699 TISSULAR BIOMARKERS ASSOCIATED WITH SURVIVAL AFTER PROSTATE CANCER HORMONAL RELAPSE

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Sex hormone binding globulin is a significant predictor of extra capsular extension in patients undergoing radical retropubic prostatectomy Salonia A.1, Gallina A.1, Briganti A.1, Suardi N.1, Zanni G.1, Matloob R.1, Colombo R.1, Da Pozzo L.F.1, Capitanio U.1, Freschi M.2, Guazzoni G.2, Rigatti P.2, Montorsi F.2 University Vita-Salute San Raffaele, Dept. of Urology, Milan, Italy, 2University VitaSalute San Raffaele, Unit. of Pathology, Milan, Italy

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Introduction & Objectives: To examine the association between Sex Hormone Binding Globulin (SHBG) and extra capsular extension (ECE) in patients undergoing radical retropubic prostatectomy (RRP), after accounting for routinely available clinical parameters. Material & Methods: A cohort of 629 consecutive patients who underwent RRP at a single Institution was used. No patient received any hormonal neo-adjuvant treatment. Serum SHBG was dosed the day before surgery (8-10 A.M.) in all cases at the same laboratory. Logistic regression models tested the association between predictors [including PSA, clinical stage, biopsy GL sum, Body Mass Index (BMI), and SHBG] and ECE at RRP. Combined accuracy of predictors were tested in regression-based models predicting ECE at RP, with or without inclusion of SHBG.



698

Risk factors for biochemical recurrence and mortality in men treated with primary androgen deprivation in the Prostate Specific Antigen era: Evidence for developing patient specific follow up regimes Hori S.1, Jabbar T.2, Vasconcelos J.C.3, Robson C.N.4, Pickard R.2, Gnanapragasam V.J.1 1 University of Cambridge, Dept. of Uro-Oncology, Cambridge, United Kingdom, 2Freeman Hospital, Dept. of Urology, Newcastle upon Tyne, United Kingdom, 3University of Cambridge, Centre for Applied Medical Statistics, Cambridge, United Kingdom, 4Northern Institute for Cancer Research, Dept. of Oncology, Newcastle upon Tyne, United Kingdom

Introduction & Objectives: Androgen deprivation (AD) remains a crucial primary therapy for prostate cancer despite the advent of PSA testing. Data on its durability and the time to biochemical recurrence however is based largely on historic patient populations who presented with more advanced disease. In this study, we asked 1) What is the mean time to biochemical relapse (BR) and disease specific mortality (DSM) in contemporary men treated with AD? 2) What prognostic factors predict these outcomes and 3) Could follow up regimes be better defined in these patients? Material & Methods: 185 patients diagnosed between 1999-2001 in a single tertiary referral centre and who received AD were included in this study. All men were diagnosed by PSA testing and prostate biopsy and had a minimum of 5 years clinical follow up. Bone scans were performed in all men with PSA>20. Univariate and multivariate analysis was performed to determine potential predictive factors for BR and DSM.

Results: Median age was 64.6 yr (mean 64; range: 41-82). Median PSA was 6.7 ng/ml (mean 24.8; range: 0.9-256). Median BMI was: 25.9 kg/m^2 (mean: 26.2; range: 17.3 – 40.1). Clinical stage was T1c, T2 or T3 in 381 (60.6%), 178 (28.3%) and 70 (11.1%) patients, respectively. Biopsy GL sum was ≤6, 7 or 8-10 in 403 (64.1%), 177 (28.1%) and 49 (7.8%) patients, respectively. Median SHBG was 35 nmol/L (mean: 37.1; range: 5.8 - 208). ECE was found in 92 (14.6%) patients. Patients with ECE had significantly higher mean±SD serum SHBG compared to those without ECE (41.1±14.7 vs. 36.4±16.7 nmol/L, respectively; p=0.013). At univariate analysis SHBG was significantly associated with ECE (OR=1.014; P=0.018). Likewise, at multivariate analysis SHBG maintained its significant association with ECE (OR=1.013; P=0.038), after accounting for PSA, clinical stage, biopsy GL sum and BMI. A model based on clinical stage, PSA, biopsy GL sum demonstrated bootstrap-corrected predictive accuracy of 63.8% which increased to 65.6% when SHBG was added (1.8% gain; p=0.48).

Results: The average age of the group was 74.9 years with a mean of 58.5 months follow up. 51% (n=94) of patients developed biochemical relapse with a disease specific mortality of 32% (n=59). 34% (n=56) of patients had evidence of metastases at diagnosis. Of those patients without metastasis, 44.5% (n=49) developed BR and 14.5% (n=16) died due to prostate cancer. In patients with metastasis, 69.6% (n=39) developed BR and 69.6% (n=39) died as a direct result of prostate cancer. For the group as a whole, predictive factors in multivariate analysis for BR and DSM were a high PSA nadir (p<0.001), a shorter time to reach nadir (p<0.001) and the presence of metastasis (p<0.001) at diagnosis. Increasing age was also an independent adverse prognostic factor for BR (p=0.012) but not for DSM. The metastatic and non-metastatic groups were then analysed separately to unmask other potential prognostic factors. In the metastatic group (n=56), factors associated with BR were similar to those of the whole cohort. Percentage biopsy core positivity however was noted to be an additional independent prognostic factor associated with DSM (p=0.01). In the non-metastatic group (n=110) clinical stage emerged as an additional independent prognostic factor for BR (p=0.011). Multivariate analysis for DSM was not possible as there were too few events in this group (n=15). In men without metastasis at diagnosis and no adverse prognostic factors, the mean time to BR was 54.4 and for DSM, 71.4 months.

