7e BIJEENKOMST WERKGROEP "MOLECULAIRE DIAGNOSTIEK IN DE PATHOLOGIE 25 januari 2012

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1 7e BIJEENKOMST WERKGROEP "MOLECULAIRE DIAGNOSTIEK IN DE PATHOLOGIE 25 januari 2012 Martijn P. Lolkema Department of Medical Oncology The Netherlands

2 Oncology 1.0

3 Oncology 2.0

4 A thousand dollar genome

5 Genetica voorspelt respons op therapie Normal cell Cancer cell with mutation Log cell survival! Log drug concentration!

6 Genetica en targeted drugs in de oncologie gaan samen Target Disease Drug Success Her2Neu Breast, stomach Herceptin, Lapatinib HR: +/ 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 BCR- ABL positive CML ALK NSCLC Specific ALK inhibitor PARP BRCA 1 and 2 associated Ovarian carcinoma, Triple neg. breast cancer Multiple PARP inhibitors BRAF BRAF mutant melanoma Specific BRAF inhibitor Promising phase I/II data, approved by FDA Promising phase I/II/III data Standard of care for BRAF mutant melanoma in 7 years of clinical development

7 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% - Denosumab SRE: 0.83 NR - Vandetinib NR Appr. 73% - (RET) Abiraterone PFS: 0.65 Appr. 29% - Vemurafenib PFS: 0.26 Appr. 90% + (BRAFV600E) Crizotinib NR Appr. 57% + (EML4-ALK)

8 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 Select appropriate cancer treatment based on patients tumor DNA profile Increase the likelihood a drug shows sufficient benefit in clinical trials to get approved; contribute to drug-discovery

9 One Week Three Weeks 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 ng ng Patient Stratification IonTorrent PGM Research SOLiD 5500xl + Biomarker Discovery Actionable Mutations > genes Profiling Cancer Pathways and Processes Start Targeted Therapy Allocation Fase1 Clinical Trial Systems Biology Targeted Resequencing ± 2000 genes Response monitoring Bioinformatic analysis Resistance / Progression Recurrence / Cure Databanking Mutations, INDELs, Copy Number Variations in vitro / in vivo Modeling of Hypotheses

10 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 actionable genen set die direct relevant zijn voor therapie Discovery Implementatie aromatase inhibitors, tamoxifen, imatinib, EGFR inhibition, sunitinib, vemurafenib,

11 Hoe zit dat nou met tumor heterogeniteit?

12 Hoe zit dat nou met tumor heterogeniteit? PJ Campbell et al. Nature 467, (2010) doi: /nature09460

13 Hoe zit dat nou met tumor heterogeniteit?

14 Dus moeten we de metastase biopteren! Vermaat J, et al. Clin Cancer Res 2011

15 Biopsie pipeline CPCT Breast Liver 3 specimens CPCT-02 (+ 1 for regular diagnostics) Tumor percentage: 80% DNA isolation: ng

16 % of samples 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 Platinum based Smoothened inhibitor CDK 4/6 inhibitor Anti hormonal Integrin antagonist No treatment BRAF inhibitor Non platinum based TKI Liver Site of Biopsy other Lymphnode Skin / Subcutaneous Lung

17 % of samples DNA yield (ng) Biopten succes percentage % of usefull biopsies Distribution of DNA yield 100 N= no DNA <250ng >250ng but <500ng >500ng ng

18 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 Melanoma Open (CPCT side study) 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

19 Samenwerken is essentieel

20 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.

21 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 Team science: andere academische centra gaan binnenkort aansluiten Logo Nuts-Ohra