1. Oliver Hakenberg Department of Urology, Rostock University Rostock, Germany New markers and strategies

2. Prostate cancer stage definition UICC localizedT1 – 2 N0 M0 locally advancedT3 – 4 N0 M0 advanced/metastaticN1 – 3 and/or M1

3. Localized prostate cancer organ-confined: T1–2 N0 M0 D‘Amico risk classification concerning recurrence after localized therapy Low risk PSA < 10 ng/ml and Gleason Score ≤ 6 andT1c to 2a Intermediate riskPSA > 10 to 20 ng/ml or Gleason 7 or cT 2b High riskPSA > 20 ng/ml or Gleason Score ≥ 8 or cT 2c D‘Amico et al

4. Prostate cancer Most common solid organ malignancy in men Incidence correlates with age Long natural course of the disease Significant vs insignificant disease PSA= clinical marker for diagnosis and follow-up

5. AG Bevölkerungsbezogener Krebsregister 2008 Age and incidence of prostate cancer Germany

6. 100 75 50 25 0 prevalence [%] 40 5060 70 80 years Age and prevalence of prostate cancer Autopsy study, n= 164 Haas et al., JNCI 2007 negative biopsy positive biopsy: 16.5 % Thompson et al., NEJM 2004

7. 2005 Demographic developments in Germany Statistisches Bundesamt 2006 Mean life expectancy of men: 77 years Mean life expectancy of men: 85 years 2050 Männer 2.9 million4.0 miollion

8. Natural course of prostate cancer diagnosis

9. Incidence and mortality of prostate cancer in Europe 1998 Davidson & Gabbay, WHO Report 2007

10. Recurrence-free survival after curative localized monotherapy in prostate cancer 1819 consecutive patients at the Memorial Sloane Kettering Cancer Center nmedian follow-up (months) 7 year PSA-recurrence- free survival rate brachytherapy7335174% EBRT3405677% radical prostatectomy7465779% Potters et al, Radiother Oncol 2004

11. Cause specific survival in 3 treatment groups stratified by D’Amico risk category. S= surgery. R= radiation therapy. O= observation. 13-year cancer-specific survival after treatment of localized prostate cancer population-based cohort study (n=1618) Albertsen et al., J Urol 2007 Tumorspezifisches Überleben

12. Chun & Djavan et al, Eur Urol 2007 PSA recurrence in 36% of patients Biochemical recurrence after RPE (retrospective study, n= 37 centres, n= 5291 patients)

13. Radical prostatectomy vs watchful waiting Disease-specific mortality and rate of metastatic progression The Holmberg study Disease-specific mortalityIncidence of metastatic progression Holmberg et al, N Engl J Med 2002

14. RPE vs ‚Watchful waiting‘ The Holmberg study with a follow-up of 10 years Bill-Axelson A et al, N Engl J Med 2005 RPEWW progression (M+)15.2%25.4% overall mortality27%32% disease-specific mortality 9.6%14.9% PCa mortality < age 65 Jahrewith RPE - 11% PCa mortality > age 65with RPE - 0,3%

15. Natural course of prostate cancer disease after PSA recurrence (n= 311) 150510 years PSA recurrence distant metastases death of disease Pound et al, JAMA 1999

16. survival Adolfsson et al, Eur Urol 2007 Natural course of grade* G1/2 prostate cancer (n=119, 1978-1982, median follow-up 24 years, median age 68 years) *conservative treatment on progression only years 15 % 44 % 70 % tumour-specific overall

17. 01234567 0 20 40 60 80 100 lowintermediatehighvery high Risk stratification for biochemical recurrence (n=1515) Years after RPE without PSA recurrence [%] Moul et al, J Urol 2001

18. Overall survival after RPE by age RPE in Austria: n=16.524 1992-2003 Mohamad et al, Eur Urol 2007, 51, 684-689

19. cumulative mortality [%] Jahre nach RPE Long-term survival after radical prostatectomy (competing risk analysis; n=1910) 15 Froehner, Wirth et al., J Urol 2009 comorbidity Second cancer other overall prostate cancer-specific 12 %

20. Cancer-specific survival after RPE depends on Gleason score CategoryEventsHazard ratio 95 % CIp Gleason-Score 2-64/6761 Gleason-Score 76/3602.730.74-10.020.13 Gleason-Score 8-1020/21924.789.74-63.01<0.0001 Years after RPE CaP-specific survival [%] Dept. of Urology, Dresden University 2007 (n=1255)

21. 0246810 50 60 70 80 90 100 Probability of survival [%] Comorbidity-specific vs disease-specific mortality after radical prostatectomy (n= 444) Years after RPE 0246810 50 60 70 80 90 100 0246810 50 60 70 80 90 100 ASA 1 (n=70) ASA 3 (n=42) comorbidity-specific PCa specific ASA 2 (n=332) Froehner, Wirth et al., Urology 2003

22. Survival after curative treatment radical prostatectomy cancer-specific survival –Gleason score –PSA –tumour extent overall survival –age –comorbidity

23. Schroeder et al, N Engl J Med 2009 48 cases of prostate cancer needed to be treated to prevent one death from prostate cancer.

