1. Current Screening Recommendations and Practical Strategies to Refine Risk Assessment Following Initial Diagnosis Judd W. Moul, M.D. FACS Professor and Chief Division of Urology Department of Surgery Duke University Medical Center Durham, NC

2. Greetings from Duke Urology and the Duke Prostate Center Durham, North Carolina

3. “PSA Poster Boys” Rupert Murdoch Linus Pauling Roger Moore Bob Dole Sean Connery Telly Savalas Pat Robertson Frank Gifford Louis Farrakhan Francois Mitterand Bob Novak Richard Petty Stan Musial Bobby Riggs Jim Calhoun Len Dawson Wayne Galloway Marv Levy Dusty Baker Don Nelson

4. “PSA Poster Boys” Rupert Murdoch Linus Pauling Roger Moore Bob Dole Sean Connery Telly Savalas Pat Robertson Frank Gifford Louis Farrakhan Francois Mitterand Bob Novak Richard Petty Stan Musial Bobby Riggs Jim Calhoun Len Dawson Wayne Galloway Marv Levy Dusty Baker Don Nelson

5. UROLOGY TIMES “Deaths from prostate cancer are on the decline, but why?” October 2003 www.urologytimes.com.

6. Estimated number of prostate cancer deaths Time (years) Prostate Cancer: Decline in Number of Deaths Between 1997 and 2007, there was an approximate decline by 35% in prostate cancer deaths ACS, 1997; ACS, 2000; ACS, 2003; ACS, 2006; ACS, 2007.

7. Most Common Lab Tests Ordered by Primary Care 2005 USA: PSA: Top 8 Laboratory Tests CBC9.6% Urinalysis8.1% Lipids or cholesterol6.5% PSA1.5% Hematocrit or hemoglobin2.8% Pap test2.7% Glucose4.3% Hgb A1c2.2%

8. American Medical News “Task force adds opinion in prostate screening debate” The preventative services panel finds inconclusive evidence to recommend testing, but encourages doctors to discuss the risk-benefit with patients January 6, 2003 www.ama-assn.org/amednews/2003/01/06/hisb0106.htm.

9. www.usatoday.com. USA TODAY “Why not test older men for prostate cancer?” August 6, 2009

10. Task Force Recommends Against PSA Screening in Men Older Than 75 Years Old Ann Intern Med 2008;149:185-191.

11. Public survey does not support recommendations to discontinue PSA screening in men at age 75 Judd W. Moul, Leon Sun, Cary N. Robertson, Kelly Maloney, Thomas J. Polascik, David M. Albala and Arthur A. Caire

12. Methods Public survey 340 participants Duke’s 2008 annual free PSA screening clinic Durham County, North Carolina, USA

13. Results: Public survey Awareness of recommendation p not aware n (%) aware n (%) Age<75208 (86.0)80 (89.9)0.345 ≥7534 (14.0)9 (10.1) RaceAfrican American137 (59.6)46 (53.5)0.608 Caucasian93 (40.4)40 (46.5) Health insuranceYes189 (78.1)70 (76.9)0.849 No53 (21.9)21 (23.1) Prostate cancer knowledgeYes178 (73.3)81 (90.0)0.004 No65 (26.7)9 (10.0) Agreed with USPSTF Yes53 (22.0)21 (23.3)0.962 No188 (78.0)69 (76.7) 73% of men unaware of recommendation 78% of men disagreed with recommendation Findings were consistent between education, awareness, and age groups

14. RCT Screening Trials for Prostate Cancer Quebec Prostate Cancer Screening Trial Prostate, lung, colon, ovarian (PLCO) ◦74,000 men (55–74 y/o, q 1 yr) European Randomized Study of Screening for Prostate Cancer ◦190,000 men (55–70 y/o, q 4 yr)

15. Oncology NEWS International “First Large PSA Screening Trial Suggests It Can Save Lives” June 1, 1998 Dr BoyleDr Labrie www.cancernetwork.com.

16. Quebec Prostate Cancer Screening Trial With permission from Labrie F et al. Prostate 2004;59(30):311-8.

17. Prostate Cancer Screening Latest Controversy: NEJM 3/18/09 ERSPC Study: 182,000 men aged 50-74 years 7 different European countries start early 90s Screening group: PSA test every four years Control group: no PSA testing. 82% in screening group had at least one PSA 8.2% vs 4.8% Ca rate at 9 year follow-up. Cancer-specific mortality reduced by 20% in screening group (27% if limiting to men tested) European Randomized Study of Screening for Prostate Cancer (ERSPC): Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320-8.

18. ERSPC-2009 Genitourinary Cancers Symposium “Prostate Cancer Screening Trial: 1,981 Biopsies Required to Save One Life for Men with PSA Below 3 ng/mL” July 25, 2008 Oncology Times 2008;30(14):33.

19. Rate % 27 38 47 53 56 0 20 40 60 80 5560657075 Age Age-dependent Overdetection Rate in a Screening Population European Randomized Study of Screening for Prostate Cancer Draisma G et al. J Natl Cancer Inst 2003;95(12):868-78.

