Biomarkers-in-mCRC生物标志物变化.ppt

Biomarkery a metastazujc kolorektln karcinomJosep TaberneroVall dHebron University HospitalBarcelona,SpainGastrointestinal Cancer Expert Forum,Lisboa,March 2009Co jsou to biomarkery?Biomarkery mohou bt meny v ndorov tkni i v tlesnch tekutinch,nap.v plazmBiomarkery prediktivn pedpovdaj odpov na konkrtn lbu Biomarkery prognostick jsou spojeny s vym rizikem rozvoje nemoci,rizikem en,agresivity nemoci a etnost peitBiomarkery jsou indiktory normlnch biologickch dj,patologickch dj i farmakologickch odpovd na lebn zsahKter biomarkery byly zkoumny u pokroilho CRC?Prognostick biomarkerymikrovaskulrn denzitaexprese VEGFexprese CD133hladiny IL-6 a IL-8hladiny srovho Tie-2 receptoru exprese angiopoietinu-2CRC=kolorektln karcinomEGFR=epidermoidn rstov faktor VEGF=vaskulrn endotelov rstov faktor IL=interleukinPrediktivn biomarkeryModultory aktivity EGFR:stav KRAS stav BRAF exprese PTENstav PI3Khladiny epiregulinu hladiny amfiregulinu dal:aktivita Topo1 u irinotekanuERCC1 u oxaliplatinyBokemeyer,et al.JCO 2009Chung,et al.Anticancer Res 2019Chung,et al.J Surg Oncol 2019Di Nicolantionio,et al.JCO 2019Loupakis,et al.JCO 2019Sessa,et al.Nat Clin Pract Oncol 2019Inhibice EGFRSignln cesta EGFR u CRC Adaptovno z Roberts and Der.Oncogene 2019mutace BRAF 10%mutace KRAS 3050%exprese EGFR 2795%EGFR mutace 1%MAPKMEKBRAFKRASTGF-Grb2SosTGF=transforman rstov faktorEGFRMon vztah mezi stavem K-ras a odpovd na monoklonln protiltky zaclen na EGFR v monoterapii i v kombinaci s irinotekanem u chemorezistentnch nemocnchOdpovdajc na standardn dvku22%Odpovdajcna zvenou dvku 5%neodpovdajc:KRAS mutace 40%neodpovdajc:BRAF mutace 10%neodpovdajc:ztrta PTENi PI3K mutac%je neznmoneodpovdajc:neznm dvod%neznmKRASdivok typKRASmutaceWong and Cunningham.JCO 2019Nemocn s ndorovou mutac KRAS nemaj vhodu z podn cetuximabu v 1.linii lby mCRC:studie CRYSTALKRAS divok typKRAS mutovanCetuximab+FOLFIRI vs FOLFIRI(n=172)Cetuximab+FOLFIRI vs FOLFIRI(n=105)OS,msce24,9 vs 21,0HR=0,84;95%CI:0,64;1,10(p=0,22)17,5 vs 17,7HR=1,03;95%CI 0,74;1,44(p=0,85)PFS,msce9.9 vs 8.7HR=0,68;95%CI:0.51;0,93(p=0.017)7,6 vs 8,1HR=1,07;95%CI:0,711.61(p=0,75)ORR,%59 vs 43HR=1,91;95%CI:0,80(p=0,003)36 vs 40HR=0.80;95%CI:0,44;1,44(p=0,46)Rougier,et al.ASCO GI 2009(abstrakt)OS=celkov peit;PFS=doba bez progrese nemociORR=etnost celkovch odpovd;HR=pomr rizikCI=interval spolehlivostiNemocn s ndorovou mutac KRAS nemaj vhodu z podn cetuximabu v 1.linii lby