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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