轉(zhuǎn)移性結(jié)腸癌靶向治療的未來治療策略研究

InvestigatingfuturetreatmentstrategieswithtargetedtherapyinmCRCHeinz-JosefLenzUniversityofSouthernCaliforniaUSC/NorrisComprehensiveCancerCenter

LosAngeles,USA作為療效預(yù)測(cè)和預(yù)后判斷的標(biāo)記物療效預(yù)測(cè)標(biāo)記物：能夠預(yù)測(cè)某種特定治療方式療效的標(biāo)記物KRAS基因突變導(dǎo)致腫瘤對(duì)EGFR抑制劑抵抗預(yù)后判斷標(biāo)記物：在不考慮治療因素的情況下能夠判斷患者結(jié)局的標(biāo)記物18號(hào)染色體長臂〔18q〕缺失某些分子標(biāo)記物具有上述兩種作用胸腺嘧啶合成酶〔Thymidylatesynthase〕表達(dá)1.LièvreA,etal.CancerRes2006;66:3992–3995;2.SargentDJ,etal.JClinOncol2005;23:2021–2027;3.Martínez–LópezE,etal.Gastroenterology1998;114:1180–1187;4.EdlerD,etal.JClinOncol2002;20:1721–1728潛在的結(jié)腸癌療效預(yù)測(cè)標(biāo)志物MeropolNJ,etal.ASCO2021藥物標(biāo)記物FluoropyrimidinesTS,DPD*,TP,MSI,MTHFRexpression/polymorphismsIrinotecanUGTpolymorphisms*,MSI,transporterpolymorphismsOxaliplatinERCC1,GSTP1,XPDexpression,transporterpolymorphismsEGFRantibodiesGeneamplification/polymorphism,RASmutation,BRAFmutation,ligandexpression,PTENexpression,VEGFlevelsVEGFinhibitorsVEGFpolymorphisms,ICAMpolymorphisms/levels,E-selectinlevels,HIF1,Glut-1,VEGFRgeneexpressionGeneralCirculatingtumorcells*FDArecognized潛在的EGFR抑制劑的療效預(yù)測(cè)標(biāo)記物EGFR1IHCdetection2FISHdetection3Mutations3Genelevels/polymorphisms1,4

KRAS1EGFRligands(EGF,heregulin,epiregulin,amphiregulin)5

COX-26VEGF61.LièvreA,etal.CancerRes2006;66:3992–3995;2.ChungKY,etal.JClinOncol2005;23:1803–1810;3.MoroniM,etal.LancetOncol2005;6:279–286;4.ZhangW,etal.PharmacogenetGenomics2006;16:475–483;5.Khambata-FordS,etal.JClinOncol2007;25:3230–3237;6.Vallb?hmerD,etal.JClinOncol2005;23:3536–3544結(jié)直腸癌〔CRC〕少見EGFR基因突變結(jié)直腸癌〔CRC〕腫瘤標(biāo)本中很少見EGFR基因突變對(duì)愛必妥單藥治療轉(zhuǎn)移性結(jié)直腸癌〔mCRC〕臨床試驗(yàn)中110例活檢標(biāo)本進(jìn)行的研究未發(fā)現(xiàn)EGFR基因突變〔外顯子18－21〕11.Khambata-FordS,etal.JClinOncol2007;25:3230–3237FISH法檢測(cè)的EGFR基因表達(dá)回憶性研究：FISH法檢測(cè)的EGFR表達(dá)水平有可能預(yù)測(cè)愛必妥療效1,2但近期的一項(xiàng)研究并未發(fā)現(xiàn)EGFR表達(dá)水平與療效之間的具有相關(guān)性30 10 20p=0.05EGFRFISH+EGFRFISH-TTP(months)CumulativedistributionfunctionCumulativesurvivalfunction0 10 20 30p=0.7EGFRFISH-EGFRFISH+Survivaltime(months)愛必妥治療mCRC〔n=85〕0.00.20.40.60.81.00.00.20.40.60.81.01.CappuzzoF,etal.AnnOncol2021;19:717–723;2.MoroniM,etal.Lancet2005;6:279–286;

