hq3wx4

+CMFq4wx3SurgeryfollowedbyradiotherapyaHcontinuedq3wtoWeek52n=115P

q3wx4CMF

q4wx3SurgeryfollowedbyradiotherapyaAP

q3wx3AP

q3wx3P

q3wx4CMF

q4wx3Surgeryfollowedbyradiotherapyan=99HER2-negativeLABC

(IHC0/1+)NOAHstudy:

neoadjuvantHerce88p=0.002p=0.004pCR(%)Baselgaetal2007;Giannietal2007HER2positive(n=228)HER2positive(n=62)NOAH研究中赫賽汀新輔助顯著提高了pCR率WithoutHerceptinWithHerceptin9080706050403020100HER2negative

(n=99)HER2negative

(n=14)234317195529TotalpopulationIBCpopulationpCR,pathologicalcompleteresponseinthebreast

IBC,inflammatorybreastcancerp=0.002p=0.004pCR(%)Baselgae89新輔助化療中參加赫賽汀明顯提高療效(16個(gè)相關(guān)研究,1,226例患者入組)aXwasgiveneitherconcurrentlyorsequentiallywithD+H

EC,epirubicin,cyclophosphamide;FEC,5-fluorouracil,epirubicin,cyclophosphamide

My,Myocet;X,Xeloda0102030405060708090100pCR(%)Antónetal2007,n=26My+P+HaUntchetal2008,n=452EC+HD+H±XHCoudertetal2007,n=70D+HMartyetal2007,n=30ECD+HLimentanietal2007,n=31D+V+H

(includingIBC)Binesetal2003,n=32D+HBursteinetal2003,n=40P+H

(includingIBC)Kellyetal2006,n=37ACP+H

(includingIBC)Harrisetal2003,n=40V+H

(includingIBC)Hurleyetal2002,n=48D+cisplatin+H

(includingIBC)Tripathyetal2007,n=28P+X+HLybaertetal2006,n=25X+D+HBuzdaretal2007,n=45PFEC+HPernasetal2007,n=33PFEC+HGiannietal2007,n=115APPCMF+H

(includingIBC)Untchetal2005,n=174ECP+H新輔助化療中參加赫賽汀明顯提高療效(16個(gè)相關(guān)研究,1,90赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionHER2,humanepidermalgrowthfactorreceptor2

EBC,earlybreastcancer;MBC,metastaticbreastcancerEBCHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeo赫賽汀已成為HER2陽(yáng)性乳腺癌的根底治療1stlineHO91一線赫賽汀治療顯著延長(zhǎng)患者的生存時(shí)間Mediansurvival(months)IHC,immunohistochemistry;P,paclitaxel

H,Herceptin;D,docetaxel;Carbo,carboplatinH0648g(IHC3+)M77001BCIRG007USOncology(IHC3+)Smithetal2001;Martyetal2005

Robertetal2006;Pegrametal2007一線赫賽汀治療顯著延長(zhǎng)患者的生存時(shí)間Mediansurvi92TAnDEM--赫賽汀聯(lián)合阿那曲唑治療HER-2(+〕激素敏感性轉(zhuǎn)移性乳腺癌臨床研究結(jié)果〔2006年圣安東尼奧〕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月歐洲推薦赫賽汀聯(lián)合芳香化酶抑制劑治療HER2與激素受體陽(yáng)性轉(zhuǎn)移性乳癌TAnDEM--赫賽汀聯(lián)合阿那曲唑治療HER-2(+〕93疾病進(jìn)展后如何合理選擇赫賽汀個(gè)體化治療方案1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numerous

PhaseIIstudiesMBCProgressionEBCHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeo疾病進(jìn)展后如何合理選擇赫賽汀個(gè)體化治療方案1stlineH94HerceptinimprovesOSifcontinuedbeyondprogressionOS(months)ContinuedHerceptinDiscontinuedHerceptinExtraetal2006Jackischetal2007;Menardetal2008p<0.0001p<0.0001p=0.0014(n=118)(n=154)(n=81)(n=112)(n=70)(n=107)ProspectiveHerminestudyGermanobservationalstudyDemetrastudyOS,overallsurvivalHerceptinimprovesOSifconti95赫賽汀在多線治療中的作用赫賽汀治療的最大獲益是持續(xù)治療臨床證據(jù)提示含赫賽汀方案治療中進(jìn)展并不等于赫賽汀耐藥,調(diào)整化療藥并繼續(xù)赫賽汀治療仍可獲益.赫賽汀通過(guò)持續(xù)抑制HER2

,在多線治療中病人仍可獲益赫賽汀在多線治療中的作用赫賽汀治療的最大獲益是持續(xù)治療96Slamonetal2006

Rastogietal2007

Suteretal2007

Perezetal2008赫賽汀輔助治療的心臟平安性aDatanotcomparableduetodifferentassessmentcriteria

CHF,congestiveheartfailure;cum,cumulativeincidence

LVEF,leftventricularejectionfraction;NR,notreported3.0NRNR18.08.6Asymptomatic

LVEFdecl