#4169 cremec initiative: characterization of patient ... · cric002p (wt kras) cric013m (mutated...

CRIC013M (mutated KRAS) CRIC002P (wt KRAS)

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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

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1400 CPT-11 treatmentCPT-11 22 mg/kg IVControl (untreated)

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Establishment of in vivo tumorgraft models

RPMI/DMSO freezing

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Surgery









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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)


(1/86)

All models collected (86)

Left (21/59)

Right (20/59)



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)



Splenicmetastasis

(1/56)


(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)



Splenicmetastasis

(1/56)


(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

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orM

odel

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ient

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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

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All types of tumor samples / CEA dosing

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p = 0.0038 (**)

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N1 + N2

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B

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Stage IV Stage IV

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p = 0.0101 (*)

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C Primary tumor samples / Differentiation

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(n=11)

(n=9)

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Per

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C Primary tumor samples / Differentiation

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Well

Fairly

Fairly

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(n=10)

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(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%

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80%

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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

#4169 cremec initiative: characterization of patient ... · cric002p (wt kras) cric013m (mutated...

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