進(jìn)展期胃癌個(gè)體化藥物治療課件

進(jìn)展期胃癌個(gè)體化藥物治療

——藥物優(yōu)化與個(gè)體化探索北京大學(xué)腫瘤醫(yī)院消化腫瘤內(nèi)科沈琳2010年5月CACA目前胃癌化療藥物氟脲嘧啶類包括口服藥：5-FU,capecitabine,S-1

紫杉醇類：紫杉醇、多稀紫杉醇。鉑類：DDP、OXA（oxaliplatin）蒽環(huán)類：EPI

拓?fù)洚悩?gòu)酶I抑制劑：Irinotecan(CPT-11),HCPT靶向治療藥物: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

方案的改良減少藥物組合——三藥變兩藥改變給藥方法——三周變兩周或一周更換藥物——新藥換老藥目的：保證療效，減低毒性！如何優(yōu)化方案1+1=21+1>2?從臨床到基礎(chǔ)序貫一線選擇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*如何優(yōu)化方案1+1>2?從基礎(chǔ)到臨床多個(gè)小樣本臨床研究顯示了紫杉醇與卡培他濱聯(lián)合應(yīng)用在胃癌一二線中都顯示出很好的前景Primaryresults---PTX+CapesequencedwithCape192patiens，158evaluated

CR2cases，PR61cases(RR39.9%)

SD74cases（46.8%）

PD21cases（13.3％）

DCR86.7%同樣是病理明確的胃腺癌，同樣的分期，接受同樣的藥物、同樣的劑量化療，取得的療效不同。臨床特點(diǎn)相同的個(gè)體，腫瘤分子生物學(xué)特性大不相同，導(dǎo)致治療效果的差異個(gè)體化？實(shí)驗(yàn)結(jié)果33例接受卡培他濱+紫杉醇化療患者中β-tubulinIII表達(dá)與療效及預(yù)后的關(guān)系：β-tubulinIII

表達(dá)分組+-+++++negativepositiveCR+PRSD+PDTotalRRP值TTP(d)P值OS(d)P值β-tubulinIII組化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064結(jié)論：β-tubulinIII低表達(dá)患者接受紫杉醇治療的療效及預(yù)后較好。Analysistherelationshipofβ－tubulinIIIexpressionandPFS、OSinAGCpatientswithCAPE+PTXβ-tubulinIII-++negativepositiveCR+PRSD+PDTotalRRPTTP(d)POS(d)Pβ-tubulinIII組化Positive8132238.1%86201Negative831172.7%0.0632370.0243880.064Patientscangotmorebenefitinβ-tubulinIIIlowexpresionsgroupOSTTPTS、DPYD、MTHFR基因分型與療效、TTP及OS的相關(guān)性：結(jié)論：在所檢測病例中未檢測到DPYD基因IVS14+1G>A突變；

TS基因5’端UTR區(qū)3R/3R基因型的療效、TTP及OS均較2R/3R基因型高；

3’端+6/+6基因型的療效及總生存期最高。

MTHFR不同基因型中，TT型的有效率及OS＞CC型＞CT型實(shí)驗(yàn)結(jié)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胃癌藥物治療的個(gè)體化選擇TS、TP、DPD?β－tubulinIII？SNP？預(yù)測療效、預(yù)后標(biāo)志物？分子標(biāo)志物18ML22697---III期多中心、隨機(jī)、對照研究隨機(jī)1:1紫杉醇＋卡培他濱

順鉑＋卡培他濱4周期直到進(jìn)展或至少6周期卡培他濱直到進(jìn)展A組B組晚期/復(fù)發(fā)胃或胃食管結(jié)合部腺癌未接受過化療，或經(jīng)新輔助、輔助化療結(jié)束超過6個(gè)月出現(xiàn)進(jìn)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