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

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

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

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

AG Bevölkerungsbezogener Krebsregister 2008 Age and incidence of prostate cancer Germany

prevalence [%] 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

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

Natural course of prostate cancer diagnosis

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

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 brachytherapy % EBRT % radical prostatectomy % Potters et al, Radiother Oncol 2004

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

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)

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

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%

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

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

lowintermediatehighvery high Risk stratification for biochemical recurrence (n=1515) Years after RPE without PSA recurrence [%] Moul et al, J Urol 2001

Overall survival after RPE by age RPE in Austria: n= Mohamad et al, Eur Urol 2007, 51,

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 %

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

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

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

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

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

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

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

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> % For „intermediate“ and „high risk“ it is always „or“

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

% overall survival 10 years after radical prostatectomy predicted beobachtet % Charlson-Score 0 Charlson-Score 1+ Charlson score nomogram underestimates survival in healthy over 70 year-olds (n=329/1910) predicted beobachtet % p= % 88 % p< Froehner et al, Urology 2009

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

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

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

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

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 months S3-Leitlinie Prostatakarzinom DGU 2009 German interdisciplinary evidence-based guidelines for the diagnosis and management of prostate cancer, update 2011

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

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

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

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

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)

Partin tables Gleason- Score cT-Stadium T1c T2a T2b T2c % (89-99) 91% (79-98) 88% (73-97) 86% (71-97) % (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

cT1acT1bcT1c cT2acT2b cT2ccT3a clinical stage Partin et al, JAMA 1997 Partin tables Likelihood of organ-confined disease PSA range ng/ml probability (%) Gleason score

ng/ml ng/ml 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)

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

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

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

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

Number of biopsy cores and prostate cancer detection rate (n=1000) Biopsy coresn prostate volume < > % 32% 21% 45% 36% 28% 48% 39% 29% 50% 40% 31% PSA < > % 26% 43% 67% 22% 33% 50% 76% 23% 36% 54% 79% 25% 37% 54% 79% Guichard et al, Eur Urol 2007, 52,

blood prostate cell shedding blood sample kidney urine urine sample

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

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

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

PCa3 DD3 in urine Hessels et al, Eur Urol 2003

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

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]

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

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

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

A new nomogram? age PSA 0-50 DRE suspicious yes - no prostate volume 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

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

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

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

Rostock