20. 27 38 47 53 56 0 20 40 60 80 5560657075 Age Age-dependent Overdetection Rate in a Screening Population European Randomized Study of Screening for Prostate Cancer Draisma G et al. J Natl Cancer Inst 2003;95(12):868-78. Rate %

21. www.cancernetwork.com. Oncology NEWS International “Most Men Don’t Need Yearly PSA Screening: PLCO Study” July 1, 2002

22. Estimated Percentage of Patients with a PSA Converting to 4ng/ml Baseline Prostate-Specific Antigen (PSA) Level (ng/ml) 0-11-22-33-4 Year 10.251.26.324 Year 20.532.512.844 Year 30.833.919.460 Year 41.46.630.477 Year 51.67.634.683

23. Prostate Cancer Screening Latest Controversy: NEJM 3/18/09 PLCO Trial: 76,693 men/10 centers: usual care vs. annual PSA for 6 years/DRE 4 yrs 86% compliance in screening group 52% of men in control group had PSA 7-yr follow up: 50 CaP deaths vs. 44 deaths Conclusion: “After 7-10 years, the rate of CaP was low and did not differ by group” Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO): Andriole GL, Grubb, III RL, Buys SS, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-9.

24. Who Should Be Biopsied: PSA Practical Tips PSA is “prostate specific” but not “prostate cancer specific” PSA elevation=BPH, prostatitis, cancer “Normal” PSA based on age and race Age 40: baseline PSA (good) »<1.0ng/ml (good) (caution) »1.0-2.4ng/ml (caution) (concern) »≥2.5ng/ml (concern) Age 60-79: PSA>4.0ng/ml

25. Prevalence of Prostate Cancer with PSA ≤4.0 ng/mL — Data from PCPT 0 5 10 15 20 25 30 PrevalenceHigh Grade 0–1.0 1.1–2.0 2.1–3.0 3.1–4.0 Thompson IM et al. N Engl J Med 2004;350(22):2239-46.

26. AUA PSA Best Practice Guidelines Age-Adjusted PSA Values by Ethnic Group Age RangeAsians African- Americans Caucasians 40-490-2.0 0-2.5 50-590-3.00-4.00-3.5 60-690-4.00-4.5 70-790-5.00-5.50-6.5 Urol Clin North Amer 1997;24:339-351.

27. “Lower PSA Velocity Threshold Recommended In Young Men” Study finds men with PSA velocities greater than 0.4 ng/mL/year are at higher risk Loeb S et al. J Urology 2007;178:2348-53.

28. Age Adjusted Prostate-Specific Antigen and Prostate Specific Antigen Velocity Cut Points in Prostate Cancer Screening Moul JW et al. J Urology 2007;177(2):499-503;discussion 503-4.

29. DPC-Age Adjusted PSAV Results PSAV value Age 40-59Age 60-69Age>70 SensitivitySpecificitySensitivitySpecificitySensitivitySpecificity 0.250.5190.8410.5570.7730.7060.499 0.500.3530.5570.3980.8640.6980.532 0.750.2650.7730.3060.9070.3720.888

30. NCCN Clinical Practice Guidelines Risk Assessment Baseline: ◦NCCN recommends baseline PSA at age 40 (also recommended by AUA) Annual Screening Recommended if: ◦PSA ≥0.6 ng/mL in 2006 ◦PSA ≥1.0 ng/mL in 2010 Biopsy Threshold at PSA of 2.5 ng/mL in Younger Men (2006 & 2010) Importance of a Digital Rectal Exam (2006 & 2010): ◦NCCN and AUA: recommended ◦ACS: optional NCCN Clinical Practice Guidelines in Oncology on Prostate Cancer V.1.2006, V.3.2010.

31. American Urological Association (AUA): Age 40 Risk Assessment “Urology Group: Prostate Screening Should Be Offered Beginning at Age 40” www.auanet.org.

32. Risk Assessment of Newly Diagnosed Patients with Localized Prostate Cancer

33. Risk Assessment-Traditional Variables Cancer risk or “type” Gleason score % biopsy cores with cancer PSA (ng/mL)PSAV*PSAD*DRE* Low<7<34%<10<2<0.15Neg. Intermediate734-50%10-20<2<0.15 Small nodule High>7>50%>20>2 Large nodule PSAV = PSA velocity (ng/ml/year); PSAD = PSA density (ng/ml of PSA in blood divided by prostate volume in cm 2 ); DRE = digital rectal examination findings

34. Prostate Px  : Systems Pathology Components Pattern Recognition Multi-spectral Imaging Proteomics Data Mining & Machine Learning Pathologic Assessment of Biomarkers

35. Platform Enables Powerful Predictive Tests Patented Systems Pathology Platform In situ single cell molecular analysis of protein HTP automated image analysis systems High-dimensional relational database management Supervised Multivariate Analytics Clinical Data Micro-Anatomical Data Protein Expression Prognostic Profile and Risk Score Final prognostic model integrates information through proprietary statistical algorithm resulting in Px  “risk” score (1-100) First platform to integrate histological features, in situ biomarkers and clinical variables to enhance understanding of disease progression Integrated Digital Feature Maps

36. Prostate Px  Prediction — Radical Prostatectomy Provides useful, objective information for all surgical candidates Detects more high-risk patients for serious disease that present as lower risk at diagnosis At diagnosis, predicts serious disease progression (metastasis, death of disease, progression through ADT) after surgery Better assesses, defines and discriminates “intermediate- risk” cases Provides unique perspective and additional discrimination for all non-surgical approaches Helps determine if the biopsy pathology aligns with total prostate pathology Donovan MJ et al. J Urol 2009;182(1):125-32.

37. Screening-Risk Assessment 2010 Population screening remains controversial Lack of consensus in current Randomized Controlled Trials Population data encouraging PSA is not perfect; but still most useful serum screening test in all of medicine PSA “tools” based on age, velocity useful On verge of better molecular marker risk assessment