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2231 IS THE PREOPERATIVE URINARY PROSTATE CANCER GENE 3 (PCA3) SCORE'S ASSOCIATED WITH GLEASON SCORE DEPENDENT TUMOUR VOLUME AND GLEASON PATTERN SPECIFIC TUMOUR VOLUME?
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THE JOURNAL OF UROLOGY姞
cancer-related death. Due to sample-specific relative miR-221 expression values , the resulting hazard ratios from the two samples are not directly comparable. We therefore normalized the miR-221 expressions from both samples to a common standard normal distribution and re-estimated hazard ratios; of note, this transformation does not affect the associations. Due to the absence of sample heterogeneity, we conducted fixed-effects meta-analyses with the normalized miR-221 hazard ratios for the different end points. The results of the metaanalyses reflect the findings of the separately analyzed samples. MiR-221 is an independant predictor for clinical failure and cancer related death in high risk PCa. CONCLUSIONS: This external validation study in combination with the metaanalysis presented underlines the potential role of miR221 as a new biomarker in high-risk Prostate cancer. Source of Funding: None
2231 IS THE PREOPERATIVE URINARY PROSTATE CANCER GENE 3 (PCA3) SCORE’S ASSOCIATED WITH GLEASON SCORE DEPENDENT TUMOUR VOLUME AND GLEASON PATTERN SPECIFIC TUMOUR VOLUME? Marco Auprich*, Sebastian Mannweiler, Graz, Austria; Felix K.H. Chun, Hamburg, Germany; Katrin Mayrhofer, Graz, Austria; Alexander Haese, Hamburg, Germany; John F. Ward, Richard Babaian, Houston, TX; Karl Pummer, Herbert Augustin, Graz, Austria INTRODUCTION AND OBJECTIVES: In a recent study, the association of the pre-operative urinary Prostate CAncer Gene 3 (PCA3) score with pathologically derived tumour volume in dependency of Gleason score was discussed. Therefore we evaluated if the PCA3 score correlates to Gleason score, Gleason score dependent tumour volume (TV) and Gleason pattern specific tumour volume. METHODS: Complete retrospective clinical and pathological data of consecutive RP men from three referral centres including pre-operative urinary PCA3 scores and computer-assisted planimetrically derived TV data were available in 287 patients, whereas in 127 of these Gleason pattern specific TV was separately measured. High grade cancer was defined as PCa presenting Gleason pattern 4 and 5. PCA3 scores were assessed preoperatively using the Progensa® assay. Spearman’s rank correlations coefficients (rs) were calculated to asses if the PCA3 score correlates with 1.) Gleason score (GS) 2.) Gleason score dependent tumour volume (GDTV), and 3.) Gleason pattern specific tumour volume (GPTV). RESULTS: Overall median PSA, PCA3 score, GS, TV and primary and secondary GL pattern TV (ml) were 5,90ng/ml (0.62–73.0), 48 (2–289), 7 (4 –10), 2.26ml (0.01–19.61) and 2.86ml (0.2–19.61) and 1.33 ml (0.3–3.76). Moreover 193 out of 287 (67.2%) patients presented with high grade PCa in detail GS was ⱕ6, 3⫹4, 4⫹3, ⱖ8 and 32.8%, 46.3%, 11.5%, and 9.4%, respectively. Significant correlations for GS, such as stratified GS into ⱕ6, 3⫹4, 4⫹3, ⱖ8 and low or high grade PC with PSA [all pⱕ0.05, correlations coefficients (rs) 0.19, 0.24, 0.12) were recorded. Moreover PCA3 correlated to GS stratified in low or high grade PC [p⫽0.054, rs ⫽0.11]. A significant correlation between TV with PSA and PCA3 [both pⱕ0.001, rs⫽0.43 and 0.24] was calculated. PCA3’s correlation changed when stratifying GS into ⱕ6, 3⫹4, 4⫹3, ⱖ8 [rs⫽ 0.29 (pⱕ0.01), 0.22 (pⱕ0.001), 0.42 (pⱕ0.02), 0.01 (p⫽0.99)]. Irrespectively of Gleason grade, PCA3 did neither correlate with primary nor secondary Gleason pattern specific TV, in contrast PSA significantly correlates with primary GPTV (pⱕ0.004, rs 0.35). CONCLUSIONS: This study confirms PCA3’s correlation to TV, and demonstrates the impact of high grade cancer. However PCA3 does not correlate to Gleason pattern specific tumour volume. With this, the limited association of this novel diagnostic marker with PCa’s aggressiveness was again demonstrated. Source of Funding: None