Conclusions: These data tested the association between SHBG and ECE. We demonstrated that SHBG is a significant multivariate predictor of ECE in patients submitted to RRP.

Conclusions: Men diagnosed in the modern era treated with primary AD and who do not have metastasis or other adverse risk factors can have extremely durable responses to AD. Stratification of patients by metastasis and risk factors identified here may help in refining current follow up regimes. We propose an algorithm for optimizing the current management of men undergoing primary AD.





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Tissular biomarkers associated with survival after prostate cancer hormonal relapse Celhay O.1, Yacoub M.2, Irani J.1, Doré B.1, Cussenot O.3, Fromont G.1 C.H.U. la Milétrie, Dept. of Urology, Poitiers, France, 2C.H.U. la Milétrie, Dept. of Pathology, Poitiers, France, 3C.E.R.E.P.P., Dept. of Urology, Paris, France

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Introduction & Objectives: Despite initial response, androgen ablation treatment for advanced prostate cancer always leads to androgen independence and progression. Patients survival remains however unpredictable, ranging from some months to several years, without any prognostic markers. The aim of the study was to analyse on samples collected after hormonal treatment failure, the impact of in situ gene expression on patient survival. Material & Methods: 31 transuretral resection tissue sample were collected from patient aged 59 to 85 years old, only treated with LHRH agonists. Using Tissue Micro-Array and Immunochemistry, we analysed the expression of genes involved in hormonal (androgen receptor, Ser210 phosphorylated androgen receptor, 5alpha reductase 1, aromatase, BCAR) and lipid (P504S) metabolism, cellular migration (E cadherin, KAI1), proliferation (Ki67, EGFr) and apoptosis (Bcl-2). The association between gene expression and overall survival was performed using Log-rank test and Cox test respectively. Results: Median global overall survival was 11.6 months (0.0–86.5). In univariate analysis, high expression of proliferation marker Ki67 (to median value, ie ≥15% of positive cells, p=0.0013; 21.5 months vs. 3.5 months) and expression of Ser210 phosphorylated androgen receptor fraction over total androgen receptor expression (to median value, ie ≥40%, p=0.005; 7.6 months vs. 21.5 months) were associated with shorter survival. No association with survival was found with the other markers. Using multivariate analysis, Ki67 expression ≥15% (p=0.0024; OR=1.09; IC95%=1.03-1.15) and Ser210 phosphorylated androgen receptor over total androgen receptor ≥40% (p=0.01; OR=1.01; IC95%= 1.00-1.02) were independent predictive factor of poor overall survival. Conclusions: When comparing prostate cancer samples after hormonal relapse for patients treated with LHRH agonists only, the proliferation index and the Ser210 phosphorylated fraction of the androgen receptor were independent factors of poor prognosis. Despite hormonal castration, progression of prostate cancer remains dependent of the androgen receptor after hormonal relapse.

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Total human kallikrein 2 - a potentially useful serum marker of bone metastasis and biochemical failure in prostate cancer Phillips J.1, Eaton C.L.2, Proctor L.2, Sokhi D.2, Cronin A.3, Vickers A.3, Lilja H.3, Hamdy F.2 Royal Hallamshire Hospital, Academic Urology Unit, Birmingham, United Kingdom, 2Royal Hallamshire Hospital, Academic Urology Unit, Sheffield, United Kingdom, 3Memorial SloanKettering Cancer Center, Dept. of Epidemiology and Biostatistics, New York, United States of America

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Introduction & Objectives: At present PSA and its derivatives remain the most clinically important serum markers in prostate cancer, with applications to all aspects of its management. Human kallikrein 2 (hK2) is a serum protease very similar to PSA, which although also expressed by the prostatic epithelium under androgenic control, has independent regulation of its serum levels. Serum hK2 has been studied as a potential marker of diagnosis and local staging in men with early prostate cancer undergoing radical prostatectomy. Here we present the first study of its use for detection of metastatic disease and prediction of biochemical failure following androgen ablation therapy. Material & Methods: Levels of serum total hk2 (thK2), total PSA (tPSA), free PSA (fPSA) and %f/tPSA were measured in peripheral blood samples collected from 389 men with histologically proven prostate cancer. The patients were classified according to clinical stage, treatment status and presence or absence of bone metastasis. Bone scans were performed in all newly diagnosed cases with a PSA ≥10ng/ml and/or Gleason score ≥7 and/or symptoms suspicious of bone involvement. Patients were periodically monitored throughout the study period. Control blood samples were collected from both young healthy males (n=14) under the age of 30 years, and older men over 60 years of age with histologically proven BPH but no malignancy (n=45). Results: Median follow-up time overall was 36 months (41 months for patients without biochemical relapse). 52 patients developed biochemical relapse and 6 patients developed new bone metastases. Patients with positive bone scans exhibited significantly higher levels of thK2, tPSA and fPSA compared to the group with negative scans (all p ≤ 0.005), with thK2 showing the strongest overall accuracy (ROC curves analysis: AUC = 0.831). For newly diagnosed men with prostate cancer, those with higher levels of thK2 (p=0.005), fPSA (p=0.03) or tPSA (p=0.05) were significantly more likely to relapse; %f/tPSA was not significantly associated with relapse (p=0.61); Serum thK2 exhibited the highest discrimination for biochemical relapse following androgen ablation therapy [concordance indices for prediction of biochemical relapse: thK2=0.688, fPSA=0.670, and tPSA=0.654]. If the analysis was limited to patients with negative bone scans only, the same result was found. Conclusions: There is evidence to suggest that serum thK2 levels better reflect the presence of bone metastasis in men with prostate cancer than PSA or its derivatives. Furthermore, elevated serum thK2 levels are associated with higher propensity to develop early biochemical relapse.

Eur Urol Suppl 2009;8(4):295