3.PersoneniN,etal.JClinOncol2007;25(18S)(AbstractNo.10569)擴(kuò)增基因的表現(xiàn)形式AlbertsonDG.TrendsGenet2006;22:447–455雙微染色體染色體區(qū)域擴(kuò)增在基因組內(nèi)廣泛分布EGFR基因轉(zhuǎn)錄〔mRNA〕水平與生存期無關(guān)a02468EGFRmRNAlevels7.3

months2.2

monthsMediansurvival(months)95%CI:

4.4–13.5months95%CI:

1.7–4.5monthsp=0.09a39例伊諾替康和奧沙利鉑耐藥的mCRC接受愛必妥單藥治療LowHigh1.Vallb?hmerD,etal.JClinOncol2005;23:3536–3544EGFR基因表達(dá)水平與愛必妥治療后患者的生存期無明顯相關(guān)性〔小樣本研究〕1EGF受體信號(hào)傳導(dǎo)通路：個(gè)性化治療的合理性Survival

(anti-apoptosis)GenetranscriptionCell-cycleprogressionMYCMYCCyclinD1FOSJUNPPCyclinD1AngiogenesisInvasionandmetastasisChemotherapy/

radiotherapyresistanceProliferation/

maturationMAPKMEKRASRAFSOSGRB2PTENAKTSTATP13KpYpYLigand:AREG/EREGTargetforEGFR-ERBITUXEGFR-TKTargetforEGFT-TKinhibitorpYYardenY,SliwkowskiMX.NatRevMolCellBiol2001;2:127–137;ChakravartiA,etal.CancerRes2002;62:4307–4315;

BaselgaJ.EurJCancer2001;37(Suppl.4):S16–S22;KawanakaH,etal.LifeSci2001;69:3019–3033

?2000AmericanAssociationforCancerResearchRakJ,etal.CancerRes2000;60:490–498VEGFTSP-1GAPDHIEC-18RAS-3RAS-4IEC-18SRC-3SRC-4Tumorvolume(mm3)25002000150010005000Time(days)0510152025IEC-18IEC-18/4AIEC-184BRAS-3RAS-4SRC-3SRC-4VEGF:潛在的生物標(biāo)記物?KRAS基因突變的理論假設(shè)KRAS基因突變能夠激活下游RAS/MAPK信號(hào)傳導(dǎo)通路，這種激活無需配體誘導(dǎo)的EGFR激活導(dǎo)致愛必妥耐藥KRAS基因突變預(yù)測(cè)愛必妥療效和判斷mCRC預(yù)后的作用有待證實(shí)LièvreA,etal.JClinOncol2021;26:374–379MAPK=絲裂原激活的蛋白激酶FoddeR,etal.NatureRevCancer2001;1:55–6740%的CRC具有KRAS基因突變

KRAS基因突變是CRC發(fā)生的早期事件KRAS基因突變并非CRC的孤立事件KRAS突變與BRAF突變相聯(lián)系，后者與CpG島甲基化表型〔CIMP〕1，2有關(guān)KRAS突變與PI3K突變相關(guān)31.YuenST,etal.CancerRes2002;62:6451–6455;2.WeisenbergerDJ,etal.NatGenet2006;38:787–793;3.LièvreA,etal.CancerRes2006;66:3992–3995

KRAS基因突變者EGFR抑制劑的療效差

－對(duì)化療耐藥mCRC進(jìn)行的回憶性分析

ReferenceTreatmentNo.ofpatients

(wild-type:mutant)Objectiveresponse,

n(%)Wild-typeMutant

LièvreA,etal.1

ERBITUX±CT89(65:24)26(40)0(0)

BenvenutiS,etal.2

PanitumumaborERBITUXorERBITUX+CT48(32:16)10(31)1(6)DeRoockW,etal.3ERBITUXor

ERBITUX+irinotecan113(67:46)27(41)0(0)

