#4169 cremec initiative: characterization of patient ... · cric002p (wt kras) cric013m (mutated...
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CRIC013M (mutated KRAS) CRIC002P (wt KRAS)
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CRLRB022P in mice
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CPT-11 (22mg/kg/ Adm)
CPT-11 IV treatment
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CRLRB022P in rats
ControlOxaliplatin (4 mg/kg/ adm)CPT-11 (40 mg/kg/ adm)Cetuximab (10 mg/kg/ adm)5-FU (30 mg/kg/ adm)
Days post implantation70605040302010
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Treatment start(D23)
ControlOxaliplatin (4 mg/kg/ adm)CPT-11 (40 mg/kg/ adm)Cetuximab (10 mg/kg/ adm)5-FU (30 mg/kg/ adm)
(4 mg/kg/ adm)CPT- adm)
(10 mg/kg/5- adm)
Days post implantation70605040302010
Med
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Days post implantation70605040302010
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Treatment start(D23)
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CRLRB022P in mice
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Days post implantation
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ControlCetuximab (12.5 mg/kg/ adm)5-FU (50.0 mg/kg/ adm)Oxaliplatin (5.0mg/kg/ adm)Cetuximab IP treatment5-FU IV treatmentOxaliplatin IV treatment
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umor
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ControlCetuximab (12.5 mg/kg/adm)5-FU (50.0 mg/kg/ adm)Oxaliplatin (5.0mg/kg/ adm)Cetuximab IP treatment5-FU IV treatmentOxaliplatin IV treatment
CRLRB022P in mice
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Days post implantation
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ian
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ControlCetuximab (12.5 mg/kg/ adm)5-FU (50.0 mg/kg/ adm)Oxaliplatin (5.0mg/kg/ adm)Cetuximab IP treatment5-FU IV treatmentOxaliplatin IV treatment
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umor
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ControlCetuximab (12.5 mg/kg/adm)5-FU (50.0 mg/kg/ adm)Oxaliplatin (5.0mg/kg/ adm)Cetuximab IP treatment5-FU IV treatmentOxaliplatin IV treatment
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umor
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CPT-11 (22mg/kg/ Adm)
CPT-11 IV treatment
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15 20 25 30 35Dayspost implantation
Med
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umor
volu
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(mm
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CPT-11 (22mg/kg/ Adm)
CPT-11 IV treatment
3
CRLRB022P in rats
ControlOxaliplatin (4 mg/kg/ adm)CPT-11 (40 mg/kg/ adm)Cetuximab (10 mg/kg/ adm)5-FU (30 mg/kg/ adm)
Days post implantation70605040302010
Med
ian
tum
our
volu
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(mm
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Treatment start(D23)
ControlOxaliplatin (4 mg/kg/ adm)CPT-11 (40 mg/kg/ adm)Cetuximab (10 mg/kg/ adm)5-FU (30 mg/kg/ adm)
(4 mg/kg/ adm)CPT- adm)
(10 mg/kg/5- adm)
Days post implantation70605040302010
Med
ian
tum
our
volu
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(mm
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Days post implantation70605040302010
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Treatment start(D23)
- adm)
5- )
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5- )
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-
- )
-
CRLRB022P in rats
ControlOxaliplatin (4 mg/kg/ adm)CPT-11 (40 mg/kg/ adm)Cetuximab (10 mg/kg/ adm)5-FU (30 mg/kg/ adm)
Days post implantation70605040302010
Med
ian
tum
our
volu
me
(mm
3 ) 10000
9000
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Days post implantation70605040302010
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ian
tum
our
volu
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3 ) 10000
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Treatment start(D23)
ControlOxaliplatin (4 mg/kg/ adm)CPT-11 (40 mg/kg/ adm)Cetuximab (10 mg/kg/ adm)5-FU (30 mg/kg/ adm)
(4 mg/kg/ adm)CPT- adm)
(10 mg/kg/5- adm)
Days post implantation70605040302010
Med
ian
tum
our
volu
me
(mm
3 ) 10000
9000
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Days post implantation70605040302010
) 10000
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Treatment start(D23)
- adm)
5- )
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INTRODUCTION
MATERIAL AND METHODS
CReMEC initiative: Characterization of patient-deri ved colorectal tumor models and correlation with pa tient profileSylvia Julien 1, Ana Merino-Trigo 2, Ludovic Lacroix 7,5, Marc Pocard 3,5, Diane Goéré 7,5, Pascale Mariani 4,5, Sophie Landron 8, Ludovic Bigot 7,5, Fariba Nemati 4,5, Louis-Bastien Weiswald 3,5, Denis Lantuas 3,5, Loïc Morgand 9,
Grégoire Prévost 1, Patrick Gonin 7,5, Virginie Dangles-Marie 3,4,5, Alain Pierré 8, Alain Bruno 8, Hugues De Thé 5,6, Hany Soliman 5,6, Manoel Nunes 2, Loreley Calvet 2, Patricia Vrignaud 2, Olivier Duchamp 9, Cyril Berthet 9.
