1. Translational Cancer Research From Laboratory to Practice William J Catalona MD Professor of Urology Director, Clinical Prostate Cancer Program Northwestern University Chicago, Illinois

2. Cancer in Perspective In the US and Globally

3. US Mortality, 2006 *Includes nephrotic syndrome and nephrosis. Source: US Mortality Data 2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009. 1.Heart Diseases631,636 26.0 2.Cancer559,888 23.1 3.Cerebrovascular diseases137,119 5.7 4.Chronic lower respiratory diseases124,583 5.1 5.Accidents (unintentional injuries)121,599 5.0 6.Diabetes mellitus 72,449 3.0 7.Alzheimer disease 72,432 3.0 8.Influenza & pneumonia56,326 2.3 9.Nephritis* 45,344 1.9 10.Septicemia34,234 1.4 RankCause of Death No. of deaths % of all deaths

4. 2009 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009. Men 766,130 Women 713,220 27%Breast 14%Lung & bronchus 10%Colon & rectum 6%Uterine corpus 4%Non-Hodgkin lymphoma 4%Melanoma of skin 4% Thyroid 3%Kidney & renal pelvis 3%Ovary 3%Pancreas 22%All Other Sites Prostate25% Lung & bronchus15% Colon & rectum10% Urinary bladder7% Melanoma of skin5% Non-Hodgkin5% lymphoma Kidney & renal pelvis5% Leukemia 3% Oral cavity3% Pancreas3% All Other Sites19%

5. * For those free of cancer at beginning of age interval. Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.3.0 Statistical Research and Applications Branch, NCI, 2008. http://srab.cancer.gov/devcan Lifetime Probability of Developing Cancer, Men, 2003-2005* † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. SiteRisk All sites † 1 in 2 Prostate 1 in 6 Lung and bronchus1 in 13 Colon and rectum1 in 18 Urinary bladder ‡ 1 in 27 Melanoma § 1 in 39 Non-Hodgkin lymphoma1 in 45 Kidney1 in 57 Leukemia1 in 67 Oral Cavity1 in 72 Stomach1 in 90 ‡ Includes invasive and in situ cancer cases § Statistic for white men.

6. Lifetime Probability of Developing Cancer, Women, US, 2003-2005* SiteRisk All sites † 1 in 3 Breast 1 in 8 Lung & bronchus 1 in 16 Colon & rectum 1 in 20 Uterine corpus 1 in 40 Non-Hodgkin lymphoma 1 in 53 Urinary bladder ‡ 1 in 84 Melanoma § 1 in 58 Ovary 1 in 72 Pancreas 1 in 75 Uterine cervix 1 in 145 Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.3.0 Statistical Research and Applications Branch, NCI, 2008. http://srab.cancer.gov/devcan * For those free of cancer at beginning of age interval. † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. ‡ Includes invasive and in situ cancer cases § Statistic for white women.

7. Cancer Incidence Rates* Among Men, US, 1975-2005 Prostate Lung & bronchus Colon and rectum Urinary bladder Non-Hodgkin lymphoma Rate Per 100,000 Melanoma of the skin PSA Era

8. Cancer Incidence Rates* Among Women, US, 1975-2005 *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database: SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2005, National Cancer Institute, 2008. Colon and rectum Rate Per 100,000 Breast Lung & bronchus Uterine Corpus Ovary Non-Hodgkin lymphoma

9. 2009 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2009. Men 292,540 Women 269,800 26%Lung & bronchus 15%Breast 9%Colon & rectum 6%Pancreas 5%Ovary 4%Non-Hodgkin lymphoma 3%Leukemia 3%Uterine corpus 2% Liver & intrahepatic bile duct 2%Brain/ONS 25% All other sites Lung & bronchus30% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney & renal pelvis3% All other sites 25%

10. Cancer Death Rates* Among Men, US,1930-2005 *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008. Lung & bronchus Colon & rectum Stomach Rate Per 100,000 Prostate Pancreas LiverLeukemia PSA Era

11. Cancer Death Rates* Among Women, US,1930-2005 *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008. Lung & bronchus Colon & rectum Uterus Stomach Breast Ovary Pancreas Rate Per 100,000

12. Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2006 Women Men Number of Cancer Deaths Men Women Source: US Mortality Data, 1930-2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009.

14. Stage of Cancer at the Time of Detection and 5-Year Survival Rates by Stage Stage at Diagnosis5-Year Survival for Stage

15. Does PSA Screening Save Lives? Flawed “PLCO study” from the U.S. study: No Better “ERSPC study” from Europe: Yes, by at least 20% Best “Goteborg study” with longer follow-up, by 44% to 56%

16. Recent* Prostate-Specific Antigen (PSA) Test Prevalence (%), by Educational Attainment and Health Insurance Status, Men 50 Years and Older, US, 2001-2006 *A prostate-specific antigen (PSA) test within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System Public Use Data Tape (2001, 2002, 2004, 2006), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2002, 2003, 2005, 2007.

