Programme for optimized treatment of Norwegian cancer patients

1. Programme for optimized treatment of Norwegian cancer patients Status, challenges and opportunities Ola Myklebost OUS - Norwegian Radium Hospital Cancer Crosslinks Jan 12th 2012

2. All cancers are different • Each cancer type is recognized as having many subtypes, with different cellular origins or reflecting different cellular phenotypes • Within these subtypes there are vast differences in mutation spectra and which cellular pathways are deranged • Even within each tumour and its metastases, there is enormous heterogeneity in geno- and phenotypes among cancer cell subpopulations • These give rise to resistant tumours

3. All patients are different • Germ-line genetic variation impinges on • Cancer development or progression • immune responses • stroma interactions • Response to therapy • Adverse and late side effects • Deep sequencing reveals a large number of rare, “private” gene variants in each individual • Their impact is not yet understood

4. New targeted therapies • Mechanistic understanding means • sensitive tumours can be identified and treated • resistant tumours can be allocated to better treatment • Expensive treatments may become cost effective • Cancers of other types having the targeted properties may potentially have benefit

5. New diagnostic options • Traditional pathology • Testing a few markers for each cancer type • Usually only certain mutations of each gene • Each new assay needs effort • High-throughput methods • Can scan large numbers of relevant markers • Can identify mutations genome-wide • Sensitivity, speed and capacity improving dramatically • Prices falling rapidly • Easily scalable

6. Deep sequencing-based tumour mutation detection • Sample tumour and blood • Sequence candidate genes in both • Compare sequence and identify somatic mutations in tumours • Are “actionable” proteins mutated? • Are the mutations likely or known to make the phenotype targetable by an available drug?

7. Norwegian initiatives toward personalized cancer care • Oslo Cancer Cluster • Initiative from Pfizer to make a Norwegian “Stratified Medicine Initiative” • National Collaboration Group for Health Research • National proposal to use tumour gene profiles to determine cancer treatment • Norw. Radium Hospital pilot study • Establishment of technology • Determine the complete sequence of all kinases and a number of cancer-related genes in 100 lung cancers • Example results

8. Lung cancer study • Project start late 2010 • 100 patients, DNA from tumour + blood • Samples from Helland and Brustugun OUS • Sequenced all kinase genes + 100 “cancer genes” • Meza-Zepeda et al. HSØ Core • Eight first pairs processed • The technology works perfectly • Bioinformatic analysis • Hovig HSØ et al. Core • Multiple possibly actionable mutations detected

9. Kinases targeted in clinical trials The majority of targets for specific cancer therapy are kinases Oleg Fedorov, Susanne Müller & Stefan Knapp nature chemical biology | VOL 6 | MARCH 2010 |

10. Genes included in “Kinome Set” Total 3,2 Mbp

11. Filtering of “private” genetic variation (Including non-exonic flanking sequence) * dbSNP

12. Example findings Tumour mutations in first 8 lung cancers: Validated

13. Vanderbilt: MyCancerGenome.org

14. DDR2 mutation

15. ”Cancer task force” (”Skrivegruppen”) Stein Kvaløy, OUS (Head) Roy Bremnes, UNN and UiTromsø Stein Kaasa, St Olav and NTNU Ragnhild A. Lothe, OUS and UiO Per Eystein Lønning, Haukeland and UiB Proposed national initiative ”Development of diagnostics and personalized cancer treatment based on genetic analyses” Based on deep sequencing of tumours Endorsed by the National cooperation group for health research Personalized cancer therapy chosen by the National council for health priorities for grant call through the Research council National cooperation group for health research (NSG)

16. Norwegian Cancer Genomics Consortium • Joint application from Oslo, Bergen and Trondheim • Key investigators • Ola Myklebost, PI, OUS • Ragnhild Lothe, OUS • Harald Holte, OUS • Per Eystein Lønning, Haukeland • Anders Waage, St Olavs • Giske Ursin, Norw. Cancer Registry • Leonardo Meza-Zepeda, OUS, Sequencing Technology • Eivind Hovig, OUS, Bioinformatics Translational medicine group

17. Plans • Applying for a budget for 4000 tumour/blood pairs • Will design custom gene capture set • Kinome + 5-600 others • Cancer types • Breast cancer • Lymphoma • Leukemia • Colorectal cancer • Malignant melanoma • Sarcoma • Multiple myeloma • Gynecological cancers • Prostate cancer

18. Main objectives I • Provide a national network for implementation of personalised cancer medicine in Norway • Provide and disseminate methodology for deep sequencing of tumour material and identification of somatic mutations • Initiate a number of research projects to determine the applicability of mutation profiles from the individual tumour for therapeutic decisions

19. Main objectives II • Provide the bioinformatics tools necessary to make mutation spectra clinically interpretable and for national data logistics • Establish a nation-wide cancer mutation database in collaboration with the Cancer Registry • Provide a dialogue on the clinical implementation of personal mutation data • Analyse the health economic impacts of improved and standardised access to molecular targeted therapies nation-wide

20. NCGC Web Page

21. Project plan

22. NCGC data logistics Bioinformatics Myeloma Sequence Lymphoma OUS Leukemia Colon National mutation database Haukeland Melanoma Prostate St Olavs Breast Cancer registry Sarcoma Clinical data Others? Accumulated national data

23. Added values from national collaboration • Population-based data • Standardized genome analysis • Equal patient access nation-wide • Standardized treatment choices • National follow-up of multiple N=1 trials (compassionate use) • National evaluation of mutation frequencies and health-economic consequences • Over time accumulation of outcome data of personalized treatments and other therapies stratified by mutation profiles

24. National Cancer Genomics Consortium Norwegian Cancer Registry St Olavs Hospital Haukeland Hospital Pharma? NCE Oslo Cancer Cluster