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乳腺癌分子靶向药物治疗进展ChemotherapyEndocrinetherapyTargetedtherapiesTreatmentofBCHIGHLIGHTSINBREASTCANCERDISEASEBIO

LOGY•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中位生存期的缩短HER2扩增过度表达年HER2正常表达年原癌基因扩增HE

R2在约20%～30%的乳腺癌组织中过度表达SlamonDJetal.Science1987;235:177–82•HER2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InhibitionofHER2-mediatedsignallingActivati

onofADCC赫赛汀的作用机制Additionalmechanisms•PreventsformationoftruncatedHER2(p95)•InhibitionofHER2-regulatedangiogenesisADCC,antibody-dependentcellularcyt

otoxicity赫赛汀已成为HER2阳性乳腺癌的基础治疗1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF

104900NumerousPhaseIIstudiesMBCProgressionHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeoEBCHER2,huma

nepidermalgrowthfactorreceptor2EBC,earlybreastcancer;MBC,metastaticbreastcancer>13,000患者入组的赫赛汀四大辅助临床研究Piccart-Gebhartetal2005Romondetal200

5;Slamonetal2006NCCTGN9831(USA)HERA(ex-USA)BCIRG006(global)NSABPB-31(USA)IHC/FISH(n=5,090)Observation1year2y

earsIHC/FISH(n=3,505)1year1yearFISH(n=3,222)1year1yearIHC/FISH(n=2,030)1yearDocetaxelDocetaxel+carboplatinDoxorubicin+cyclop

hosphamideHerceptinStandardCTxPaclitaxelIHC,immunohistochemistryFISH,fluorescenceinsituhybridisationCTx,chemotherapy赫赛汀可减少三分

之一的死亡风险012B-31/N9831ACPH3HERACTxH1year2Medianfollow-up,yearsOverallsurvivalbenefitBCIRG006ACDH3BCIRG00

6DCarboH3FavoursHerceptinFavoursnoHerceptinHRSlamonetal2006Perezetal2007;Smithetal2007H,Herceptin;AC,doxorubicin,cyclophosphamideP,paclitaxel;D,

docetaxel;Carbo,carboplatinHR,hazardratioSizeofsquarerepresentssamplesize;horizontalbarsindicate95%confidenceintervals无论肿瘤大小，赫赛汀均显示DFS获益

Slamonetal2006Perezetal2007;Smithetal2007>2-5cmBCIRG006>2-5cm>5cm0.00.52.51.01.52.00-2cmN9831/B-310-2cm>5cmACDH<2cmDCarboH<2cm≥2cm≥2cmFavours

HerceptinFavoursnoHerceptinHRHERADFS,disease-freesurvival无论淋巴结情况，赫赛汀均显示DFS获益N,node1-3+nodesFavoursHerceptinFavoursnoHerceptin0.00.

52.51.01.52.01-3+nodes≥4+nodesNotassessedN9831/B-31N-4-9+nodes>10+nodesDCarboHN-N+N+BCIRG006N-ACDHN-HERAHRSla

monetal2006Perezetal2007;Smithetal2007无论年龄大小，赫赛汀均显示DFS获益35-49years0.00.52.51.01.52.0HERA<35years50-59

years≥60yearsN9831/B-31<40years≥60years40-49years50-59yearsFavoursHerceptinFavoursnoHerceptinHRPerezetal

2007;Smithetal2007赫赛汀的新辅助治疗研究进展1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO179

29EGF104900NumerousPhaseIIstudiesMBCProgressionHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIs

tudiesNeoEBCNOAHstudy:neoadjuvantHerceptinforLABCaHormonereceptor-positivepatientsreceiveadjuvanttamoxifenAP

,doxorubicin60mg/m2,paclitaxel150mg/m2;H,Herceptin8mg/kgloadingthen6mg/kgP,paclitaxel175mg/m2;CMF,cyclophosphamid

e600mg/m2,methotrexate40mg/m2,5-fluorouracil600mg/m2LABC,locallyadvancedbreastcancer;q3w,every3weeks;q4w,every

4weeksHER2-positiveLABC(IHC3+and/orFISH+)n=113H+APq3wx3H+Pq3wx4Hq3wx4+CMFq4wx3SurgeryfollowedbyradiotherapyaHcontinuedq3wtoWeek52n=115Pq

3wx4CMFq4wx3SurgeryfollowedbyradiotherapyaAPq3wx3APq3wx3Pq3wx4CMFq4wx3Surgeryfollowedbyradiotherapyan=99HER2-negativeLA