mCRC:studie OPUSKRAS divok typKRAS mutovanCetuximab+FOLFOX4 vs FOLFOX4(n=134)Cetuximab plus FOLFOX4 vs FOLFOX4(n=99)OS,msceNRNRPFS,msce7,7 vs 7,2HR=0,57,95%CI:0,36,0,91(p=0,016)5,5 vs 8,6HR=1,83,95%CI:1.09,3,06(p=0,019)ORR,%61 vs 37OR=2,54,95%CI:1,24,5,23(p=0,011)33 vs 49OR=0,51,95%CI:0,22,1,15(p=0,106)Bokemeyer,et al.JCO 2009OR=odds ratio;NR=nehleno Mutace BRAF11/79(14%)Divok typ BRAF68/79(86%)odpovdajc0/11(0%)22/68(32%)neodpovdajc11/11(100%)46/68(68%)mutace KRAS34/113(30%)Divok typ KRAS79/113(70%)odpovdajc2/34(6%)*22/79(28%)*neodpovdajc32/34(94%)*57/79(72%)*Dal nemocn nebudou zejm odpovdat na lbu inhibitory EGFR i z dvodu BRAF mutacStav BRAF u divokho typu KRAS(n=79)Stav KRAS(hodnotiteln nemocn n=113)Nemocn s mCRC len panitumumabem i cetuximabem,n=114*p0,05(p=0,011)p0,05(p=0,029)Di Nicolantionio,et al.JCO 2019Di Nicolantonio,et al.JCO 2019BRAF divok typBRAF mutacep=0,0010Nemocn s KRAS divokm typem100806040200OS(%)0200400600800 1 000 1 2001 400BRAF divokBRAF mutacep10 msce v medinu OSBevacizumab v 1.linii pin vhodu vem nemocnm nezvisle na K-ras stavuKRAS divokKRAS mutovanBevacizumab+IFL vs IFL(n=152)Bevacizumab+IFL vs IFL(n=78)OS,msce27,7 vs 17,6HR=0,58;95%CI:0,30;1,0(p=004)19,9 vs 13,6HR=0,69;95%CI:0,4;1,3(p=0.26)PFS,msce13,5 vs 7,4 HR=0,44;95%CI:0,3;0,7(p0,0001)9,3 vs 5,5 HR=0,41;95%CI:0,2;0,7(p=0,008)ORR,%60,0 vs 37,3(p=0,006)43,2 vs 41,2(p=0,86)Hurwitz,et al.Oncologist 2009Duln inhibice1614121086420PFS(msce)KRAS divok typKRAS mutace10.5p=0,1012.58.610.7XELOX+bevacizumabXELOX+bevacizumab+cetuximabTol,et al.NEJM 2009CAIRO-2:pidn cetuximabu k bevacizumabu v 1.linii CRC nepin dnou vhodu,tento fakt nen zvisl na stavu K-rasp=0,0431614121086420PFS(msce)chemoterapie na basi irinotekanuchemoterapie na basi oxaliplatinyHR(95%CI):1.50(0.822.76)p=0,016HR(95%CI):1.25(0.911.71)HR(95%CI):1.36(1.041.77)HR(95%CI):1.19(0.652.21)PACCE:zkrcen PFS po pidn panitumumabu k bevacizumabu v 1.linii CRC nezvisle na K-ras stavuKRAS divok typ(n=115)KRAS mutace(n=86)KRAS divok typ(n=404)KRAS mutace(n=260)chemoterapie+bevacizumabchemoterapie+bevacizumab+panitumumabHecht,et al.JCO 2009ZvremlBiomarkery pomhaj lpe urit vhodnou lbu nemocnch s CRClNemocn s K-ras mutac nesm dostat lbu protiltkami clenmi na EGFR lBiomarkery signln cesty BRAF a PI3K a jejich mutace budou dle urovat ty nemocn,kter nebudou odpovdat na lbu protiltkami clenmi na EGFRlBevacizumab je jedin biologikum s prokzanm prodlouenm peit v 1.linii nezvisle na stavu biomarker