FinocchiaroG,etal.4

ERBITUX±CT81(49:32)13(27)2(6)

DiFioreF,etal.5

ERBITUX+CT59(37:22)12(32)0(0)

Khambata-FordS,etal.6

ERBITUX80(50:30)5(10)0(0)

AmadoRG,etal.7

Panitumumab208(124:84)21(17)0(0)1.LièvreA,etal.JClinOncol2021;26:374–379;2.BenvenutiS,etal.CancerRes2007;67:2643–2648;3.DeRoockW,etal.AnnOncol2021;19:508–515;4.FinocchiaroG,etal.ASCO2007(AbstractNo.4021);5.DiFioreF,etal.BrJCancer2007;96:1166–1169;6.Khambata-FordS,etal.JClinOncol2007;25:3230–3237;7.AmadoRG,etal.JClinOncol2021;26:1626–1634靶病灶縮小百分比

－可評(píng)價(jià)KRAS基因狀態(tài)患者的資料BSC=Bestsupportivecare;Pmab=panitumumabAmadoRG,etal.JClinOncol2021;26:1626–1634Change(%)MutantPmab+BSCPR(17%)SD(34%)PD(36%)Wild-typePatientPatientBSCaloneChange(%)Change(%)PatientPatientPR(0%)SD(12%)PD(70%)PR(0%)SD(8%)PD(60%)16012080400-40-8016012080400-40-80Change(%)PR(0%)SD(12%)PD(75%)16012080400-40-8016012080400-40-80KRAS基因突變可預(yù)測(cè)

愛必妥治療患者的生存期和有效率

ReferenceNo.ofpatientsKRASmutant(%)Objectiveresponse

rate(%)Wild-typevsmutant(KRAS-evaluablepopulation)AllpatientsKRASmutantPFS(weeks)OS(months)

LièvreA,etal.13043370–16.3vs6.9(p=0.016)

DiFioreF,etal.2

593720023.9vs13.0(p=0.015)–DeRoockW,etal.3,a1134125024.0vs12.0(p=0.074)9.9vs6.3(p=0.020)

LièvreA,etal.892729031.4vs10.1(p=0.0001)14.3vs10.1(p=0.026)1.LièvreA,etal.CancerRes2006;66:3992–3995;2.DiFioreF,etal.BrJCancer2007;96:1166–1169;3.DeRoockW,etal.AnnOncol2021;19:508–515;4.LièvreA,etal.JClinOncol2021;26:374–379aInthecombinationtherapygroup(mutantvswild-type):PFS=12vs34weeks(p=0.016);OS=6.3vs10.3months(p=0.003)KRAS基因突變狀態(tài)對(duì)生存期的影響1.000.750.500.250.00020406080100Time(weeks)p=0.0001Progression-freesurvival(PFS)aTime(months)p=0.026Overallsurvival(OS)a1.000.750.500.250.000102030SurvivalprobabilitySurvivalprobabilityKRASwild-typeKRASmutantMedianPFS(95%CI),weeksMedianOS(95%CI),months31.4(19.4–36)14.3(9.4–20)10.1(8–16)10.1(5.1–13)Wild-typemutantan=88an=88LièvreA,etal.JClinOncol2021;26:374–379KRAS突變狀態(tài)和愛必妥皮膚毒性與總生存期〔OS〕的關(guān)系Time(months)1.000.750.500.250.000102030p=0.000815.6months(95%CI:10.9–22)10.7months(95%CI:8.3–16.3)5.6months(95%CI:2.8–10.6)Survivalprobability2goodprognosticfactors(wild-typeandgrade2/3skintoxicity)