BC(IHC0/1+)p=0.002p=0.004pCR(%)Baselgaetal2007;Giannietal2007HER2positive(n=228)HER2positive(n=62)NOAH研究中赫赛汀新辅助

显著提高了pCR率WithoutHerceptinWithHerceptin9080706050403020100HER2negative(n=99)HER2negative(n=14)234317195529TotalpopulationIBCpopulationpCR,

pathologicalcompleteresponseinthebreastIBC,inflammatorybreastcancer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)aXwasgiveneitherconcurrentlyorsequentiallywithD+HEC,epirubicin,cyclophosphamide;FEC,5-fluorouracil,epirubicin,cyclop

hosphamideMy,Myocet;X,Xeloda0102030405060708090100pCR(%)Antónetal2007,n=26My+P+HaUntchetal2008,n=452EC+HD+H±XH

Coudertetal2007,n=70D+HMartyetal2007,n=30ECD+HLimentanietal2007,n=31D+V+H(includingIBC)Binesetal2003,n=32D+HBursteinetal2003,n=40P+H(

includingIBC)Kellyetal2006,n=37ACP+H(includingIBC)Harrisetal2003,n=40V+H(includingIBC)Hurleyetal2002,n=48D+cisplatin+H(includingIBC)Tripathyetal20

07,n=28P+X+HLybaertetal2006,n=25X+D+HBuzdaretal2007,n=45PFEC+HPernasetal2007,n=33PFEC+HGiannietal2007,n=115AP

PCMF+H(includingIBC)Untchetal2005,n=174ECP+H赫赛汀已成为HER2阳性乳腺癌的基础治疗1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEAR

elapse2nd+linesGBG-26BO17929EGF104900NumerousPhaseIIstudiesMBCProgressionHER2,humanepidermalgrowthfactorreceptor2EBC,earlybreastcancer;MBC,metastatic

breastcancerEBCHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeo一线赫赛汀治疗显著延长患者的生存时间01020304050PHPCarboHDHDCa

rboHDHDalonePHPaloneMediansurvival(months)IHC,immunohistochemistry;P,paclitaxelH,Herceptin;D,docetaxel;Carbo,carboplatinH0648g(IHC3+)M

77001BCIRG007USOncology(IHC3+)Smithetal2001;Martyetal2005Robertetal2006;Pegrametal2007TAnDEM--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）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选择赫赛汀个体化治疗方案1stlineHO648gM77001USOncologyBCIRG007CHATTAnDEMRHEARelapse2nd+linesGBG-26BO17929EGF104900Numer

ousPhaseIIstudiesMBCProgressionEBCHERANSABPB-31NCCTGN9831BCIRG006AdjuvantNOAHMDACCGeparQuattroNumerousPhaseIIstudiesNeoHerceptinimprovesOSifcontinu

edbeyondprogressionOS(months)ContinuedHerceptinDiscontinuedHerceptinExtraetal2006Jackischetal2007;Menardetal2008p<0.0001p<

0.0001p=0.0014(n=118)(n=154)(n=81)(n=112)(n=70)(n=107)ProspectiveHerminestudyGermanobservationalstudyDemetrastudyOS,ov

erallsurvival0510152025303540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H

ER2,在多线治疗中病人仍可获益Slamonetal2006Rastogietal2007Suteretal2007Perezetal2008赫赛汀辅助治疗的心脏安全性aDatanotcomparableduetodifferentassessmentcriter

iaCHF,congestiveheartfailure;cum,cumulativeincidenceLVEF,leftventricularejectionfraction;NR,notreported3.0NRNR18.08.6Asympto

maticLVEFdecline,%aH1yearACPHACPHACDHDCarboHArmHERANSABPB-31NCCTGN9831BCIRG0061,6789475701,0681,05

6nSevereCHF,%0.63.8cum(5yr)3.3cum(3yr)1.90.4Cardiacdeath,n00000•Age>50(5.1%-5.4%)•Useofhypertensivem

edications(6.8%)•BaselineLVEF50-54(12.9%)Rastogietal.AbstractLBA513ASCO2007•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•化疗→H•DH→F

EC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):antiHER2agent•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Ⅱ区结合，抑制二聚体的形成•抑制HER2与EGFR和HER3

形成二聚体。Herceptin+pertuzumabprovidesclinicalbenefittopatientsprogressingonHerceptinGelmonetal2008ResponseCRPRORRSDfor6months(≥Cycle8)CBRPDMe

dianPFSn(%)n=665(7.6)11(16.7)16(24.2)17(25.8)33(50.0)33(50.0)24weeksHerceptin+pertuzumabisawell-toleratedcombination01020304050607

