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28 4 @ /28 'CLLFN C.1 28 28 'CLLF( 28 ( 'CLL.( 28 < ' J 'CLLFN9 'CLLFNR H 'CLLG( # 28 28 PHCM??1( E E 28 M 28 : L #:"D "( P #8 /: /: ( Moroni et al. 2005 31 mcrc Score EGFR gene/ nucleus (CNG). ncreased EGFR CNG was defined as the presence of three or more signals per nucleus. 9/20 (45) Of the 9 patients with CNG 8 responded and 1 non responded to cetuximab or panitumumab, suggesting a genetic basis of response to anti-egfr treatment Frattini et al. 2007 27 mcrc 1) Loss if 1 copy of chr 7 in >50 of cells 2) Disomy if 2 copies of chr 7 in >50 of cells 3) Low polysomy f 3 or 4 copies of chr 7 in >50 of cells 4) Marked polysomy if >4 copies of chr 7 in >50 of cells 5) Amplification if R> 3 in at least 10 of cells 0/27 (0) 3/27 (11) 0/27 (0) 1/27 (59) 8/27 (30) Patients whit amplification or marked polysomy have a increased likelihood to response to cetuximab therapy (depending from K-ras and PTEN status) while the disomic one in generally are resistant SartoreBianchi et al 2007 58 mcrc Score EGFR gene/nucleus and use the cut off value. FSH + if > 2.5 and/or > 40 chr 7 polysomy FSH - if 2.5 and/or 40 chr 7 polysomy 38-39/58 20-19/58 Patients with disomic or low polisomy of chr7 have a reduced likelihood to response to panitumumab Cappuzzo et al. 2007 85 mcrc Score EGFR /nucleus and use the cut off value. FSH + if > 2.92 FSH - if 2.92 43/85 (50) 42/85 (50) Patients with EGFR CNG have an increased likelihood to response to cetuximab therapy @ @ '7 O <?L??PGHV CLL0L.B.BC ( C M J : L P U /: /: 28 M?GHCM.B1( 28 0HCM PL1( F G?C C?U?BU 'CLL. @ @ '7 O H M #:"D "( CLLMN BM<??PB/??F.( PHCM??1( E E 28 28 M 'CLL0/ G?BU Observations 28 F?C?U Number of cases and FSH interpretation criteria 0HCM PL1( 28 Type M?GHCM.B1( 'CLL. Cases 28 28 ( M U Authors and year J H 28 CLLMN BM<??PB/??F.( 10
28@ @ 28@ @ TCL/PL1 TFL1 TCL/PL1 TFL1 :PR R/ :PR R/ :42# J TPL1 7 2R T./?L1 :42# J TPL1 7 2R T./?L1 45 2R?'C 45 2R?'C R/ R/ < / 1# W/ MBH??PML1( PFH??PPL1( > Wild Type Mutated KRAS Response Rate Response Rate Study Patients mutations () () () Moroni et al 31 32 38 20 Di Fiore et al 59 37 32 0 Frattini et al 27 37 53 10 Benvenuti et al 48 33 31 Khambata-Ford et al 80 38 10 0 Karapetis et al 394 42 13 1 Lievre et al 89 27 40 0 and account for about 40 of NR patients De Roock et al 113 41 41 0 Amado et al 427 43 17 0 Van Cutsem et al 540 3 59 3 Bokemeyer et al 233 42 1 33 K-Ras mutations associated with cetuximab/panitumumab resistance : 'CLLB CCHMBC01( CHPFG1( #/.MHMBMC1( PCHPFBF1( p<0.05, two-tailed Fisher s exact test R/ @ /28 "# X X 'O 5 CLL0NCG<.ML./.M?C( http://www.fda.gov/aboutfda/centersoffices/cder/ucm172905.htm R/ 7 W/ W/ 1# MBH??PML1( PFH??PPL1( G0HMB0G1(??HMB?F1( > > #/ p<0.05, two-tailed Fisher s exact test CCHMBC01(.MHMBMC1(?!? CHPFG1( PCHPFBF1( R/ @ /28 "# X X 'O 5 CLL0NCG<.ML./.M?C( CCHG0PC1( LH??L1( #/ FGHG0G01(??H???LL1( p<0.05, two-tailed Fisher s exact test 7 @ J R/@/ "# X X 'O 5 CLL0NCG<.ML./.M?C( 11
