进展期胃癌个体化药物治疗课件

进展期胃癌个体化药物治疗

——药物优化与个体化探索北京大学肿瘤医院消化肿瘤内科沈琳2010年5月CACA目前胃癌化疗药物氟脲嘧啶类包括口服药：5-FU,capecitabine,S-1

紫杉醇类：紫杉醇、多稀紫杉醇。铂类：DDP、OXA（oxaliplatin）蒽环类：EPI

拓扑异构酶I抑制剂：Irinotecan(CPT-11),HCPT靶向治疗药物:Herceptin，AVASTIN,C225,…..RandomizedPhaseIIIStudyInFirstLineForAGC

StudyRegimenNRR(%)pOSpV3252006DCFCF10310538.723.2.01210.2m

8.5m

.0064KangY2006XPFP16015641290.0310.5m

9.3m0.27S.Al-Batran2006FLOFP9810234270.0125.7(TTP)3.80.081Wasaburo2008S-1+PDDS-11451505431.00213.0m11.0m.04JAjani5FU+PDDS-1+PDD50852124.222.5NS7.9m8.6mNSCunningham2008

ECFECXEOFEOX24924123523940.746.442.447.9NS9.9m9.9m9.3m11.2mNS

方案的改良减少药物组合——三药变两药改变给药方法——三周变两周或一周更换药物——新药换老药目的：保证疗效，减低毒性！如何优化方案1+1=21+1>2?从临床到基础序贯一线选择NNHNFOOOHOOHOHNNFOOHOOHOHNNHFOOTPDPDAnabolicpathwayTumor5’-DFUR5-FUTP:ThymidinephosphorylaseDPD:DihydropyrimidinedehydrogenaseFUPAFBALFUH2(inactive)XelodaGrowthinhibitionFHHHHNNHOOFactorsthataffectXelodaEfficacy

TheefficacyofCapecitabinecorrelatedwiththeratioofTP/DPD.DPDexistsinvarioustypesofhumancancers0 5 10 15 200 50 100 150 200*(mg/kg)Exp.1

ControlTaxolTaxotereVincristineVinblastineVindesineMitomycinCDoxorubicinCDDPExp.2

ControlMethotrexateCPA100151.53557.51050200DPD

(pmol/mgprotein/min)

*

P<0.05vs.ControlbytheStudent’st-test********InductionofTPbyantitumoragents

(HumanWiDrcoloncancerxenograft)CombinationwithTPup-regulatorsExp.3

oxaliplatin*如何优化方案1+1>2?从基础到临床多个小样本临床研究显示了紫杉醇与卡培他滨联合应用在胃癌一二线中都显示出很好的前景Primaryresults---PTX+CapesequencedwithCape192patiens，158evaluated

CR2cases，PR61cases(RR39.9%)

SD74cases（46.8%）

PD21cases（13.3％）

DCR86.7%同样是病理明确的胃腺癌，同样的分期，接受同样的药物、同样的剂量化疗，取得的疗效不同。临床特点相同的个体，肿瘤分子生物学特性大不相同，导致治疗效果的差异个体化？实验结果33例接受卡培他滨+紫杉醇化疗患者中β-tubulinIII表达与疗效及预后的关系：β-tubulinIII

表达分组+-+++++negativepositiveCR+PRSD+PDTotalRRP值TTP(d)P值OS(d)P值β-tubulinIII组化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064结论：β-tubulinIII低表达患者接受紫杉醇治疗的疗效及预后较好。Analysistherelationshipofβ－tubulinIIIexpressionandPFS、OSinAGCpatientswithCAPE+PTXβ-tubulinIII-++negativepositiveCR+PRSD+PDTotalRRPTTP(d)POS(d)Pβ-tubulinIII组化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064Patientscangotmorebenefitinβ-tubulinIIIlowexpresionsgroupOSTTPTS、DPYD、MTHFR基因分型与疗效、TTP及OS的相关性：结论：在所检测病例中未检测到DPYD基因IVS14+1G>A突变；

TS基因5’端UTR区3R/3R基因型的疗效、TTP及OS均较2R/3R基因型高；

3’端+6/+6基因型的疗效及总生存期最高。

MTHFR不同基因型中，TT型的有效率及OS＞CC型＞CT型实验结果GenotypeCR+PRSD+PDPValueTTP(d)PValueOS(d)PValueTS-VNTR+G/CSNP*GroupAGroupB124120430.2741291490.9512052610.372TS-VNTR(28bprepeat)2/33/3233036270.1401291780.2572472500.869TS-1494del6+6/+6+6/-6-6/-672422732240.8311491221520.2792611702050.076MTHFR-C677TCCCTTT1419201334160.143179158970.2352502072730.947注：GroupA:2R/2R+2R/3C+3C/3C；GroupB:2R/3G+3G/3C+3G/3G胃癌药物治疗的个体化选择TS、TP、DPD?β－tubulinIII？SNP？预测疗效、预后标志物？分子标志物18ML22697---III期多中心、随机、对照研究随机1:1紫杉醇＋卡培他滨

顺铂＋卡培他滨4周期直到进展或至少6周期卡培他滨直到进展A组B组晚期/复发胃或胃食管结合部腺癌未接受过化疗，或经新辅助、辅助化疗结束超过6个月出现进展N=320ProtocoldesignofToGAHER2-positive

advancedGC

(n=584)5-FUorcapecitabinea

+cisplatin(n=290)R

aChosenatinvestigator’sdiscretion

GEJ,gastroesophagealjunction5-FUorcapecitabinea

+cisplatin+trastuzumab(n=294)StratificationfactorsadvancedvsmetastaticGCvsGEJmeasurablevsnon-measurableECOGPS0-1vs2capecitabinevs5-FUPhaseIII,randomized,open-label,international,multicenterstudy

1Bangetal;Abstract4556,ASCO20093807patientsscreened1810HER2-positive(22.1%)HER2-positivityrate

Europe(23.6%)

Asia(23.5%)

Taiwan5.9%

(n=34)

Australia32.8%

(n=61)

China22.6%±

（n=590）PositiveratioofHER2issimilarinEurope/Asiaarea,butdifferentamongcountries113OSinIHC2+/FISH+orIHC3+(exploratoryanalysis)1.00.20.0363432302826242220181614121086420Time(months)11.816.0FC+TFCEvents120

136HR0.6595%CI0.51,0.83Median

OS16.0

11.8Event0.70.921819840531242011228218196170170141142112122

96100758453653951281000No.

atrisk392028132022/11/27InvestigatorinitiatedstudiesinAGCEXTRAstudyAphaseIIstudyofcetuximab(Erbitux®)withcisplatinandcapecitabine(Xeloda)as1stlinetreatmentintheadvancedgastriccancerHazardratio95%CIPvaluerash0.3870.163-0.9220.032TGFα1.0400.457-2.3680.925EGF0.6040.277-1.3160.204EGFA61Gpolymorphism0.4250.202-0.8950.024PredictivemarkerstocetuximabinEXTRAstudySkinrash2/3:17.57mRash0/1:7.77mTGF-α-high12.867mTGF-α-low7.767mEGFA61GGG13.300mEGFA61G:GA8.9