0DiarrhoeaFatigueNauseaRashHeadacheArthralgiaCoughAnorexiaAstheniaDizzinessMusclespasmsMyalgiaParaesthesiaPruritusVomitin

gPatients(%)Adverseevents,allgradesAdverseevents,grades3/4Gelmonetal2008•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（ZD183

9，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-2GeyerCE,etal.ASCO2006.ClinicalSci

enceSymposium.EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancerRefractory,progressivemetastaticorlocallyadvancedHER2+breastcancerp

reviouslytreatedwithanthracycline,taxane,ortrastuzumab(N=528planned*)Lapatinib1250mgdaily+Capecitabine2000mg/m2dailyf

orDays1-14,3-weekcycles(n=160)Capecitabine2500mg/m2dailyforDays1-14,3-weekcycles(n=161)Follow-up:untilprogressionorunacceptabletoxicity*Studyenrollm

entterminatedearlybyIDMCduetosuperiorityofcombinationarminprimaryendpoint.EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancer(cont’d)•Lo

ngertimetoprogression•36.9vs19.7wks(P=.00016)•Longerprogression-freesurvival•36.9vs17.9wks(P=.000045)•Fewerprogressionsordeaths•38%vs48%•Respons

e(independentreview)•Overall:22.5%vs14.3%(P=.113)GeyerCE,etal.ASCO2006.ClinicalScienceSymposium.Progression-FreeSurvival(%)Time(W

ks)2040608001001020304050CapecitabineLapatinib+capecitabineITTpopulation2007.3FDA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•39patients(38patientsprogressionafterradiothrapy)New/progressivemeasurable(>1cm)brainmetastases•Treatment:L

apatinib750mgpoBID•Result1.2patientsPR158dand347d2.5patientsSD>16weeksMedianTTP3.2monthsMST6.57months3.1patienth

adresponse,butdidnotmeetRECISTLapatinib成为Trastuzumab耐药或脑转移患者新选择LapatinibforBrainMetastasesinHer2+CancerLinetal.ASCO2006;NCI-CTEP6969trialLapatinib+T

rastuzumabforTrastuzumabprogressingonHer2+CancerASCO2008Progression-FreeSurvivalOverallSurvivalinITTPopulation0200DaysGefitin

ib--表皮生长因子受体酪氨酸激酶抑制剂1306090120150400600800100012001400Tumourvolume(mm3)Massarwehetal.BreastCancerResTreat2002Fu

lvestrantFulvestrant+gefitinibOestradiolFulvestrantplusgefitinibdelaysresistanceinMCF-7/HER2tumoursinvivoPhaseIITrialofGefitinibinAdvancedBr

eastCancerPartialresponseStablediseaseClinicalbenefitProgressivedisease156(66%)3ER-positive(n=9)ER-negative(n=18)112(11%)16Robertsonetal.ASCOProc

.2003⚫AcquiredresistancetoTAM(n=27)orER-negativetumours(n=27)GefitinibLD1000mg(D1)Dailydose500mg/dayuntildiseaseprogressionorunacceptabletoxicity

Erlotinib--小分子EGFR酪氨酸激酶抑制剂previoustherapywitheitherananthracyclineorataxaneforMBCErlotinib（150mgorallydaily）+gemcitabine

（1000mg/m2,Days1、8,3-weekcycles）Apartialresponse(PR)rateof17%hasbeenreported(ASCO2005)N0234：Erlotinib+Gemcitabine

N0234：Erlotinib+Gemcitabine•ResultTNNON-TNPPR25%14%0.30CBR25%22%0.75PFS72d98d0.13OS227d738d0.0002TN*=ER(-)/PR(-)/HER-2(-)三阴ASCO2007西妥昔单抗(Cetu

ximab，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。Ⅲ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,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page11617815222829

36434950576470RANDOMIZATIONSURGERYNimotuzumabAC用药方案J.Soriano,N.Batista,etal.EuropeanJournalofCancerSupplemen

ts,Vol5No4,Page116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。PatientsDoseAgeRaceTNMStageDiagnoseNGERHER-20

15045WT4bN0M0IIIBIDC3NegNeg025040WT3N1M0IIIAILC3Neg3+035044WT3N1M0IIIAIDC3Pos2+0510059BT4bN1M0IIIBIDC3NegNeg0610063BT4bN1M0IIIBIDC2NegNeg1310046BT3

N1M0IIIAIDC1PosNeg0720064WT4bN1M0IIIBIDC3NegNeg0820042WT3N1M0IIIAIDC3PosNeg0920042WT4aN1M0IIIBIDC3Neg3+1

040058WT4bN0M0IIIBIDC2PosNeg1140059BT4bN1M0IIIBIDC3Neg3+1240034WT3N1M0IIIAIDC1PosNegJ.Soriano,N.Batista,etal.EuropeanJournalofCan

cerSupplements,Vol5No4,Page116➢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400mg剂量下是安全的，有很好的耐受性结论J.Soriano,N.Batista,etal.

