EGFR基因单核苷酸多态性与酪氨酸激酶抑制剂敏感性的关联研究

EGFR基因单核苷酸多态性与酪氨酸激酶抑制剂敏感性的关联研究第1页/共18页靶向性与特异性医疗卫生经济学预测疗效和个体化治疗：靶向治疗领域亟待解决的关键性临床问题第2页/共18页EGFR受体酪氨酸激酶抑制剂CIFNONHNOONNHNOON吉非替尼（gefitinib）Clinicalcharacteristics

RaceSexSmokingstatusHistologicalsubtypeSkinrashEGFRstatusoractivationExpressionMutationsPhosphorylationPolymorphism第3页/共18页SingleNucleotidePolymorphism(SNP)人类表型差异的主要来源疾病易感性药物敏感性表型差异性第4页/共18页EGFR基因SNPs与Gefitinib敏感性的关联研究目的药物靶标基因的遗传变异对靶向药物疗效的影响方法国际研究所取得的公共数据资源高通量基因分型技术的发展候选基因的全基因分析策略意义发掘与Gefitinib疗效相关的SNP探讨个体化靶向治疗的可行性将药物遗传学的研究手段引入分子靶向治疗领域第5页/共18页EGFR基因结构以及候选的遗传变异根据HapMap数据库公布的EGFR基因座195.3kb区域235个SNP数据第6页/共18页特征n(%)特征n(%)年龄(岁)组织学类型

<6049(58.3)腺癌67(79.8)6035(41.7)其它†17(20.2)性别吉非替尼治疗‡男36(42.9)二线治疗44(52.4)女48(57.1)三线治疗40(47.6)吸烟状态临床疗效吸烟15(17.9)

PR

31(36.9)不吸烟69(82.1)

SD

20(23.8)WHO能力评分

PD

33(39.3)

022(26.2)

CB51(60.7)

162(73.8)84例NSCLC患者临床特征及吉非替尼疗效

†

包括12个鳞状细胞癌和5个大细胞癌‡每天口服250mg第7页/共18页SequencingtargetGenotypeResponderNon-responderPbNo.(%)No.(%)Exon18155,077cG>A(intron18)dGG46(58.2)33(41.8)0.270GA

3(100.0)0(0.0)AA0(0.0)0(0.0)Exon19155,639G>A(rs2017000)GG12(57.1)9(42.9)0.896AG30(61.2)19(38.8)AA

6(54.5)5(45.5)155,646C>T(rs17290371)CC49(62.0)30(38.0)0.296CT

1(25.0)

3(75.0)155,812C>T(rs712831)CC13(56.5)10(43.5)0.912CT29(61.7)18(38.3)TT

7(58.3)

5(41.7)激酶活性区SNP与吉非替尼疗效的关系第8页/共18页SequencingtargetGenotypeResponderNon-responderPbNo.(%)No.(%)Exon20161,518G>A(rs13243364)GG39(57.4)29(42.6)0.193AGandAA12(75.0)

4(25.0)161,817T>C(rs10241326)TT36(55.4)29(44.6)0.064CTandCCe15(78.9)

4(21.1)161,956T>C(rs10241451)TT43(58.1)31(41.9)0.302CT

8(80.0)

2(20.0)162,093G>A(rs1050171)GG36(55.4)29(44.6)0.064AGandAAf15(78.9)

4(21.1)Exon21172,793G>A(rs6970262)GG44(61.1)28(38.9)1.000AG

4(66.7)

2(33.3)172,978G>C(rs17337331)GG34(60.7)22(39.3)0.850CGandCCg12(63.2)

7(36.8)第9页/共18页4个EGFR标签SNP与吉非替尼疗效的关系GenotypeResponderNonresponderPNo.(%)No.(%)rs4947492A>G0.578AA22(56.4)17(43.6)AG22(66.7)11(33.3)GG

7(70.0)

3(30.0)rs11977388T>C0.444TT17(58.6)12(41.4)TC29(65.9)15(34.1)CC

5(45.5)

6(54.5)rs2075102C>A0.854CC33(60.0)22(40.0)CA18(62.1)11(37.9)AA

0

(0.0)

1(100.0)rs7809028G>A0.085GG24(66.7)12(33.3)0.027GA18(69.2)

8(30.8)AA

7(38.9)11(61.1)Responder:PR+SD;Nonresponder:PD第10页/共18页GenotypeResponderNonresponderPNo.(%)No.(%)rs2293347G>A(D994D)

0.012GG42(71.2)17(28.8)GA9(39.1)14(60.9)AA

0(0.0)

1(100.0)0.004GG42(71.2)17(28.8)GA+AA9(37.5)15(62.5)功能SNP与吉非替尼疗效的关系Rs2293347&CA-SSR*<0.001GGandshorterCA19(90.5)

2(9.5)AG/AAandshorterCA

4(80.0)

1(20.0)GGandlongerCA23(60.5)15(39.5)AG+AAandlongerCA

5(26.3)14(73.7)*CA-SSRinintron1第11页/共18页Variablers2293347(D994D)genotypeGG,No.(%)AG+AA,No.(%)PAge(years)0.682<6034(57.6)15(62.5)6025(42.4)

9(37.5)Sex0.437Male24(40.7)12(50.0)Female35(59.3)12(50.0)WHOperformancestatus0.726015(25.4)

7(29.2)144(74.6)17(70.8)Smokingstatus0.832Non-smoker48(81.4)20(83.3)Smoker11(18.6)

4(16.7)Histologicalsubtype0.762Adenocarcinoma47(79.7)19(82.6)Othera12(20.3)

4(17.4)Gefitinibtherapy0.7842ndline30(50.8)13(54.2)3rdline29(49.2)11(45.8)第12页/共18页Rs2293347与NSCLC患者生存第13页/共18页吉非替尼治疗患者的预后分析VariableProgression-freesurvivalOverallsurvivalHR95%CIPHR95%CIPSex1.000.57-1.780.9880.500.25-1.030.061Smokingstatus2.201.04-4.620.0381.870.83-4.230.133WHOPS1.650.90-3.010.1052.671.13-6.290.025Histologicaltype1.430.78-2.630.2521.650.78-3.490.186rs2293347G>A2.291.30-4.030.0041.470.75-2.870.263CA-SSR1.240.71-2.180.4491.230.62-2.430.