0goodprognosticfactors(KRASmutantandgrade0/1skintoxicity)1goodprognosticfactor(wild-typeorgrade2/3skintoxicity)LièvreA,etal.AACRAnnualMeeting2007(Abstract5671)epiregulin(EREG)和/或amphiregulin(AREG)表達(dá)上調(diào)可通過與EGFR形成自分泌環(huán)路促進(jìn)腫瘤生長1a)EGFR配體在CRC中的作用1.Khambata-FordS,etal.JClinOncol2007;25:3230–3237b)ERBITUXb)依賴EGFR信號(hào)傳導(dǎo)通路的腫瘤對(duì)愛必妥治療更加敏感1EGFR配體高表達(dá)可預(yù)測(cè)愛必妥治療能夠獲得更長的無進(jìn)展生存期〔PFS〕HighLowEGFRligandexpression020406080100120140MedianPFS(days)103.5

days115.5

days57

days57

daysn=110,ERBITUXmonotherapy;DCR=疾病控制率〔diseasecontrolrate〕EREGAREG1.Khambata-FordS,etal.JClinOncol2007;25:3230–3237EGFR配體高表達(dá)患者的DCR和中位PFS具有明顯優(yōu)勢(shì)(EREGp=0.0002;AREGp=<0.0001)1Epiregulin表達(dá)水平對(duì)KRAS突變型和野生型患者PFS和OS的影響TejparS,etal.ASCOGI2021(AbstractNo.411)KRASstatusEpiregulinexpressionMedianPFS(months)MedianOS(months)All<0.52331226>0.52333045.9Overall1836Wild-type<0.52331231.6>0.52333665.4Overall2444.3Mutant<0.52331222.9>0.52331229.1Overall1224.3p<0.001p<0.001LenzH-J,etal.(unpublisheddata)COX-2多態(tài)性COX-2基因多態(tài)性與愛必妥療效的關(guān)系PRPRPRSDSDSDPDPD0102030405060708090100G/G(n=78)G/C(n=30)C/C(n=4)

p=0.097Patients(%)NagashimaF,etal.ASCO2007(AbstractNo.4129)

COX-2765GC多態(tài)性與接受愛必妥治療mCRC患者的PFS相關(guān)NagashimaF,etal.ASCO2007(AbstractNo.4129)

MonthssincestartofERBITUXtreatmentEstimatedPFSprobability0.00.10.20.30.40.50.60.70.80.91.0036912Log-rankp-value=0.031

G/G(n=87)G/C(n=34)C/C(n=4)COX-2T+8473C多態(tài)性與接受愛必妥治療mCRC患者的PFS相關(guān)12EstimatedPFSprobabilityMonthssincestartofERBITUXtreatment1.00.90.80.70.60.003690.50.40.30.20.1C/C(n=19)T/T(n=58)T/C(n=48)Log-rankp-value=0.003抗體依賴性細(xì)胞毒作用〔ADCC〕CourtesyofDrArteagaFCγ受體2a和3a的多態(tài)性與PFS相關(guān)ZhangW,etal.JClinOncol2007;25:3712–3718EstimatedPFSprobability1.00.90.80.70.60.0MonthssincestartofERBITUXtherapy0369120.50.40.30.20.1FCγ2A:H/HprH/Rand

FCγ3AF/ForF/V(n=22)Log-rankp-value=0.004FCγ2A:R/Ror

FCγ3AV/V(n=13)FCγ受體3a多態(tài)性與愛必妥和bevacizumab的療效相關(guān)〔BOND2〕LenzH,etal.ASCOGI2007(AbstractNo.401)Responserate(%)60504030200FCγreceptor3a

F/F(n=9)V/F(n=12)V/V(n=12)10Fisher’sexacttestp=0.054ResponseinpatientstreatedwithERBITUX/bevacizumab對(duì)多個(gè)分子生物學(xué)標(biāo)記物的分析檢測(cè)多個(gè)指標(biāo)有可能提高預(yù)測(cè)療效的效力PTENloss1EGFRligands2PI3Kmutations3EGFRgenecopynumber41.LoupakisF,etalASCO2021(AbstractNo.4003);2.TejparS,etal.ASCOGI