EuropeanJournalofCancerSupplements,Vol5No4,Page116苏尼替尼（Sunitinib）--小分子多靶点酪氨酸激酶抑制剂NHONHH3CCH3NHONCH3CH3•Select

iveinhibitorof:–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。SunitinibinBreastCancerPatientsmulticentri

cphaseIIstudywith64patients*OnePRnotyetconfirmed.N=64PartialResponse*7(11%)StableDisease>6months3(5%)OverallClinicalBenefit10(16%)p

atientshadreceived3.5differentchemotherapies（anthracyclineortaxane）85%ofpatientshadreceivedadjuvantchemotherasunitinib50mg/d•多激酶抑制剂：丝氨酸/苏氨酸：C-Raf(R

af-1)和B-Raf1酪氨酸激酶受体：VEGFR-2、VEGFR-3、PDGFR-b、FLT-3和c-KITRASRAS内皮细胞或外周血管增殖转移血管发生：小管形成PDGF-VEGFVEGFR-2PDGFR-旁分泌刺激分化线粒体程序性死

亡肿瘤细胞PDGFVEGFEGFProliferationSurvival线粒体EGFHIF-2细胞核VHL内分泌环ApoptosisERKERKRASRASMEKMEKRAF细胞核ERKERKMEKMEKRAFRAFRAF多吉美多吉美多激酶抑制剂：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-KITWilhelmSetal.ClinCancerRes.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-β阻断Raf/MEK/ERK途径,抗肿瘤血管生成及肿瘤细胞增殖SofitinibphaseIIinMBC•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Angiogenesisisinvolvedthroughouttumourformation,growthandmetastasisAdaptedfromPoonRT,etal.JClinOncol2

001;19:1207–25StagesatwhichangiogenesisplaysaroleintumourprogressionPremalignantstageMalignanttumourTumourgrowthVascula

rinvasionDormantmicrometastasisOvertmetastasis(Avasculartumour)(Angiogenicswitch)(Vascularisedtumour)(Tumourcellintravasation)(Seedingindistantorga

ns)(Secondaryangiogenesis)血管生成的双向调节机制ActivatorInhibitorAngiostatinEndostatinThrombospondin-1VEGFbFGFP

DGFBevacizumab(MonoclonalAntibodytoVEGF)•Humanizedtoavoidimmunogenicity(93%human,7%murine)•Recognizesallisoform

sofvascularendothelialgrowthfactor,Kd=8x10-10M•Terminalhalflife17-21days715casesStratify:•DFI<24mos.v

s.>24os.•<3vs.>3metastaticsites•Adjuvantchemotherapyyesvs.no•ER+vs.ER-vs.ERunknown•ageRANDOMIZEPaclitaxel+BevacizumabPaclitaxelE2100:StudyDesig

n-线治疗晚期乳腺癌的Ⅲ期临床研究28-DayCycle:Paclitaxel90mg/m2D1,8and15Bevacizumab10mg/kgD1and15AllpatientsMeasurableDisease010203040PaclitaxelOverall

ResponseRatePac+BevE2100:Response31623633025034.3%16.4%28.2%14.2%P<0.0001P<0.0001E2100:ProgressionFreeSurvivalHR=0.498(0.401-0.6

18)LogRankTestp<0.001Months0.00.10.20.30.40.50.60.70.80.91.0PFSProportion0102030Pac.+Bev.10.97monthsPaclitaxel6.11month

sBevacizumabToxicityNCI-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=0.0004NCCN•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。Ph

aseIItrialofCapecitabine+Bevacizumab2007ASCOResult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（metronomicche

motherapy）称为抗血管生成化疗(antiangiogenicchemotherapy)•低剂量化疗的优势Metronomicchemotherapy+bevacizumabMetronomicchemothe

rapy+bevacizumabConclusions•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(farnesyltransferaseinhibitors，FTIs)•Bcl-2反义核酸G3139Sensitivity(+)Sensitivity(-)ResponderSurvivalbenefitNon-Respo

ndersToxicitywithoutsurvivalbenefitDelayineffectivetreatmentTheFuture-TailoredTherapyMolecularprofiling122Righttherapyforrightpatient3

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