7 @ 'E??P 7 R UUYLL.ELL??( # R PFH??PPL1( CHPFG1(U PCHPFBF1(UU W/4R MBH??PML1( CCHMBC01(UU.MHMBMC1(UU R/ PCH0BPG1(# RPFH??PPL1( BRAF mutational status on Wild-Type KRAS tumors UYLL.ELLCB( # 7??HMB?F1( LH??L1(U??H???LL1(U W/47 G0HMB0G1( CCHG0PC1(U FGHG0G01(U 7??H0B?C1(# 7??H??P?L1( 7AGLL2 FL1 @ R/7 R/7 F01 # "# X X 'O 5 CLL0NCG<.ML./.M?C( 4 7AGLL2 "# X X 'O 5 CLL0NCG<.ML./.M?C( 7 @ 'E??P 28@ @ UUYLL.ELL??( # UYLL.ELLCB( # R R PFH??PPL1( CHPFG1(U PCHPFBF1(UU BRAF mutational status on Wild-Type KRAS tumors 7??HMB?F1( LH??L1(U??H???LL1(U W/4R MBH??PML1( CCHMBC01(UU.MHMBMC1(UU W/47 G0HMB0G1( CCHG0PC1(U FGHG0G01(U R/ PCH0BPG1(# RPFH??PPL1( FL1 @ R/7 R/7 F01 # "# X X 'O 5 CLL0NCG<.ML./.M?C(?!? 7??H0B?C1(# 7??H??P?L1( TCL1 :42# TPL1 :PR J 45 R/ 7 2R 2R?'C TPL/FL1 T?L1 :RP #@ W/ Evaluation of KRAS status 18 B.H??L0G1(?.H??L?F1( Mutated KRAS Wild-type KRAS CCHB.CP1( > LH?.L1( Very low or no probability of clinical benefit Mutated BRAF or Mutated PK3CA Evaluation of BRAF and PK3CA #/ MPHB.MM1(?.H?.?LL1( p<0.001, two-tailed Fisher s exact test :RP @ J High probability of clinical benefit Wild-type BRAF and Wild-type PK3CA /7X X 'CLLBNGB<?0.?/?0.M( /7 'CLLB( 12
: : 8?/ 0#,!/#9@0#!/!/#9#. Z Q 00 #! 1# /!# 9 Q +##"##"=<-R LF?[J[LG' LG?[J[L0' '7OCLLBN?LL<?L0M/?LBF( <R/ :K4)5 PM 244 A"=0 C?.M1( A"=0 CCGL1(!#?GFP1(!#?.FL1( " R/ PHPM01(κEL0P':YLLLL?( :4 8 R/ >?HPMCM1( W/ 8?C <?C @ @ : /28< 24 ( :<CH?C?M1( #<?LH?C0P1( cases EGFR HC EGFR FSH K-Ras BRAF PTEN HC clinical T M T M T M T M T M response 1 + + CNG CNG WT WT WT WT + + PR 2 + + CNG CNG WT WT WT WT + + PR 3 + + D D WT WT V00E V00E + + NR 4 + + D D WT WT WT WT + + NR 5 + + CNG CNG G12S G12S WT WT + + NR + + CNG CNG G12A G12A WT WT + + NR 7 + + CNG CNG WT WT WT WT - - NR 8 + + D CNG G12A G12A WT WT - - NR 9 + + D CNG G12D G12D WT WT + + NR 10 + + D CNG G12A G12A WT WT - - NR 11 + + D CNG WT WT V00E V00E - - NR 12 + + CNG CNG G12D WT WT WT + + NR > 9 R/ 8?C CHPM.F1( W/ 4 R/ /28 '7OCLLBN?LL<?L0M/?LBF( '7OCLLBN?LL<?L0M/?LBF( R/ < / R/< Wild Type Mutated KRAS Response Rate Response Rate Study Patients mutations () () () Moroni et al 31 32 38 20 Di Fiore et al 59 37 32 0 Frattini et al 27 37 53 10 Benvenuti et al 48 33 31 Khambata-Ford et al 80 38 10 0 Karapetis et al 394 42 13 1 Lievre et al 89 27 40 0 De Roock et al 113 41 41 0 Amado et al 427 43 17 0 Van Cutsem et al 540 3 59 3 Bokemeyer et al 233 42 1 33 : 'CLLB NT 13
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