24. Prostate cancer cases from the European Randomized Study of Screening for Prostate Cancer Screening arm:n=139 PCa cases from 21210 screened men Control arm:n=1149 PCa cases from 21166 control cases Zhu et al, Eur Urol 2011 Disease-specific survival Overall survival

25. Overdiagnosis? Overtreatment? Management ≠ active treatment Management options for localized prostate cancer watchful waiting active surveillance radical prostatectomy radiotherapy

26. What basis do we have for a management decision? type and stage of prostate cancer –risk stratification –PSA, Gleason score, tumour extent on biopsy age and life extectancy comorbidity patient preference

27. Risk stratification according to D‘Amico Risk stratification for recurrence after local treatment local stagePSA (ng/ml) Gleason score 5 year PSA- recurrence-free survival after RPE low riskT1c-T2a< 10685% intermediate riskT2b> 10750% high riskT2c-T3a> 208-1033% For „intermediate“ and „high risk“ it is always „or“

28. Life expectancy according to age and comorbidity ICED Score n= 451 Albertsen et al, J Urol, 1996

29. 100 80 50 % overall survival 10 years after radical prostatectomy predicted 90 70 beobachtet 60 74 % Charlson-Score 0 Charlson-Score 1+ Charlson score nomogram underestimates survival in healthy over 70 year-olds (n=329/1910) 100 80 50 predicted 90 70 beobachtet 60 69 % p=0.46 62 % 88 % p<0.0001 Froehner et al, Urology 2009

30. New strategies Watchful Waiting „expectant observation“ observation = no treatment symptomatic/palliative treatment if and when symptoms occur only then: androgen ablation

31. Watchful Waiting (WW) option for localized prostate cancer if there is no indication for treatment with curative intent –age –comorbidity –patient preference –if WW is chosen despite a feasible option and possibility for curative treatment, extensive informed consent of the patient is of paramount importance

32. New strategies Active Surveillance localized low risk prostate cancer with an indication for curative treatment well differentiaited prostate cancer = „insignificant prostate cancer“ active curative treatment is only undertaken, if and when the disease course shows aggressive growth Close follow-up including rebiopsies

33. Conditions for active surveillance PSA ≤ 10 ng/ml Gleason score ≤ 6; stage T1c und T2a; tumour seen in ≤ 2 biopsy cores* ≤ 50% tumour tissue in any core S3-Leitlinie Prostatakarzinom DGU 2009 German interdisciplinary evidence-based guidelines for the diagnosis and management of prostate cancer, update 2011

34. What does active surveillance entail? PSA + DRE every 3 months for the first 2 years if PSA remains stable, further follow-up every 6 months repeat biopsies every 12-18 months S3-Leitlinie Prostatakarzinom DGU 2009 German interdisciplinary evidence-based guidelines for the diagnosis and management of prostate cancer, update 2011

35. When to stop active surveillance? if and when –PSA doubling time < 3 years –repeat biopsy Gleason score > 6 tumour extent > 2 cores and/or > 50%/core –patient preference Life expectancy > 10 years? No Yes Active curative treatment Watchful Waiting S3-Leitlinie Prostatakarzinom DGU 2009

36. Pathologic results of AS primary vs delayed RPE National Swedish Cancer registry Holmström et al, Eur Urol 2010 Warlick et al, J Natl Cancer Inst 2006 Khatami et al, Scand J Urol Nephrol 2003 Khatami et al, Int J Cancer 2007

37. Prostate cancer mortality is not influenced by AS Holmström et al, Eur Urol 2010

38. Which decisions must be taken? 1. is curative treatment indicated? age + comorbidity 2. active treatment or active surveillance? 2a. Active Surveillance feasible? 3. surgery or radiotherapy life expectancy risk stratification for recurrence nomograms Gleason score Extent of tumour in biopsy patient preference

39. Risk estimation nomograms probability of organ-confined disease with RPE (Partin tables) likelihood of biochemical recurrence after RPE (Han tables) likelihood of 10-year survival after RPE (Walz nomogram)

40. Partin tables Gleason- Score cT-Stadium T1c T2a T2b T2c 2 - 495% (89-99) 91% (79-98) 88% (73-97) 86% (71-97) 5 - 690% (88-93) 81% (77-85) 75% (69-81) 73% (63-81) 3+4 = 779% (74-85) 64% (56-71) 54% (46-63) 51% (38-63) Partin et al, JAMA 1997; Urology 2001 Likelihood of organ-confined stage (%) with PSA < 2.5 ng/ml

41. cT1acT1bcT1c cT2acT2b cT2ccT3a 0 20 40 60 80 100 8-10 7 6 5 2-4 clinical stage Partin et al, JAMA 1997 Partin tables Likelihood of organ-confined disease PSA range 4.1-10 ng/ml probability (%) Gleason score

42. 6-3+44+38-10 0 20 40 60 80 100 0-4 ng/ml 4.1-10 ng/ml 10.1-20 ng/ml 20+ ng/ml % PSA recurrence after 10 years (0.2 ng/ml) PSA Gleason score Han & Partin et al, J Urol 2003 Probability of PSA recurrence after RPE with organ-confined prostate cancer (n=2091)