1Ipsen, 2sanofi-aventis, 3Hôpital Lariboisière , 4Institut Curie, 5Cancéropole d’Ile de France, 6Institut Universitaire d'Hématologie, Paris, 7Institut Gustave Roussy, Villejuif, 8Institut de recherche Servier, Croissy sur Seine, 9Oncodesign, Dijon, France.
RESULTS
CONCLUSION
#4169
Well characterized models representing the heterogeneity of human colorectal cancers (CRC) are needed to develop effective therapeutic agents. Establishment of such tools will allow a better prediction of the clinical outcome, taking into account the diversity of each patient tumor phenotype and genotype. For this purpose, we have associated efforts from hospitals, academic groups, biotech and pharmaceutical companies. The goal of this consortium is to create an experimental tumor model resource center to improve or strengthen drug development. From May 2007 to January 2009, 86 surgical specimen s [59 primary (P) tumors, 19 metastasis (M), and 8 peritoneal carcinomatosis (C)] were collected from C RC patients (with informed consents and negative HBV, HCV, and HIVs serologies). Tumor samples were subcutaneously xenografted in nude mice and characterized as described below. We report here the results on our panel of models.
� Patients were informed and gave their consent for providing surgical tumor samples to CReMEC and for HIV1, HIV2, HBV and HCV serological status testing.
� Tumor samples were collected in 3 medical centers o f the Paris-Ile-de-France area: Institut Curie, Institut Gu staveRoussy, Hôpital Lariboisière.
� Fresh tumor material was conditioned into RPMI 1640 with 200 U/mL penicillin, 200 µg/mL streptomycin and 2.5 µg/mL fungizone.
� Initial xenografting was carried out at the site of sampling, within 12 hours after specimen collection. Procedu res were performed according to ethical guidelines for animal care and handling.
� 20-40 mg fragments were xenografted subcutaneously either in the flank or in the interscapular area, in 3-5 immunodeficient SWISS nude mice
� Grafted mice were kept for a maximum of 4 months wi thout tumor growth.
Clinical data collectionRelevant clinical information was collected by the attending physician and included in a standardized d ata sheet.Identification of the data sheet is anonymous.
Histological characterizationSamples were fixed for a maximum of 48 hours in alc ohol-formalin-acetic acid (AFA) and embedded in par affin. 5 µm sections were stained with hematoxylin-eosin-saffron.
Molecular characterization – sequencingCGH array analysis: Evaluation of genome-wide, gene copy number was eva luated using a 244k CGH array Agilent technology. It was carried out on DNA from the patient sample o r at an early passages (P0/P1), and at the passage u sed for the pharmacological evaluation (P8-9).
DNA sequencing: The following genetic markers, relevant in CRC, wer e selected for sequencing: APC (exons 9 & 16), KRAS(exons 2 & 3), BRAF (exons 11 & 15), TP53 (exons 2 to 11), CTNNB1 (exon 3), PIK3CA (exons 10 and 21), FBXW7 (exons 4 to 11), EGFR (exons 18 to 21) and AKT1 (exon 4). Sanger direct sequencing was performed a fter PCR amplification of exons of genes harboring hotspot mutations as described in Catalog ue Of Somatic Mutations In Cancer (COSMIC: http://www.sanger.ac.uk/genetics/CGP/cosmic/ ).
