Robert Bristow MD PhD FRCPC

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1 Robert Bristow MD PhD FRCPC Clinician-Scientist and Professor, Radiation Oncology and Medical Biophysics, University of Toronto and Ontario Cancer Institute/ (UHN) Head, PMH-CFCRI Prostate Cancer Research Program Lead: CPC-GENE Prostate Cancer Sequencing Project CCRC Public Forum November 2011

2 In 2011: close to 25,000 men will be diagnosed with prostate cancer and more than 4,000 will die from it On average, more than 400 men are diagnosed each week Discuss PSA testing at age depending on risk factors and discuss with your family doctor But how do we individualize information as there are different types of prostate cancer!

3 Risk factors: age, family history, high-fat diet, African ancestry Currently, the extent and prognosis of prostate depends on: (1) a digital rectal exam (DRE) and spread of disease (TNM) (2) the prostate specific antigen (PSA) blood test (3) the pathologic grade (Gleason score)

4 Indolent Disease Active Disease Surgery = Radical Prostatectomy Robots or laprascopic Aggressive Disease Hormone Therapy (injections/tablets) Active Surveillance Radiotherapy or brachytherapy (seeds) Chemotherapy Combinations Increasing Stage and Aggression

5 RISK GROUPS LOW: T1/T2; PSA <10; GS 4-6 (Brachy, HIFU, Cryo, EBRT; Surgery, AS) INTERMEDIATE: T1/T2; GS 7; PSA (Brachy/EBRT +/- Hormones; Surgery, Other) HIGH: PSA > 20; GS 8-10; T3-T4 (EBRT + Hormones+/- Chemo; New Agents, Surgery)

6 Decreased mortality for men with prostate cancer New technologies in biology and imaging DNA/RNA/Protein CHIPs to diagnose mutations (FISH and CHIPs!) THE Use of MRI and PET techniques to predict tumour spread and response pre- and post-therapy UNDERSTANDING New biologic targets and new drugs/hormone therapies Drugs that target back-up hormone pathways and intermittent hormone therapy immune therapies, seek and destroy radioisotopes Challenge is to have individual biomarkers of response OF Better use of PSA-DT and kinetic analyses to predict local resistance and systemic spread Active Surveillance : patients who have indolent disease PERSONAL Choose those patients who require local and systemic therapy Select best patients for best salvage therapies GENETICS 10 years of improved technology: Hypofractionation, precision targeting, IMRT, robotic surgery, HIFU, cryotherapy, sub-prostate targeting, less side-effects

7 The 20 th century approach to cancer: Seek and destroy The 21 st century approach: target and control Personalized genetic medicine New diagnostic tests New drugs and technologies Best treatment for patients To treat patients with fewer side effects. To prevent deaths in patients who are currently incurable.

8

9 Localized Distant Spread

10 No Mutation BRCA1 BRCA2

11 ICGC Marker Paper Nature 464, (15 April 2010)

12 July 2010: World Map of Comprehensive Cancer Genome Projects

13 Low Risk; Indolent Disease Active Surveillance Intermediate/High Risk: Non-Indolent, Curable Surgery or Radiotherapy +/- Adjuvant Metastatic: Aggressive Disease Hormone Therapy, Chemotherapy, Immunotherapy, Radionuclides Additional Role Of Genetic Analyses: Predict indolent disease Prevent overtreatment Despite Prognostic Factors of GS, T, PSA: Failure ~ % Predict hidden metastases Provide best local treatment Predict hormone (castrate) resistance Personalize chemotherapy

14 Castrate Resistant Disease (125 specimens) (UK, CAN) Radical Prostatectomy (> 700 specimens): (UK, FRA, GER, CAN) XRT Pre-treatment Biopsies (Hypoxia Measurements) (160 specimens): (UK, CAN) DNA and RNA (All; shared SOPs) CRACK THE CODE! WHOLE GENOME SEQUENCING (CAN, UK, FRA) DNA Sequence Analyses (International Discussion) Correlate Mutations and Hypoxia to Outcome Following Therapy New Clinical Test For Best Therapies

15 Pathologist Delineates Tumor Cells In Prostate Biopsy Micro-dissect Tissue and Extract DNA and RNA Cy5 Labelled Reference DNA Cy3 Labelled Tumor DNA Diagnostic Or Research Core Biopsy Prostate Cancer Genetic Signature Gains and losses are reflected in the fluorescence signal intensity ratios along the chromosome; hits are then validated hits by locus-specific probes using FISH Ishkanian et al; Acta Oncologica, 2010

16 Relapse-free Rate N = 115 BF events = 33 PGA in , n=37, 5y RFR=90% PGA in , n=35, 5y RFR=67% PGA in , n=36, 5y RFR=62% Time To Biochemical Relapse (months) Ishkanian, Bristow, Sykes, Lam, Milosevic et al; 2011

17 Escaping Metastases Hypoxia leads to chromosomal rearrangements and aggressive cells capable of spread (metastasis)

18 Hypoxic Fraction Low Hypoxic Fraction High 255 patients Median 6.6y FU Milosevic et al Submitted; 2011

19 H&E HRP-PIMO GLUT-1 PIMO-IF

20 PERSONALIZED MEDICINE: PROSTATE CANCER The study of cancer genetics is unlocking the secrets of indolent and non-indolent prostate cancer These secrets will give rise to new diagnostic tests and new treatments within the next 5-10 years These will be genetic secrets that can be used to individualize treatment for men with prostate cancer Canada is leading the partnership internationally: Don t Compete-Collaborate! Thank you to the patients who kindly agreed to let us study their genetics and agree to clinical trials

21 Bristow-Orillia-2008

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