CPCT - Moleculaire Pathologie

7e BIJEENKOMST
WERKGROEP "MOLECULAIRE DIAGNOSTIEK IN DE
PATHOLOGIE
25 januari 2012
Martijn P. Lolkema
Department of Medical Oncology
The Netherlands
Oncology 1.0
Oncology 2.0
http://nextarchitects.com/
A “thousand dollar genome”
Genetica voorspelt respons op therapie
Normal cell
Cancer cell with
mutation
Log cell
survival!
Log drug
concentration!
Genetica en targeted drugs in de oncologie gaan
samen
Target
Disease
Drug
Success
Her2Neu
Breast, stomach
Herceptin,
Lapatinib
HR: +/- 0.50 for progression
free survival for Her2+
breast cancer patients
after surgery
c-KIT
GIST
Imatinib
Majority of patients show
impressive responses
BCR-Abl
CML
Imatinib
>50% response in BCRABL positive CML
ALK
NSCLC
Specific ALK
inhibitor
Promising phase I/II data,
approved by FDA
PARP
BRCA 1 and 2 associated Ovarian
carcinoma, Triple neg. breast
cancer
Multiple PARP
inhibitors
Promising phase I/II/III data
BRAF
BRAF mutant melanoma
Specific BRAF
inhibitor
Standard of care for BRAF
mutant melanoma in 7
years of clinical
development
Gerichte therapie heeft een betere effectiviteit
Oncologie registraties 2011 FDA
HR primary outcome
% pts with
benefit
Biomarker
included
Cabazitaxel
PFS: 0.70
Appr. 40%
-
Ipilumimab
OS: 0.72
Appr. 10%
-
SRE: 0.83
NR
-
NR
Appr. 73%
- (RET)
Abiraterone
PFS: 0.65
Appr. 29%
-
Vemurafenib
PFS: 0.26
Appr. 90%
+ (BRAFV600E)
NR
Appr. 57%
+ (EML4-ALK)
Denosumab
Vandetinib
Crizotinib
Het “Center for Personalized Cancer Treatment” probeert
therapie voor oncologie patienten effectiever te maken
Increase the likelihood of a given treatment
being beneficial to patients; reduce the use
of ineffective treatment
•“Our mission is to provide more effective
cancer treatment by offering personalized
therapy and increasing the number of drugs
that reaches the market and becomes available
to patients”
Increase the likelihood a drug shows
sufficient benefit in clinical trials to get
approved; contribute to drug-discovery
Select
appropriate
cancer treatment
based on
patients’ tumor
DNA profile
Het CPCT wil de toekomst van persoonlijke behandeling
in Nederland vormgeven
Center for Personalized Cancer Treatment
Patient with Metastatic Disease
2-4 Biopsies
Pathological Analysis
DNA Isolation
100-500 ng
Patient Stratification
Research
IonTorrent PGM
SOLiD 5500xl
+
Biomarker
Discovery
Profiling Cancer Pathways
and Processes
Actionable Mutations
>50-100 genes
Start Targeted
Therapy
Allocation Fase1
Clinical Trial
Systems Biology
Response monitoring
Resistance /
Progression
Recurrence /
Cure
Targeted Resequencing
± 2000 genes
Bioinformatic analysis
Databanking
in vitro / in vivo
Modeling of
Hypotheses
Mutations, INDELs,
Copy Number Variations
Three Weeks
One Week
10-50 ng
De huidige opzet van de CPCT activiteiten
Patienten met
standaard therapie
Patienten in CPCT
studies
Fase I studie
patienten
NGS met 2000 genen set:
ontdekken van
genetische afwijkingen
die correleren met
therapie respons
Ion Torrent 100-200
“actionable” genen
set die direct
relevant zijn voor
therapie
Discovery
Implementatie
aromatase inhibitors, tamoxifen,
imatinib, EGFR inhibition,
sunitinib, vemurafenib,
Hoe zit dat nou met tumor heterogeniteit?
Hoe zit dat nou met tumor heterogeniteit?
PJ Campbell et al. Nature 467, 1109-1113 (2010)
doi:10.1038/nature09460
Hoe zit dat nou met tumor heterogeniteit?
Dus moeten we de metastase biopteren!
Vermaat J, et al. Clin Cancer Res 2011
Biopsie pipeline CPCT
Breast
Liver
3 specimens CPCT-02
(+ 1 for regular diagnostics)
Tumor percentage: 80%
DNA isolation: 10400 ng
Biopten naar tumor types en orgaan
CRC
RCC
Sarcoma
NET
Melanoma eye
Carcinoid
Upper GI
Head/Neck
HCC
Cystic adenoid
Cervix
Myoepithelial
Melanoma
Gallbladder
Head/Neck
Ovarian
CRC
CRC
Breast
Pancreatic
CRC
CRC
Endometrial
Breast
Head/Neck
Vulva
RCC
CRC
Site of Biopsy
TKI
BRAF inhibitor
% of samples
25
20
15
10
5
Platinum based
Li
ve
r
ot
Sk
Ly
he
in
m
ph r
/S
n
ub
cu ode
ta
ne
ou
s
Non platinum based
Smoothened inhibitor
CDK 4/6 inhibitor
Anti hormonal
Integrin antagonist
No treatment
0
2
4
6
8
Lu
ng
0
Biopten succes percentage
Distribution of DNA yield
% of usefull biopsies
N=65
100
75
50
no DNA
<250ng
>250ng but <500ng
>500ng
25
0
DNA yield (ng)
% of samples
15000
10000
5000
0
500ng
Klinische protocollen
Protocol
Short Description Tumor type
Status
M10PKS
Sunitinib PK
All comers
Accrual completed
CPCT-01
Irinotecan mCRC
Colorectal
carcinoma
Open
CPCT-02
Bioptenprotocol
All comers
Open
CPCT-03
Everolimus solide
tumoren
All comers
Ethics approval, in process of activation
N03LAM
T-cel immuniteit
melanoom
(CPCT side study)
Melanoma
Open
Within CPCT-02 we will focus on obtaining paired biopsies for patients treated with standard of care
systemic treatments such as aromatase inhibitors, tamoxifen, imatinib, EGFR inhibition, sunitinib,
vemurafenib, to improve the efficacy of treatment with these targeted agents
Samenwerken is essentieel
Conclusies
•
De komende tijd gaan we de komst van echte therapie op maat
zien
•
Nederland heeft met het CPCT een van de consortia die in staat is
om dit te implementeren
•
De eerste noodzakelijke stappen zijn gezet
•
De rol van de patient is heel belangrijk en we zijn op zoek naar een
manier om effectief patienten te benaderen en te activeren om aan
dit onderzoek deel te nemen. Daarnaast is het belangrijk om dit
soort initiatieven te toetsen aan patienten meningen.
Acknowledgments
UMC Utrecht and
Hubrecht laboratory,
Utrecht
Cuppen group
Ies Nijman
Wigard Kloosterman
UMC Utrecht:
Emile Voest
Paul van Diest
Maurice van den Bosch
Marco Koudijs
Sjoerd Elias
Geert Cirkel
Christa Gadellaa
Marlous Hoogstraat
Nicolle Besselink
Stef van Lieshout
EMC/Daniel
den Hoed
Rotterdam
Stefan Sleijfer
Ron Mathijsen
John Martens
Jacqueline Kloth
NKI/AvL
Amsterdam
Rene Bernards
Lodewyk Wessels
Jan Schellens
Neeltje Steeghs
Nienke Lankheet
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