Vol. 187, No. 4S, Supplement, Wednesday, May 23, 2012
2232 THE NOVEL USE OF URINARY EXOSOMES TO EXAMINE SURVIVIN EXPRESSION IN CASTRATION RESISTANT PROSTATE CANCER James Lin*, Anna Scott, Piruz Motamedinia, Guillermo Salazar, Kendall Bate, Michael Lipsky, Neda Sadeghi, Wayne D Comper, James M McKiernan, Daniel P Petrylak, Leileata Russo, New York, NY INTRODUCTION AND OBJECTIVES: Given the numerous new agents for the treatment of patients with castration resistant prostate cancer (CRPC), identification of biological markers is essential to predicting response and providing a rationale for sequencing treatments. Microvesicles, including exosomes, are small lipid bilayer vesicles released from all cells into bodily fluids. Exosomes, which carry high integrity RNA from their parent cells, can be used to reliably interrogate the transcriptional profile of various organs in a non-invasive manner. Using urinary exosomes we examined Survivin expression, an inhibitor of apoptosis implicated in hormone independent tumor growth, in different disease states of men with advanced prostate cancer. METHODS: Following Columbia University IRB approval and obtaining informed consent, urine samples were collected prior to a digital rectal exam from 4 groups of patients: radical prostatectomy with no evidence of disease (RP-NED, n⫽37) or alive with disease (RP-AWD, n⫽22), and ablative therapy (external radiation therapy or cryotherapy) with no evidence of disease (ABL-NED, n⫽13) or alive with disease (ABL-AWD, n⫽14). These patients were further categorized as CRPC and non-CRPC for the RP-AWD (n⫽11 & n⫽11) and ABL-AWD (n⫽8 & n⫽6) groups, respectively. Urinary exosomal mRNA was isolated and GAPDH and Survivin were analyzed via RT-qPCR. To compare expression levels, genes were standardized to GAPDH and relative quantitation (RQ) was calculated using the DataAssist program (v.2.0). RESULTS: Survivin expression was significantly higher in the RP-AWD group compared to the RP-NED group (RQ 3.63, p⫽0.03). A similar trend was also observed for patients with ablation therapy as their primary treatment (RQ 3.23, p⫽0.057). When stratified into CRPC and non-CRPC, increased Survivin expression was associated with castration resistance for RP-NED versus RP-AWD CRPC (p⫽0.0422) and ABL-NED versus ABL-AWD CRPC (P⫽0.0291). Additionally, Survivin expression was significantly higher in the ABL-AWD patients with CRPC versus those with non-CRPC (RQ 6.30, p⫽0.027). CONCLUSIONS: Using urinary exosomal RNA, Survivin levels are elevated in men with CRPC. This non-invasive assay may be utilized to follow prostate cancer patients over time and monitor gene expression during treatment, giving greater insight into the molecular changes that occur during disease progression and response to treatment. Source of Funding: Exosome Diagnostics, Doris Duke Charitable Foundation
2233 AN INITIAL SERUM PSA LEVEL LESS THAN 5 NG/ML AT DIAGNOSIS DOES NOT CORRELATE WITH TUMOR VOLUME IN LOW RISK PROSTATE CANCER PATIENTS. IMPLICATIONS FOR CONSERVATIVE TREATMENTS Fabio Castiglione*, Maarten Albersen, Alberto Briganti, Nazareno Suardi, Andrea Gallina, Firas Abdollah, Ettore Di Trapani, Federico Pellucchi, Paolo Dell’Oglio, Alessandro Nini, Renzo Colombo, Giorgio Guazzoni, Patrizio Rigatti, Francesco Montorsi, Milano, Italy INTRODUCTION AND OBJECTIVES: Active surveillance is a valid management strategy for newly diagnosed low risk prostate cancer (PCa). In fact a well differentiated, low volume tumor can be identified based on initial patient characteristic at diagnosis. However, the association between baseline parameters such as PSA and tumor volume has been poorly studied in pts with low risk disease. The aim of the study was to assess whether PSA levels accurately predicts tumor volume in low risk PCa pts who are candidates for non invasive treatment.
