Marco Auprich

Contemporary Role of Prostate Cancer Antigen 3 in the Management of Prostate Cancer

CONTEXT Newly discovered biomarkers ideally should prove clinical usefulness, provide additional detection, staging, and prognosis information to improve individual risk assessment, and potentially permit targeted cancer therapy. OBJECTIVE To review, display, and evaluate the current evidence regarding the biologic and analytic approach of urinary prostate cancer gene 3 (PCA3) in prostate cancer (PCa) detection, staging, and prognosis, and its therapeutic potential. EVIDENCE ACQUISITION A systematic and comprehensive Medline search was performed using the Medical Subject Headings search terms PCA3, DD3, UPM3, prostate cancer, cell-lines, prostate tissue, prostate biopsy, detection, diagnosis, radical prostatectomy, staging, grading, progression, and gene therapy. Results were restricted to English-language papers published within the period 1999-2011. EVIDENCE SYNTHESIS The PCA3 gene is highly overexpressed in specific PCa cell lines and prostatic tumours. In 2006, a simple and robust urine test (Progensa) became commercially available. Despite its costs, prostate cancer antigen 3 (PCA3) is superior to prostate-specific antigen (PSA) and percent free PSA in the early detection of PCa. PCA3 improves the diagnostic accuracy of externally validated nomograms among men with an elevated PSA undergoing biopsy. PCA3 independently predicts low-volume disease and pathologically insignificant PCa but is not associated with locally advanced disease and is limited in the prediction of aggressive cancer. Preliminary data demonstrate that combining PCA3 with other new biomarkers further improves diagnostic and prognostic accuracy. Finally, findings of the first PCA3-Gene-ViroTherapy study suggest therapeutic potential by exploiting PCA3 overexpression. CONCLUSIONS PCA3, integrated in novel biopsy nomograms or risk stratification tools, can be used to counsel or confirm biopsy indications. If confirmed in further studies, using PCA3 together with established staging risk factors could assist clinicians in specific pretreatment decision making. So far no evidence for the usefulness of PCA3 in active surveillance programs has been presented.

Initial Prostate Biopsy: Development and Internal Validation of a Biopsy-specific Nomogram Based on the Prostate Cancer Antigen 3 Assay

BACKGROUND Urinary prostate cancer antigen 3 (PCA3) assay in combination with established clinical risk factors improves the identification of men at risk of harboring prostate cancer (PCa) at initial biopsy (IBX). OBJECTIVE To develop and validate internally the first IBX-specific PCA3-based nomogram that allows an individual assessment of a mans risk of harboring any PCa and high-grade PCa (HGPCa). DESIGN, SETTING, AND PARTICIPANTS Clinical and biopsy data including urinary PCA3 score of 692 referred IBX men at risk of PCa were collected within two prospective multi-institutional studies. INTERVENTION IBX (≥ 10 biopsy cores) with standard risk factor assessment including prebiopsy urinary PCA3 measurement. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PCA3 assay cut-off thresholds were investigated. Regression coefficients of logistic risk factor analyses were used to construct specific sets of PCA3-based nomograms to predict any PCa and HGPCa at IBX. Accuracy estimates for the presence of any PCa and HGPCa were quantified using area under the curve of the receiver operator characteristic analysis and compared with a clinical model. Bootstrap resamples were used for internal validation. Decision curve analyses quantified the clinical net benefit related to the novel PCA3-based IBX nomogram versus the clinical model. RESULTS AND LIMITATIONS Any PCa and HGPCa were diagnosed in 46% (n=318) and 20% (n=137), respectively. Age, prostate-specific antigen, digital rectal examination, prostate volume, and PCA3 were independent predictors of PCa at IBX (all p<0.001). The PCA3-based IBX nomograms significantly outperformed the clinical models without PCA3 (all p<0.001). Accuracy was increased by 4.5-7.1% related to PCA3 inclusion. When applying nomogram-derived PCa probability thresholds ≤ 30%, only a few patients with HGPCa (≤ 2%) will be missed while avoiding up to 55% of unnecessary biopsies. External validation of the PCA3-based IBX-specific nomogram is warranted. CONCLUSIONS The internally validated PCA3-based IBX-specific nomogram outperforms a clinical prediction model without PCA3 for the prediction of any PCa, leading to the avoidance of unnecessary biopsies while missing only a few cases of HGPCa. Our findings support the concepts of a combination of novel markers with established clinical risk factors and the superiority of decision tools that are specific to a clinical scenario.