Determination of Microsatellite Instability (MSI) status: The MSI status was determined according to the Cons ensus Conference (or Revised Bethesda Guidelines) ( J. Natl Cancer Inst 2004, 96, 261-268) recommendations using the follow ing five quasimonomorphic markers: NR21, BAT26, BAT25, NR24 and NR22.
Pharmacological characterizationTested agents: 5-fluorouracil (5-FU), oxaliplatin (L-OHP), irinotec an (CPT-11) or cetuximab, were tested.
In vivo determination of antitumor activity: Tumor fragments were subcutaneously xenografted in SCID mice or nude rats. Tumor-bearing animals were randomized when the mean tumor volume reached 100-200 mm 3 in mice or 500-700 mm 3 in rats. Compounds were formulated in glucose 5% in water. 3 cytotoxic drugs were IV administered, and tested at 70% of their respective highest non toxic dose and using the fol lowing regimen in mice: 5-FU at 56 mg/kg/adm Q4Dx2 (30 mg/kg/adm Q7Dx3 in rats) , L-OHP at 5 mg/kg/adm Q4Dx2 (4 mg/kg/adm Q4Dx3 in rats), CPT-11 at 22 mg/kg/adm, Q2Dx3 (40 mg/ kg/adm, Q7Dx3in rats) ; 1 targeting therapy was IP administrated: c etuximab at 12.5 mg/kg/adm, (Q3Dx2)x2 (10 mg/kg/adm, IV, Q7Dx3 in rats).Antitumor activity was evaluated by calculating the ∆(T/C) ratio:
∆∆∆∆(T/C) (%) = X 100median T VOL- DY – median T VOL-DX
median C VOL- DY – median C VOL-DX
Preservation of the tumor phenotype and genotype
Clinical characteristics and in vivo tumorgraft take rate
Scoring criteria: - = ∆(T/C) > 42 %+ = 10 < ∆(T/C) ≦ 42 %++ = 0 ≦ ∆(T/C) ≦10 % (stable disease) +++ = ∆(T/C) <0 % (tumor regression)
84125CPT-11
73415Cetuximab
00227L-OHP
051775-FU
++++++-Activity score
22
4
4<10%
10-50%
>50%
Mucus Secretion
22
4
4<10%
10-50%
>50%
Mucus Secretion
Tum
orM
odel
s Differentiation2
1213
2 1WDWD, MDWD, MD, PD
MD, PDPD, UD
Differentiation2
1213
2 1WDWD, MDWD, MD, PD
MD, PDPD, UD
Mutations 1000KRAS/BRAF
++++++-Activity score
41311EGFR mutated pathway
3213EGFR wild-type pathway*
0002BRAF
0021KRAS/PIK3CA
3118KRAS
Fresh
tumors
Surgery
* Patient identification
* Patient clinical history
* Patient informed consent
* Negative HIV, HBV, HCV serology
Paraffin
Tumor bank
Snap-frozen
Database
Tumor growth
Molecular
Histological
Pharmacological
Characterization
26 31 36 41 46 510
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1400 CPT-11 treatmentCPT-11 22 mg/kg IVControl (untreated)
Days after tumor inoculation
Med
ian
tum
or s
ize
(mg
+/-
IQR
)
Tumor
grafting
P0P2 – P6
Establishment of in vivo tumorgraft models
RPMI/DMSO freezing
Fresh
tumors
Surgery
Fresh
tumors
Surgery
* Patient identification
* Patient clinical history
* Patient informed consent
* Negative HIV, HBV, HCV serology
* Patient identification
* Patient clinical history
* Patient informed consent
* Negative HIV, HBV, HCV serology
Paraffin
Tumor bank
Snap-frozenParaffin
Tumor bank
Snap-frozen
Database
Tumor growth
