大肠癌个体化治疗实践和探讨专家讲座

大肠癌个体化治疗

实践与探讨江苏省肿瘤医院内科陆建伟大肠癌个体化治疗实践和探讨专家讲座第1页概述大肠癌是常见恶性肿瘤之一，在世界范围内西方发达国家为显著高发地域，美国大肠癌发病率至今仍居其肿瘤发病第三位。我国大肠癌发病率在80年代初远低于美国，约相差3倍以上。但近年来我国大肠癌发病率增加幅度呈连续上升趋势，大城市发病率已达恶性肿瘤发病第三位、农村为第五位，均较20年前增高。－年，江苏省肿瘤医院收住大肠癌新病例数：外科：1113例；内科：1216例；放疗科：285例近半个世纪来，尽管外科手术学有了很大进步，但大肠癌生存率仍没有较大提升。大约33%病人会出现复发，近半数病人死于转移。化疗已成为大肠癌综合治疗一个主要组成部分。

江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第2页已经同意用于大肠癌治疗药品agentCommercialname5-fluorouracil5-fluorouracilFolinicacidLeucovorinIrinotecanCampto®orCamptosar®OxaliplatinEloxatin®BevacizumabAvastin®CetuximabErbitux®S－1CapecitabineXeloda®Uracil/tegafurUFTRaltitrexed羟基喜树碱HCPT概述江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第3页概述化疗药品在毒性和抗瘤作用方面表现出显著个体差异,所以对详细个体而言,就极难选择出最正确治疗方案。遗传变异是影响治疗疗效和毒性一个主要原因。药品代谢酶、膜运转蛋白、治疗靶点相关基因编码发生遗传改变是判别药品异常药代学或药效学高危病人有效工具。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第4页氟尿嘧啶相关代谢酶基因多态

与大肠癌化疗疗效关系5－氟尿嘧啶是治疗大肠癌最有效、最惯用化疗药品之一。与其它药品组成了各种有效化疗方案。LF、FOLFOX、FOLFRI方案江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第5页

FdUMP:5-氟尿嘧啶脱氧核苷5`-单磷酸盐FdUrd:5-氟尿嘧啶脱氧核苷MS:蛋氨酸合酶

MTHFR:亚甲基四氢叶酸还原酶THF:四氢叶酸

TK:胸腺嘧啶脱氧核苷激酶

TP:胸腺啶磷酸化酶

TYMS(TS):胸苷酸合成酶

5,10-CH2-THF:5,10-亚甲基四氢叶酸5-CH3-THF:5-甲基四氢叶酸5-FU:5-氟尿嘧啶DHF:二氢叶酸;DHFR:二氢叶酸还原酶DHFU:二氢氟尿嘧啶

DPYD:二氢嘧啶脱氢酶dTMP:脱氧胸苷5`-单磷酸盐dUMP:脱氧尿苷5`-单磷酸盐5－氟尿嘧啶代谢路径江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第6页胸苷酸合成酶（TS)基因多态与5－FU疗效关系与5－FU化疗疗效相关基因多态存在于TS基因5’区和3’UTR区。TS基因起动子5’区28bp序列重复多态(TS2R和TS3R)将影响基因表示。2R表现为TS基因低表示，3R表现为TS基因高表示。3’区－6bp表现出细胞内TS基因低表示。3R/3RmRNA表示是2R/2R3.6倍。3R/3RmRNA表示是2R/3R2.1倍。28％－56％3R等位基因上存在G＞C单核苷酸多态，2R/3G、3C/3G、3G/3G)mRNA高表示，2R/2R、2R/3C、3C/3CmRNA低表示。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第7页TS基因多态种族差异江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第8页Associationbetweengenotypesandresponsetochemotherapyinthe80patients

No.ofpatients(%)

GenotypesNo.ofpatients(%)Respondersa(N=34)Non-respondersa(N=46)P-valueTS5'-UTR

2R/2R

16(20)10(30)6(13)

2R/3R

38(47)14(40)24(52)0.19

3R/3R

26(33)10(30)16(35)

TS5'-UTR

b

2R/2R,2R/3C,3C/3C

48(60)26(76)22(48)0.011§

2R/3G,3C/3G,3G/3G

32(40)8(24)24(52)

TS3'-UTR

-6/-6

30(38)11(32)19(41)

-6/+6

40(50)20(59)20(44)0.37

+6/+6

10(12)3(9)7(15)

Liver-onlymetastaticcolorectalcancerpatientsandthymidylatesynthasepolymorphismsforpredictingresponseto5-fluorouracil-basedchemotherapy。BrJCancer.Sep2;99(5):716-21.