THE JOURNAL OF UROLOGY姞
cancer-related death. Due to sample-specific relative miR-221 expression values , the resulting hazard ratios from the two samples are not directly comparable. We therefore normalized the miR-221 expressions from both samples to a common standard normal distribution and re-estimated hazard ratios; of note, this transformation does not affect the associations. Due to the absence of sample heterogeneity, we conducted fixed-effects meta-analyses with the normalized miR-221 hazard ratios for the different end points. The results of the metaanalyses reflect the findings of the separately analyzed samples. MiR-221 is an independant predictor for clinical failure and cancer related death in high risk PCa. CONCLUSIONS: This external validation study in combination with the metaanalysis presented underlines the potential role of miR221 as a new biomarker in high-risk Prostate cancer. Source of Funding: None
2231 IS THE PREOPERATIVE URINARY PROSTATE CANCER GENE 3 (PCA3) SCORE’S ASSOCIATED WITH GLEASON SCORE DEPENDENT TUMOUR VOLUME AND GLEASON PATTERN SPECIFIC TUMOUR VOLUME? Marco Auprich*, Sebastian Mannweiler, Graz, Austria; Felix K.H. Chun, Hamburg, Germany; Katrin Mayrhofer, Graz, Austria; Alexander Haese, Hamburg, Germany; John F. Ward, Richard Babaian, Houston, TX; Karl Pummer, Herbert Augustin, Graz, Austria INTRODUCTION AND OBJECTIVES: In a recent study, the association of the pre-operative urinary Prostate CAncer Gene 3 (PCA3) score with pathologically derived tumour volume in dependency of Gleason score was discussed. Therefore we evaluated if the PCA3 score correlates to Gleason score, Gleason score dependent tumour volume (TV) and Gleason pattern specific tumour volume. METHODS: Complete retrospective clinical and pathological data of consecutive RP men from three referral centres including pre-operative urinary PCA3 scores and computer-assisted planimetrically derived TV data were available in 287 patients, whereas in 127 of these Gleason pattern specific TV was separately measured. High grade cancer was defined as PCa presenting Gleason pattern 4 and 5. PCA3 scores were assessed preoperatively using the Progensa® assay. Spearman’s rank correlations coefficients (rs) were calculated to asses if the PCA3 score correlates with 1.) Gleason score (GS) 2.) Gleason score dependent tumour volume (GDTV), and 3.) Gleason pattern specific tumour volume (GPTV). RESULTS: Overall median PSA, PCA3 score, GS, TV and primary and secondary GL pattern TV (ml) were 5,90ng/ml (0.62–73.0), 48 (2–289), 7 (4 –10), 2.26ml (0.01–19.61) and 2.86ml (0.2–19.61) and 1.33 ml (0.3–3.76). Moreover 193 out of 287 (67.2%) patients presented with high grade PCa in detail GS was ⱕ6, 3⫹4, 4⫹3, ⱖ8 and 32.8%, 46.3%, 11.5%, and 9.4%, respectively. Significant correlations for GS, such as stratified GS into ⱕ6, 3⫹4, 4⫹3, ⱖ8 and low or high grade PC with PSA [all pⱕ0.05, correlations coefficients (rs) 0.19, 0.24, 0.12) were recorded. Moreover PCA3 correlated to GS stratified in low or high grade PC [p⫽0.054, rs ⫽0.11]. A significant correlation between TV with PSA and PCA3 [both pⱕ0.001, rs⫽0.43 and 0.24] was calculated. PCA3’s correlation changed when stratifying GS into ⱕ6, 3⫹4, 4⫹3, ⱖ8 [rs⫽ 0.29 (pⱕ0.01), 0.22 (pⱕ0.001), 0.42 (pⱕ0.02), 0.01 (p⫽0.99)]. Irrespectively of Gleason grade, PCA3 did neither correlate with primary nor secondary Gleason pattern specific TV, in contrast PSA significantly correlates with primary GPTV (pⱕ0.004, rs 0.35). CONCLUSIONS: This study confirms PCA3’s correlation to TV, and demonstrates the impact of high grade cancer. However PCA3 does not correlate to Gleason pattern specific tumour volume. With this, the limited association of this novel diagnostic marker with PCa’s aggressiveness was again demonstrated. Source of Funding: None