Accuracy of 3-Tesla Magnetic Resonance Imaging for the Staging of Prostate Cancer in Comparison to the Partin Tables

Background: An accurate prediction of final pathological stage is essential for proper patient selection to determine who will experience maximum benefit from radical prostatectomy. In this context, the Partin tables represent one of the most widely used statistical prediction tools. Purpose: To compare the accuracy in predicting pathological stage in patients intended for radical prostatectomy between 3-Tesla (T) magnetic resonance imaging (MRI) and the Partin tables in a prospective trial. Material and Methods: 27 men with staging results from 3T MRI using a phased-array coil were compared in terms of staging accuracy with whole-mount-section histopathologic analyses as the standard of reference. Probabilities for pathological stages were estimated according to the Partin tables. Spearman rank correlation and discriminant analysis were calculated to assess relationships. Results: Histopathological evaluation revealed organ-confined disease (OC) in 21 (77.8%) and extracapsular extension (ECE) in six (22.2%) men. Three-Tesla MRI staging was accurate in all patients with OC and in four out of the six men with ECE. Accuracy of local staging was 85.2% (23 of 27). Sensitivity was 66.7% (95% confidence interval [CI] 0.223–0.957) and specificity 100% (95% CI 0.839–1) for the detection of ECE. Findings of MRI and the Partin tables showed a Spearman rho of 0.780 vs. 0.254 for OC and 0.780 vs. 0.363 for ECE, respectively. Compared to the Partin tables, MRI revealed standardized canonical discriminant function coefficients of 0.992 (P<0.001) vs. 0.205 (P=0.432) for OC and 0.965 (P<0.001) vs. 0.329 (P=0.197) for ECE, respectively. Conclusion: 3T MRI showed a high accuracy for the staging of clinically localized prostate cancer, and it was significantly more accurate in predicting the final pathological stage than the Partin tables.

Development of a Multiplexed Urine Assay for Prostate Cancer Diagnosis

BACKGROUND Several studies have demonstrated the value of DNA methylation in urine-based assays for prostate cancer diagnosis. However, a multicenter validation with a clinical prototype has not been published. METHODS We developed a multiplexed, quantitative methylation-specific polymerase chain reaction (MSP) assay consisting of 3 methylation markers, GSTP1, RARB, and APC, and an endogenous control, ACTB, in a closed-tube, homogeneous assay format. We tested this format with urine samples collected after digital rectal examination from 234 patients with prostate-specific antigen (PSA) concentrations > or =2.5 microg/L in 2 independent patient cohorts from 9 clinical sites. RESULTS In the first cohort of 121 patients, we demonstrated 55% sensitivity and 80% specificity, with area under the curve (AUC) 0.69. In the second independent cohort of 113 patients, we found a comparable sensitivity of 53% and specificity of 76% (AUC 0.65). In the first cohort, as well as in a combined cohort, the MSP assay in conjunction with total PSA, digital rectal examination status, and age improved the AUC without MSP, although the difference was not statistically significant. Importantly, the GSTP1 cycle threshold value demonstrated a good correlation (R = 0.84) with the number of cores found to contain prostate cancer or premalignant lesions on biopsy. Moreover, samples that exhibited methylation for either GSTP1 or RARB typically contained higher tumor volumes at prostatectomy than those samples that did not exhibit methylation. CONCLUSIONS These data confirm and extend previously reported studies and demonstrate the performance of a clinical prototype assay that should aid urologists in identifying men who should undergo biopsy.

A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy.

Study Type – Diagnosis (exploratory cohort)

Head to head comparison of three generations of Partin tables to predict final pathological stage in clinically localised prostate cancer

OBJECTIVE To perform a head to head comparison between three generations of Partin tables, namely from 1997, 2001 and the last updated version of 2007. MATERIAL AND METHODS The external validations were based on clinical and pathological data of 687 consecutive patients undergoing radical prostatectomy for clinically localised prostate cancer between 2003 and 2008. Three versions of the Partin tables were compared for their accuracy and performance to predict final pathological stage using receiver operating characteristic (ROC) curve and Loess plots analyses. RESULTS Of the whole cohort, 76.2% of men were presented with organ-confined disease (OC), 17.0% had extraprostatic extension (ECE), 6.0% showed seminal vesicle involvement (SVI) and 1.2% had lymph node involvement (LNI). The area under the receiver operating characteristic curve (AUC) of the Partin Tables 1997, 2001 and 2007 was 0.731, 0.727 and 0.722 for OC; 0.671, 0.662 and 0.650 for ECE; 0.795, 0.788 and 0.779 for SVI as well as 0.826, 0.786 and 0.746 for LNI, respectively. CONCLUSION All three generations of the Partin tables showed a good accuracy to predict OC, SVI and LNI. However, the predictive accuracy for ECE was only modest. Overall, the newer versions of the Partin tables could not exceed the version of 1997 in their predictive accuracy for any pathological stage and they failed to demonstrate a clear advantage. Our results underline the necessity to perform external validations before the implementation of a new predicting tool.