江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第9页亚甲基四氢叶酸还原酶（MTHFR)基因多态与5－FU疗效关系MTHFR基因最常见是C677T和A1298C多态。前者在677位点发生C－T改变,使酶活性显著降低,后者在1298位点发生A－C改变,也影响酶活性,多态使体内5,10-MTHF水平升高,增强5-FU抗瘤作用。结肠癌和乳腺癌细胞株试验室研究中发觉MTHFR基因C677T多态性将影响叶酸浓度和在细胞内分布,同时改变癌细胞生长和对化疗敏感性。所以研究MTHFR基因多态性对预测癌细胞对5-FU敏感性可能含有较高临床价值。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第10页Kaplan–Meiersurvivalcurvesforpatientsinrelationto(a)MTHFRC677Tpolymorphism(logrank=0.01,p=0.92)and(b)MTHFRA1298Cpolymorphism(logrank=10.67,p=0.001)

Kaplan–Meiersurvivalcurvesforpatientsafter5-FU-basedchemotherapy(n=135)inrelationtotheMTHFRC677Tgenotypes(logrank=3.86,p=0.05)andMTHFRA1298Cgenotypes(logrank=6.82,p=0.009)

AssociationofpolymorphismsMTHFRC677TandA1298Cwithriskofcolorectalcancer,geneticandepigeneticcharacteristicoftumors,andresponsetochemotherapy.IntJColorectalDis.Feb;25(2):141-51

江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第11页

MTHFRGenePolymorphismandResponse(79patients)MTHFR,methylenetetrahydrofolatereductase.＊&#:P=0.04MTHFRGenePolymorphismResponseNoResponseTotalNo.ofPatientsNo.ofPatients%No.ofPatients%C677T

CC1134＃216632

CT821＃307938

TT667＊3339A1298C

AA1739276144

AC725217528

CC3375638JournalofClinicalOncology,Vol23,No7(March1),:pp.1365-1369江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第12页二氢嘧啶脱氢酶基因多态性5-Fu在体内去除模式为分解代谢，与尿嘧啶降解相同。在肝脏内，超出80%5-Fu被其分解代谢限速酶—二氢嘧啶脱氢酶（Dihydropyrimidinedehydrogenase,DPD)所灭活。DPD活性在不一样个体中波动范围在8-21倍之间。DPD酶活性降低可造成5-Fu分解代谢率下降，5-Fu活性代谢产物增多，以致造血系统、神经系统及胃肠道毒性反应增加.大约3-5%人群携带杂合性失活突变基因DPYD，0.1%携带DPD纯合性失活突变。DPD功效缺点影响嘧啶代谢，造成一系列临床症状出现，尤其是神经系统症状。在DPD基因中已经明确存在多个位点遗传变异，等位基因IVS14＋1位点G＞A(DPYD*2A)突变，以该基因为模板转录mRNA缺乏第14外显子，翻译出缩短55个氨基酸DPD蛋白缺乏酶活性，而且马上被蛋白酶降解。早期研究表明，大约25%病人在5-Fu治疗后出现3-4度毒性反应肿瘤患者携带杂合性DPYD2A等位基因。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第13页AssociationofDPYDGenotypesWithIsolatedTypesofToxicityDPYDwt/*2ANo.%Toxicity(Overall)OR:4.67;95%CI:1.54to14.2,P=.010*Grade3to465.5Grade0to271.2DiarrheaOR:3.3,95%CI:0.9to12.3,P=NS*Grade3to435.1Grade0to2101.6MucositisOR:5.8,95%CI:1.71to19.4,P=.013*Grade3to447.7Grade0to291.4LeucopeniaOR:10.19,95%CI:3.0to35.1,P=.0021*Grade3to4412.5Grade0to291.4*ComparedwithDPYDwt/wt.Roleofgeneticandnongeneticfactorsforfluorouraciltreatment-relatedseveretoxicity:aprospectiveclinicaltrialbytheGerman5-FUToxicityStudyGroupJClinOncol.May1;26(13):2131-8