Molecular
Histological
Pharmacological
Characterization
26 31 36 41 46 510
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1400 CPT-11 treatmentCPT-11 22 mg/kg IVControl (untreated)
Days after tumor inoculation
Med
ian
tum
or s
ize
(mg
+/-
IQR
)
Database
Database
Tumor growth
Molecular
Histological
Pharmacological
Characterization
Tumor growth
Molecular
Histological
Pharmacological
Characterization
26 31 36 41 46 510
200
400
600
800
1000
1200
1400 CPT-11 treatmentCPT-11 22 mg/kg IVControl (untreated)
Days after tumor inoculation
Med
ian
tum
or s
ize
(mg
+/-
IQR
)
26 31 36 41 46 510
200
400
600
800
1000
1200
1400 CPT-11 treatmentCPT-11 22 mg/kg IVControl (untreated)
CPT-11 treatmentCPT-11 22 mg/kg IVControl (untreated)
Days after tumor inoculation
Med
ian
tum
or s
ize
(mg
+/-
IQR
)
Tumor
grafting
P0P2 – P6
Establishment of in vivo tumorgraft models
RPMI/DMSO freezing
Tumor
grafting
P0P2 – P6
Establishment of in vivo tumorgraft models
RPMI/DMSO freezing
PR: Partial ResponseCR: Complete ResponseTFS: Tumor Free Survival
Tumor takerate (%)
Parameter Class Number Frequency(%)
Site of origin Primary 37 66.1 62.7Peritonealcarcinosis 5 8.9 62.5
Metastasis# 14 25.0 73.7
Sex Female 35 62.5 66.0Male 21 37.5 63.6
Age 0−50y 11 20.4 78.6[ 50y ; 60y] 12 24.5 50.0[ 60y ; 70y] 12 20.4 60.0[ 70y ; 80y] 15 24.5 68.2
>80y 6 10.2 100Stage 0 - I 2 3.7 22.2
II 8 14.8 57.1III 13 24.1 92.9IV 31 57.4 70.4
Patient characteristics in the collection
# hepatic, splenic and mesenteric lymph node metastasis
Tumor takerate (%)
Parameter Class Number Frequency(%)
Site of origin Primary 37 66.1 62.7Peritonealcarcinosis 5 8.9 62.5
Metastasis# 14 25.0 73.7
Sex Female 35 62.5 66.0Male 21 37.5 63.6
Age 0−50y 11 20.4 78.6[ 50y ; 60y] 12 24.5 50.0[ 60y ; 70y] 12 20.4 60.0[ 70y ; 80y] 15 24.5 68.2
>80y 6 10.2 100Stage 0 - I 2 3.7 22.2
II 8 14.8 57.1III 13 24.1 92.9IV 31 57.4 70.4
Patient characteristics in the collection
# hepatic, splenic and mesenteric lymph node metastasis Significant correlation* between CEA serum level of patient and tumor take of all types
Significant distribution* of primary tumors in rega rds of lymph node status (panel A, N1 = 1 to 6, N2 = 7 to 15 positive regional lymph nodes), stages (panel B) an d differentiation status (panel C).No other significant correlation were found among t he following parameters: gender, age, resection ext ent, lymphatic embolies, perinervous invasion, initial tr eatment, genotype
* p values were calculated with logical regression test
Gene mutation profile and response to chemotherapy
Histopathological analyses completed for 30 colon tumor models were in concordance to those observed in the corresponding patient’s tumor.CGH analysis showed very similar profile between early and advance passagesThe expression and localization of ββββ-catenin, CEA, CAIX, EGFR, CD105 and LYVE-1 is ongoing.