43. Nomogram for the probability of 10 year survival after RPE (n=5955) survival (10 years) Walz et al., J Clin Oncol 2007 Example: 75 years, Charlson score 0 71 % points (sum) comorbidity (Charlson score) age (years) points

44. Markers Evolving diagnositic issues Evolving therapeutic issues Evolving long-term strategies

45. PSA screening Rotterdam Screening Study, 1997 PSA ng/ml) %

46. PSA-based diagnosis (ng/ml) % of men Thompson et al, N Engl J Med 2004, 350, 2239ff

47. Number of biopsy cores and prostate cancer detection rate (n=1000) Biopsy coresn6121821 prostate volume <35 35-55 >55 444 336 220 37% 32% 21% 45% 36% 28% 48% 39% 29% 50% 40% 31% PSA <4 4-10 10-20 >20 101 631 188 80 16% 26% 43% 67% 22% 33% 50% 76% 23% 36% 54% 79% 25% 37% 54% 79% Guichard et al, Eur Urol 2007, 52, 430-35

48. blood prostate cell shedding blood sample kidney urine urine sample

49. PCa markers markers of genetic polymorphism –CYP3A4*1B epigenetic changes –glutathione S-transferase 1 (GSTP1) hypermethylation overexpressed genes –PCa3 DD3 –PSMA gene fusion –ETS gene fusion markers of bone metabolism (type I collagen crosslinks/fragments) –deoxypyridinoline DPD –α-carboxyl terminal telopeptide α-CTX –bone morphogenetic protien 6 BMP6 –osteoprotegerin > 100 different potential markers van Gils et al, Eur Urol 2005

51. PSA in urine PSA – serine protease (kK3) serum/urine ratio –serum PSA range 4-10 ng/ml –sensitivity 42-84%, specificity 80-89% 1,2 PSA reported in urine after RPE 3 – periurethral glands? Irani et al, Urology 2005 Irani et al, J Urol 1997 Iwakiri et al, J Urol 1993

52. PCa3 DD3 prostate-specific gene overexpressed in PCa (median 66x) –identified by differential display analysis non-coding –special RT-PCR needed high negative predictive value (90%) shown in men with PSA > 3 ng/ml before biopsy Hessels et al, Eur Urol 2003

53. PCa3 DD3 in urine Hessels et al, Eur Urol 2003

54. urine-based PCa3 DD3 diagnosis detection of PCa cells by RNA detection Hessels et al, Eur Urol 2003

55. PCa3 DD3 values and repeat biopsies Haese et al, Eur Urol 2008 prospective, multicentre n= 467 men with 1 or 2 previous biopsies „attentive“ DRE + urine sample Urine sample: quantitate PCa3DD3 and PSA mRNA PCa3DD3 score: [PCa3 mRNA]/ [PSA RNA]

56. Relationship between PSA, PCA3 and prostate volume Haese et al. Eur Urol 2008 Mean PSA value Mean PCA3 value Prostate volume (ml)

57. Diagnostic value of PCa3 DD3 at different cut-offs cut-offsensitivityspecificity PCa3 score2073%51% 3547%72% 5035%82% %fPSA25%83%23% Haese et al, Eur Urol 2008

58. Diagnostic value of PCa3 DD3 at different serum PSA levels PCa3 DD3 mean sensitivityspecificity serum PSAn < 44341.850%65% 4 – 1030341.649%74% > 1011247.343%69% Haese et al, Eur Urol 2008

59. A new nomogram? age 30-85 PSA 0-50 DRE suspicious yes - no prostate volume 20-220 previous biopsy yes - no PCa3 DD3 score < 17 yes - no n=1206 men with 10-core biopsy from 2 multicentre prospective studies 5% gain in predictive accuracy of model by addition of PCa3 DD3 at cutoff of 17 Chun et al, Eur Urol 2009

60. detection of tumour cells based on DNA detection MSP for GSTP 1 hypermethylation GSTP 1 Woodson et al, J Urol 2008

61. GSTP1 hypermethylation % positiven/nspecificity Goessl et al, 200036%4/11100% Cairns et al, 200121.4%6/28n.d. Goessl et al, 200173%29/4098% Jeronimo et al, 200230.4%21/6995% 18.4%13/6993% Gonzalgo et al, 200338.9%7/18n.r. Henrique & Jeronimo, Eur Urol 2004

62. ETS gene fusion in PCa gene fusion discovered in PCa TMPRSS2:ERG –5‘untranslated region of the prostate-specific androgen- induced transmembrane protease serine 2 gene –E26 (ETS) family of transcription factors in 42% of men with PCa 1 sensitivity 37%, specificity 93% before biopsy 2 sensitivity 32%, specificity 93% before biopsy 3 Laxman et al, Cancer Res 2008 Hessels et al,Clin Cancer Res 2007 Groskopf et al, 2008 Tomlins et al, Eur Urol 2009

63. Rostock