Vol. 187, No. 4S, Supplement, Wednesday, May 23, 2012
2232 THE NOVEL USE OF URINARY EXOSOMES TO EXAMINE SURVIVIN EXPRESSION IN CASTRATION RESISTANT PROSTATE CANCER James Lin*, Anna Scott, Piruz Motamedinia, Guillermo Salazar, Kendall Bate, Michael Lipsky, Neda Sadeghi, Wayne D Comper, James M McKiernan, Daniel P Petrylak, Leileata Russo, New York, NY INTRODUCTION AND OBJECTIVES: Given the numerous new agents for the treatment of patients with castration resistant prostate cancer (CRPC), identification of biological markers is essential to predicting response and providing a rationale for sequencing treatments. Microvesicles, including exosomes, are small lipid bilayer vesicles released from all cells into bodily fluids. Exosomes, which carry high integrity RNA from their parent cells, can be used to reliably interrogate the transcriptional profile of various organs in a non-invasive manner. Using urinary exosomes we examined Survivin expression, an inhibitor of apoptosis implicated in hormone independent tumor growth, in different disease states of men with advanced prostate cancer. METHODS: Following Columbia University IRB approval and obtaining informed consent, urine samples were collected prior to a digital rectal exam from 4 groups of patients: radical prostatectomy with no evidence of disease (RP-NED, n⫽37) or alive with disease (RP-AWD, n⫽22), and ablative therapy (external radiation therapy or cryotherapy) with no evidence of disease (ABL-NED, n⫽13) or alive with disease (ABL-AWD, n⫽14). These patients were further categorized as CRPC and non-CRPC for the RP-AWD (n⫽11 & n⫽11) and ABL-AWD (n⫽8 & n⫽6) groups, respectively. Urinary exosomal mRNA was isolated and GAPDH and Survivin were analyzed via RT-qPCR. To compare expression levels, genes were standardized to GAPDH and relative quantitation (RQ) was calculated using the DataAssist program (v.2.0). RESULTS: Survivin expression was significantly higher in the RP-AWD group compared to the RP-NED group (RQ 3.63, p⫽0.03). A similar trend was also observed for patients with ablation therapy as their primary treatment (RQ 3.23, p⫽0.057). When stratified into CRPC and non-CRPC, increased Survivin expression was associated with castration resistance for RP-NED versus RP-AWD CRPC (p⫽0.0422) and ABL-NED versus ABL-AWD CRPC (P⫽0.0291). Additionally, Survivin expression was significantly higher in the ABL-AWD patients with CRPC versus those with non-CRPC (RQ 6.30, p⫽0.027). CONCLUSIONS: Using urinary exosomal RNA, Survivin levels are elevated in men with CRPC. This non-invasive assay may be utilized to follow prostate cancer patients over time and monitor gene expression during treatment, giving greater insight into the molecular changes that occur during disease progression and response to treatment. Source of Funding: Exosome Diagnostics, Doris Duke Charitable Foundation
2233 AN INITIAL SERUM PSA LEVEL LESS THAN 5 NG/ML AT DIAGNOSIS DOES NOT CORRELATE WITH TUMOR VOLUME IN LOW RISK PROSTATE CANCER PATIENTS. IMPLICATIONS FOR CONSERVATIVE TREATMENTS Fabio Castiglione*, Maarten Albersen, Alberto Briganti, Nazareno Suardi, Andrea Gallina, Firas Abdollah, Ettore Di Trapani, Federico Pellucchi, Paolo Dell’Oglio, Alessandro Nini, Renzo Colombo, Giorgio Guazzoni, Patrizio Rigatti, Francesco Montorsi, Milano, Italy INTRODUCTION AND OBJECTIVES: Active surveillance is a valid management strategy for newly diagnosed low risk prostate cancer (PCa). In fact a well differentiated, low volume tumor can be identified based on initial patient characteristic at diagnosis. However, the association between baseline parameters such as PSA and tumor volume has been poorly studied in pts with low risk disease. The aim of the study was to assess whether PSA levels accurately predicts tumor volume in low risk PCa pts who are candidates for non invasive treatment.