The majority of tumor models were non-mucinous adenocarcinomas
Splenicmetastasis
(1/86)
Mesentericlymph node
(1/86)
All models collected (86)
Left (21/59)
Right (20/59)
Primary tumor(59/86)Carcinosis (8/86)
HepaticMetastasis (16/86)
Ovarianmetastasis
(1/86)
Left (4/6)
Rect.(18/59)Left (5/8)
Right (3/8)
Left (9/16)
Right (5/16)
Rect.(2/16)
Splenicmetastasis
(1/86)
Mesentericlymph node
(1/86)
All models collected (86)
Left (21/59)
Right (20/59)
Primary tumor(59/86)Carcinosis (8/86)
HepaticMetastasis (16/86)
Ovarianmetastasis
(1/86)
Left (4/6)
Rect.(18/59)Left (5/8)
Right (3/8)
Left (9/16)
Right (5/16)
Rect.(2/16)
Right colon
Left colon
Rectum
Models growing on nude mice (56)
Primary tumor(37/56)Carcinosis (5/56)
HepaticMetastasis (12/56)
Splenicmetastasis
(1/56)
Mesentericlymph node
(1/56)
Left (15/37)
Right (13/37)Rect.(9/37)
Left (4/5)
Right (1/5 )
Left (6/12) Right (5/12)
Rect. Right colon
Left colon
Rectum
Right colon
Left colon
Rectum
Models growing on nude mice (56)
Primary tumor(37/56)Carcinosis (5/56)
HepaticMetastasis (12/56)
Splenicmetastasis
(1/56)
Mesentericlymph node
(1/56)
Left (15/37)
Right (13/37)Rect.(9/37)
Left (4/5)
Right (1/5 )
Left (6/12) Right (5/12)
Rect.
Only 1 model showed a poor differentiated (PD) to undifferentiated (UD) characteristic, as well as its correspondent patient
Similar CGH profiles between early and advance passage s
Loss in chromosomes 3p and 4q in advance passage
Most models with EGFR mutated pathway are resistant to Cetuximab, nevertheless several Cetuximab sensitive KRAS-mutated models have been identified.
Patient: CR-IGR-034PPatient: CR-LRB-010P Patient: CR-LRB-008M
P10: CR-LRB-010P P11: CR-LRB-008M P11: CR-IGR-034P
Pat
ient
Tum
orM
odel
Well DifferentiatedWell to Moderate
Differentiated Poor to UnDifferentiated
Patient: CR-IGR-034PPatient: CR-LRB-010P Patient: CR-LRB-008M
P10: CR-LRB-010P P11: CR-LRB-008M P11: CR-IGR-034P
Patient: CR-IGR-034PPatient: CR-LRB-010P Patient: CR-LRB-008M Patient: CR-IGR-034PPatient: CR-IGR-034PPatient: CR-LRB-010PPatient: CR-LRB-010P Patient: CR-LRB-008MPatient: CR-LRB-008M
P10: CR-LRB-010P P11: CR-LRB-008M P11: CR-IGR-034PP10: CR-LRB-010PP10: CR-LRB-010P P11: CR-LRB-008MP11: CR-LRB-008M P11: CR-IGR-034PP11: CR-IGR-034P
Pat
ient
Tum
orM
odel
Pat
ient
Tum
orM
odel
Well DifferentiatedWell to Moderate
Differentiated Poor to UnDifferentiated
Sensitivity to Cetuximab versus mutated genes involved in EGFR pathway ∆T/C = -41% (Day 31),
9/10 PR & 4/10 CR
CRIGR023MGAIN
LOSS
CRIGR002CGAIN
LOSS
* Mutations of PTEN or other genes related to EGFR pathway have not been yet characterized
Multiple mutation profiles are observed in our tumo r panel (n=60), matching the human tumor genetic heterogeneity Pharmacological studies exhibit diversity in the response to chemotherapy13/29 tumorgrafts show tumor regression after treat ment with at least one standard monotherapy
Diversity of colorectal cancers is fully addressed in this collection of patient-derived tumor models.
Genotype and phenotype are largely preserved throughout the model establishment process.
Difference of gene mutation and drug sensitivity profiles are observed between the models.
Plan to complete the full correlation analysis between clinical data, gene mutations, transcriptome
profile, ex-vivo and in vivo drug sensitivity.
Perspectives to fully exploit this new collection for new drug candidate selection.