江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第14页乳清酸磷酸核糖转移酶基因多态

在5－FU转化为有活性核苷酸磷酸化过程中乳清酸磷酸核糖转移酶（OrotatePhosphoribosyltransferase，OPRT)起着主要作用。5－FU经过乳清酸磷酸核糖转移酶等一系列酶转换为5-氟-2‘-脱氧尿苷酸盐或者磷酸化为活性代谢产物三磷酸氟脲嘧啶。三磷酸氟脲嘧啶被广泛内装在RNA（即F-RNA)中，破坏正常RNA加工处理和功效发挥。已经有报道，在一小鼠模型中，5-FU诱导胃肠毒性与F-RNA相关，而与5-氟-2‘-脱氧尿苷酸盐水平无关。另外，奥特拉西，一个乳清酸磷酸核糖转移酶抑制剂，能降低氟脲糖苷磷酸盐水平，随之小肠中F-RNA降低70%，以及胃肠道毒性降低。综合这些结果，应该考虑到在乳清酸磷酸核糖转移酶在正常小肠中表示与5-FU诱导胃肠道毒性相关。对日本乳清酸尿症患者进行uridinephosphorylase缺乏分子研究显示与疾病相关三种单核苷酸多态性，其中乳清酸磷酸核糖(基)转移酶Gly213Ala多态现象可能能预测5-FU诱导毒性。小样本分析发觉Ala/Ala基因型患者3－4度腹泻发生率为100％，而Gly/Gly基因型仅为2．7％。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第15页UGT1A1多态与CPT－11化疗副反应性关系CPT-11在体内经过羧酸酯酶作用转化为活性代谢产物SN-38，肝脏内尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1)使SN-38转化为极性更强失活化合物—葡萄糖醛基化SN-38。腹泻和白细胞降低症是CPT-11主要不良反应，与SN-38水平正相关。UGT1A1表示含有很高变异。研究显示SN-38葡萄糖醛基化率在不一样个体中差异最高达50倍。最常见变异为在开启子去TATA盒中插入一个双核苷酸（TA)，产生等位基因UGT1A1＊28，它可使SN-38葡萄糖醛基化下降，从而引发体内活性SN-38显著升高，增加毒副作用发生和程度。也有研究发觉严重毒性反应只发生在携带UGT1A1＊28杂合子和UGT1A1＊28纯合子患者，UGT1A1基因型与中性粒细胞绝对计数显著相关。回顾性研究发觉：在出现严重腹泻或中性粒细胞降低患者中，15%病例为UGT1A128纯合子或31%为杂合子携带者。无显著毒副反应发生患者中UGT1A128纯合子和杂合子携带者分别仅占3%和11%。所以，对患者进行UGT1A1基因型判定，有利于临床对CPT-11严重毒副反应预测。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第16页UGT1A1statuscorrelationwithirinotecan-associatedtoxicityandtreatmentefficacyAuthornTumourCTXscheduleUGT1A1nHaematotoxicitygrade3/4Delayeddiarrhoeagrade3/4Coteetal.89CRCCPT-11180mg/m2q2w+5-FU/LVWT(6/7)(7/7)42508162550P=0.06162725P=0.31Rouitsetal.75CRCCPT-1185mg/m2q1w,180mg/m2q2w+5-FU/LVWT(6/7)(7/7)41479104071P=0.001132029NSMarcuelloetal.95CRCCPT-11+5-FU/tomudex80mg/m2q1w,180mg/m2q2w,350mg/m2q3wWT(6/7)(7/7)424711152740

P=0.2173370

P=0.005McLeodetal.520CRCIFL(CPT-11:125mg/m2d1,8,15,and22every6weeks),reduceddose100mg/m2,IROX(CPT-11:200mg/m2q3w),FOLFOXWT(6/7)(7/7)4644914.818.236.2P=0.007(neutropeniagrade4)NSRothetal.628CRC5-FU/LVor5-FU/LV+CPT-11(CPT-11:180mg/m2q2w)WT(6/7)(7/7)44431325.525.944.8P=0.006(6/6>6/7>7/7)16.010.78.0P=0.02(6/6>6/7>7/7)Liuetal.128mCRCCPT-11180mg/m2q2w+5-FU/LVWT(6/7)(7/7)79.715.64.74.953.8P<0.015.926.9P<0.01江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第17页Kras基因突变指导结直肠癌治疗靶向治疗是近年来肿瘤治疗领域新热点，尤其是针对表皮生长因子受体（Epidermalgrowthfactorreceptor，EGFR)药品更是被广泛应用，而且还有大量相关药品在研发之中。大量临床研究资料证实，Kras基因突变状态与针对EGFR药品，如西妥昔单抗（Cetuximab)和帕尼单抗（Panitumumab)等疗效相关。Kras检测目标检测基因状态,筛选取药人群。Kras基因是EGFR信号通路中主要分子之一，位于染色体12p12.1上，编码21kD（p21)蛋白。突变型Kras不依赖刺激信号激活，即突变型Kras基因不受上游EGFR基因状态影响，一直处于激活状态,只有野生型Kras基因受上游EGFR信号刺激影响，这也是含有突变型Kras基因患者反抗EGFR药品治疗无效理论基础。检测Kras基因突变,对判断这些肿瘤发生发展、预后以及了解肿瘤治疗效果含有一定意义。江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第18页AssociationBetweenKRASStatusandResponsetoPanitumumaborCetuximabTherapyinPatientsWithColorectalCancer

Wild-typeKRASMutatedKRAS

nPtsOR(n)RR(%)nPtsOR(n)RR(%)AmadoetalPanitumumab12421178400FreemanetalPanitumumab384112400BenvenutietalPanitumumab,cetuximab,orcetuximab+chemotherapy3210311616MoronietalPanitumumab,cetuximab,orcetuximab+chemotherapy2183810220LievreetalCetuximab6526402400Khambata-FordetalCetuximab505103000FinocchiaroetalCetuximab4913273226CervantesetalCetuximabCetuximab+chemotherapy29298162855191906032LievreetalCetuximaborcetuximab+chemotherapy1711651300DiFioreetalCetuximab+chemotherapy4312281600TejparetalCetuximab+chemotherapy4717213000BokemeyeretalCetuximab+chemotherapy613761521733VanCutsemetalCetuximab+chemotherapy172102591053836FrattinietalCetuximab+chemotherapy1795310110江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第19页江苏省肿瘤医院内科在胃肠癌

个体化治疗中实践江苏省肿瘤医院内科大肠癌个体化治疗实践和探讨专家讲座第20页AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadvancedGastricCancer（－)AssociationBetweengenotypeStatusandResponseto5-FUbaseChemotherapyin173PatientsWithadva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