18. What are the latest guidelines for PSA testing?

19. 2009 NCCN Guidelines for PCa Detection National Comprehensive Cancer Network (NCCN) “PSA testing is effective and needs to be more rigorously conducted in high-risk men” “… at age 40, high-risk men be offered a baseline PSA and prostate exam and if their PSA is 1.0 or greater, they should have annual follow-up testing Consider prostate biopsy for PSA is higher than 2.5 or increasing by more than 0.35 per year

21. 2010 NCCN Guidelines “Screening in men over 75 years should be considered individually” “It is neither the intent nor the suggestion of the panel that all men diagnosed with prostate cancer require treatment”

22. 2009 NCCN PCa Management Guidelines A significant change incorporated into the updated NCCN Guidelines for PCa is the recommendation for active surveillance for many men “Very low risk” category added using a modified Epstein criteria. Only AS offered and recommended in this category when life expectancy is < 20 years Men with “low-risk’ prostate cancer who have a life expectancy of less than 10 years should be offered and recommended active surveillance “Together, you and your doctor can carefully weigh several factors to determine whether active surveillance—that is, not treating the cancer, but instead watching for any indication that the cancer is growing—might be the best course of action”

23. What about active surveillance or watchful waiting?

24. Toronto active surveillance update UNPROVEN HYPOTHESIS: active surveillance may reduce overtreatment while retaining option for curative treatment if the cancer is progressing 47% whose cancer was found to be progressing were free of tumor recurrence after 5 yrs Less than 50% had cancer that was still contained in the prostate at the time of surgery In Swedish watchful waiting series with 20 years of follow-up, almost 50% died of prostate cancer

25. Johns Hopkins: RRP in Patients Failing Active Surveillance 48 patients who failed active surveillance and were treated with surgery 35% had extension of cancer outside the prostate gland, 15% had cancer at the surgical margins, 6% had seminal vesicle/lymph node involvement

26. Does prostate cancer run in families?

28. LocusSNP OR Chicago OR All Combined Reference 8q24rs14472951.501.53 Amundadottir et al. Nature Genetics 2006 Gudmundsson et al. Nature Genetics 2007a 8q24rs169019792.321.66Gudmundsson et al. Nature Genetics 2007a 17q12rs44307961.411.22Gudmundsson et al. Nature Genetics 2007b 17q24rs18599621.251.20Gudmundsson et al. Nature Genetics 2007b 2p15rs7210481.221.15Gudmundsson et al. Nature Genetics2008 Xp11.22rs59455721.23 Gudmundsson et al. Nature Genetics 2008 5p15rs4016811.061.07Rafnar et al. Nature Genetics 2008 5p15rs27360981.201.13Rafnar et al. Nature Genetics 2008 3q21s109348531.211.12Gudmundsson et al. Nature Genetics 2009 8q24rs169020941.161.21Gudmundsson et al. Nature Genetics 2009 19q13rs81024761.151.12Gudmundsson et al. Nature Genetics 2009 11q13 refinement SNPrs112285651.161.23Gudmundsson et al. Nature Genetics 2009 Prostate Cancer Risk Allele Discovery: Collaboration of William Catalona with deCODE genetics, Inc.

29. Might prostate cancer patients carry genetic variants that predispose to other types of cancer?

32. Do genetic factors determine prostate cancer aggressiveness?

33. Identification of factors associated with risk for aggressive PCa is urgently needed

34. Prostate SPOREs Genetics Working Group William Catalona co-chairNorthwestern Janet Stanford co-chairFred Hutchinson CC Robert Jenkins Mayo Clinic Robert Klein Memorial Sloan-Kettering John Witte UCSF Matt FreedmanHarvard Kathy CooneyMichigan Michael IttmannBaylor William B. IsaacsJohns Hopkins Alternates Ken Offit Memorial Sloan-Kettering Phil Febbo U Calif San Francisco S pecialized P rogram O f R esearch E xcellence

39. What else is in the pipeline?

40. A new “nanotechnology” PSA blood test that is 300 times more sensitive than currently- available tests

41. Pro-PSA (p2PSA) Multicenter Pivotal Trial (Beckman-Coulter Incorporated) Pro-PSA is more accurate than PSA for detecting prostate cancer and aggressive forms of the disease William J. Catalona, MD, Lead Investigator. Sites: Baylor, Erasmus, Harvard, Johns Hopkins, Mayo, Michigan, Northwestern, UCLA All subject enrollment and sample testing has been completed. The database is locked and all analyses are complete. All monitoring has been completed. BCI audits at 5 sites are complete. Close-out visits have been completed at 3 sites and all remaining close-out visits have been scheduled for this year. EU approval was received July 2009 and product is available in the EU as of 10/16/09. FDA submission Review of the clinical section of the FDA submission is complete and has been forwarded to the BCI regulatory department for final review. The primary and secondary hypotheses were verified. Results look good. FDA submission for approval in November 2009.