∆T/C = < 0 % (Day 36), 10/10 CR + 100% TFS
0
CE
A (
ng/m
L)
Positive xenograft take
5
10
15
2025
30
35
40
4550
170175180
41
11
2.3
8
27
p = 0.0292 (*)
All types of tumor samples / CEA dosing
Negativexenograft take
0
5
10
15
2025
30
35
40
4550
170
180
41
11
2.3
8
27
p = 0.0292 (*)
0
CE
A (
ng/m
L)
Positive xenograft take
5
10
15
2025
30
35
40
4550
170175180
41
11
2.3
8
27
p = 0.0292 (*)
All types of tumor samples / CEA dosing
Negativexenograft take
0
5
10
15
2025
30
35
40
4550
170
180
41
11
2.3
8
27
p = 0.0292 (*)
AP
erce
ntag
e(%
)
N0
N0
N1 + N2
N1 + N2
0
20
40
60
80
100
120
(n=11)
(n=26)
(n=5)
(n=17)
Primary tumor samples / Lymph node status
Positive xenograft take
Negativexenograft take
p = 0.0038 (**)
N0
N0
N1 + N2
N1 + N2
0
20
40
60
80
100
120
(n=11)
(n=26)
(n=5)
(n=17)
p = 0.0038 (**)
AP
erce
ntag
e(%
)
N0
N0
N1 + N2
N1 + N2
0
20
40
60
80
100
120
(n=11)
(n=26)
(n=5)
(n=17)
Primary tumor samples / Lymph node status
Positive xenograft take
Negativexenograft take
p = 0.0038 (**)
N0
N0
N1 + N2
N1 + N2
0
20
40
60
80
100
120
(n=11)
(n=26)
(n=5)
(n=17)
p = 0.0038 (**)
B
Stages 0-I
Stages 0-I
Stage II
Stage II
Stage III
Stage III
Stage IV Stage IV
0
20
40
60
80
100
120
(n=7)
(n=6)
(n=7) (n=6)
(n=13)
(n=14)
Primary tumor samples / Stages
Negativexenograft take
Positive xenograft take
p = 0.0101 (*)
Per
cent
age
(%)
Stages 0-I
Stages 0-I
Stage II
Stage II
Stage III
Stage III
Stage IV Stage IV
0
20
40
60
80
100
120
(n=7)
(n=6)
(n=7) (n=6)
(n=13)
(n=14)
p = 0.0101 (*)
B
Stages 0-I
Stages 0-I
Stage II
Stage II
Stage III
Stage III
Stage IV Stage IV
0
20
40
60
80
100
120
(n=7)
(n=6)
(n=7) (n=6)
(n=13)
(n=14)
Primary tumor samples / Stages
Negativexenograft take
Positive xenograft take
p = 0.0101 (*)
Per
cent
age
(%)
Stages 0-I
Stages 0-I
Stage II
Stage II
Stage III
Stage III
Stage IV Stage IV
0
20
40
60
80
100
120
(n=7)
(n=6)
(n=7) (n=6)
(n=13)
(n=14)
p = 0.0101 (*)
C Primary tumor samples / Differentiation
0
Well
Well
Fairly
Fairly
Weakly
20
40
60
80
100
120
(n=10)
(n=11)
(n=9)
(n=25)
Per
cent
age
(%)
p = 0.0287 (*)
Negativexenograft take
Positive xenograft take
0
Well
Well
Fairly
Fairly
Weakly
20
40
60
80
100
120
(n=10)
(n=11)
(n=9)
(n=25)
p = 0.0287 (*)
C Primary tumor samples / Differentiation
0
Well
Well
Fairly
Fairly
Weakly
20
40
60
80
100
120
(n=10)
(n=11)
(n=9)
(n=25)
Per
cent
age
(%)
p = 0.0287 (*)
Negativexenograft take
Positive xenograft take
0
Well
Well
Fairly
Fairly
Weakly
20
40
60
80
100
120
(n=10)
(n=11)
(n=9)
(n=25)
p = 0.0287 (*)
Similar tumor response ranges have been observed in mice and rats
∆∆∆∆T/C in miceL-OHP: 45%5-FU: 45%
Cetuximab: 78%
∆∆∆∆T/C in ratL-OHP: 104%
5-FU: 63%Cetuximab: 19%
CPT-11: 1%
∆∆∆∆T/C in miceCPT-11 < 0%
70%
80%
80%
50%
70%
90%
60%
80%
80%
50%
90%
90%
70%
60%
90%
60%
40%
100%
40%
70%
40%
80%
50%
80%
50%
80%
80%
80%
80%
50%
90%
40%
80%
30%
90%
80%
90%
90%
85%
60%
85%
50%
60%
70%
40%
40%
80%
50%
30%
50%
70%
90%
70%
80%
80%
50%
50%
50%
50%
80%
CR
IGR
023M
CR
IC00
4M
CR
IC00
7M
CR
IGR
007P
CR
IGR
025P
CR
LRB
010P
CR
LRB
011M
CR
LRB
013P
CR
LRB
014P
CR
IC01
8P
CR
IC00
2P
CR
IC00
3P
CR
IC02
5M
CR
IGR
004P
CR
IGR
008P
CR
LRB
007P
CR
IGR
015P
CR
LRB
019C
CR
IGR
021P
CR
IC02
0P
CR
IC02
1M
CR
IGR
032P
CR
IGR
029P
CR
IGR
012P
CR
IGR
014P
CR
IC01
2P
CR
IC01
3M
CR
LRB
008M
CR
LRB
009C
CR
IGR
003P
CR
IGR
009P
CR
IGR
016P
CR
IGR
020P
CR
IGR
001M
CR
IGR
038C
CR
LRB
017P
CR
IGR
034P
CR
LRB
018P
CR
LRB
003P
CR
LRB
004P
CR
LRB
015P
CR
IC00
6M
CR
IC01
9P
CR
IC02
9P
CR
IC02
8M
CR
IGR
002P
CR
IGR
002C
CR
IGR
052M
CR
LRB
005P
CR
IGR
047P
CR
IGR
048M
CR
LRB
022P
CR
IC00
8P
CR
IC00
9M
CR
IC01
0P
CR
IGR
011C
CR
IGR
039P
CR
IGR
043P
CR
IC00
5P
CR
IC01
4P
TP53 62%1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 0 1 1 1 0 1 1 0 0 0 0 0 0 0 0
APC 53%1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0
KRAS 45%1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0
PIK3CA 10%1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
FBXW7 8%0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
BRAF 5%0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 * 0 0 0 0 0 0 0 0 0 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
CTNNB1 3%0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
EGFR 2%0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
AKT1 0%0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
MSI status MSS MSS MSS MSS MSS MSS MSS MSS MSS MSS MSS MSS MSS MSI-L MSI-L MSS MSS MSS MSS MSS MSS MSS MSS MSS MSI-L MSS MSS MSS MSI-L MSS MSS MSS MSS MSI-L MSI-H MSI-H MSS MSI-L MSI-L MSS MSS MSI-L MSI-L MSI-L MSS MSS MSS MSS MSS MSS MSS MSS MSS MSS
Xenograft 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 0 1 0 1 1 1 1 1 1 0 1 1 1 1 1 1 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 0
CGH Analysis 0 1 1 0 0 1 0 0 0 0 0 1 0 1 1 0 0 0 0 0 0 1 0 1 1 0 0 0 1 0 0 1 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 80 0 0 0 1 0
Other ERCC1-A138T FCGR2A-F196Y * BRAF-N594D
5-FU + - - - - + + + ++ + + ++ + + + + + ++ + - + ++ + ++ + + - + -
l-OHP - - - - - - - - - - - - + - - - + - - - - - - - - - - - -
CPT-11 + + ++ + ++ +++ - +++ - + - - +++ - + ++ + +++ + + + + +++ ++ + +++ +++ + +++
CETUXIMAB + ++ +++ + - - +++ +++ +++ - - - +++ + - +++ - - - - - - ++ ++ +++ + - - -
Mutation MSI-L Low (MSI-L) or High (MSI-H) microsatellite instability Wild-type No data available Model from the same patient Xenograft model established CGH analysis % above sample name: % of tumor cells in the analyzed sample
Scoring criteria: - = ∆(T/C) > 42 % + = 10 < ∆(T/C) ≦ 42 % ++ = 0 ≦ ∆(T/C) ≦10 % (stable desease) +++ = ∆(T/C) <0 % (tumor regression) Characterization in progress % beside gene name: % of mutations among all sequen ced samples
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