Diagnostic Yield of Touch Imprint Cytology of Prostate Core Needle Biopsies

Touch imprint cytology may provide additional information to core needle biopsy interpretation according to previous reports. The aim of this study was to investigate the diagnostic yield of this method in the diagnosis of prostate carcinoma. For this purpose, 452 transrectal prostate needle biopsies were evaluated from 56 patients. All patients were clinically suspicious of having prostate carcinoma. Two touch imprints were prepared from each fresh biopsy cylinder. Results of the standard histology and of the touch imprint evaluation were compared. Histologically negative biopsy cylinders were further evaluated for prostate carcinoma by fine step serial sectioning. The standard histological examination showed adenocarcinoma in 27 patients. Touch imprint cytology revealed atypical cells suspicious of carcinoma in 38 patients. This group included all 27 patients with positive standard histology and further 11 patients with initially negative core biopsy. Following serial sectioning, in three out of these 11 samples, histological evidence of a carcinoma could be proven. Fine step serial sectioning of all 29 core biopsies negative for carcinoma by standard histological examination, 26 patients remained negative. All three core biopsies initially negative by standard histology but positive after serial sectioning had cytology findings suspicious of carcinoma. We conclude, that in problematic cases the additional use of touch imprint cytology and serial sectioning of prostate core needle biopsies significantly improve the diagnostic accuracy.

Shift of tumor features in patients with clinically localized prostate cancer undergoing radical prostatectomy since the beginning of the PSA era

ZusammenfassungZIEL: Die Einführung der Bestimmung des prostata-spezifischen Antigens (PSA) hat die Diagnostik und das Management des Prostatakarzinoms nachhaltig verändert. Wir untersuchten die zeitlichen Veränderungen klinischer und histopathologischer Tumoreigenschaften seit den Anfängen der PSA-Ära bei klinisch lokalisierten Prostatakarzinomen, die einer radikalen Prostatektomie unterzogen wurden. PATIENTEN UND METHODE: Während 1993 und 2004 wurden 1351 Patienten wegen eines klinisch lokalisierten Prostatakarzinoms radikal prostatektomiert. Daten über klinische und histopathologische Tumorcharakteristika wurden kontinuierlich in unserer Datenbank erfasst und im Hinblick auf zeitliche Veränderungen analysiert. ERGEBNISSE: Die jährliche Operationsfrequenz stieg während dieses 12-jährigen Zeitraumes um 272% von 43 auf 160 Eingriffe pro Jahr (r = 0,930; p < 0,01). Die Karzinomdiagnosen ausschließlich auf einen pathologisch erhöhten PSA-Wert basierend zeigten einen massiven Anstieg von 7% auf 70% (r = 0,986; p < 0,01). Anderseits sank die Rate an Prostatakarzinomen, welche nur wegen eines auffälligen Tastbefundes diagnostiziert wurden, von 18% im Jahre 1993 auf 4% in den Jahren 2002 bis 2004. Während des Beobachtungszeitraumes kam es zu einem signifikanten Anstieg organbegrenzter Karzinome von 47% auf 79% (r = 0,774; p < 0,01). Stadien mit schlechter Prognose zeigten einen deutlichen Rückgang, so sank die Rate an pT3b Tumoren von 26% auf 3% (r = −0,729; p < 0,01). SCHLUSSFOLGERUNG: Während der Jahre 1993 und 2004 kam es zu einem dramatischen Anstieg an Prostatakarzinomen, die ausschließlich auf Grund eines erhöhten PSA-Wertes diagnostiziert wurden. Ebenso zeigte sich eine signifikante Verschiebung hin zu organbegrenzten Tumoren mit guter Prognose. Unsere Daten bestätigen Trends, die in den Vereinigten Staaten vor etwa 6 bis 8 Jahren beobachtet wurden.SummaryAIM: To analyze trends of clinical and tumor characteristics over a 12-year period since the beginning of the prostate-specific antigen (PSA) era in a consecutive series of radical prostatectomies. PATIENTS AND METHODS: Between 1993 and 2004 a consecutive series of 1351 patients underwent radical prostatectomy for clinically localized prostate cancer (PC) in a single institution. Clinical and histopathological information was entered into our computer database and analyzed for changes over time. RESULTS: The annual frequency of surgical interventions increased from 43 to 160 (272%) during the observation period (r = 0.930; p < 0.01). The detection of PC based solely on pathological PSA levels rose impressively from 7% to 70% (r = 0.986; p < 0.01). The rates of organ-confined disease also increased significantly from 47% to 79% (r = 0.774; p < 0.01). Stage pT3a decreased somewhat from 28% to 18% (r = −0.389; n.s.) whereas pT3b decreased significantly from 26% to 3% (r = −0.729; p < 0.01). CONCLUSION: During the 12-year period, PC was increasingly detected on the basis of a pathological PSA level only and shifted significantly to more organ-confined stages. With a time delay, these findings are consistent with trends observed in large centers in the USA.

Prostate cancers detected by saturation repeat biopsy impairs the Partin tables’ accuracy to predict final pathological stage

Study Type – Diagnostic (exploratory cohort)

307 PARTIN TABLES′OVERALL ACCURACY TO PREDICT FINAL PATHOLOGICAL STAGE DETERIORATES IN PATIENTS WITH PROSTATE CANCERS DETECTED BY SATURATION RE-BIOPSY

low and intermediate risk vs. high risk). The BRFS rates in the NCCN low-, intermediate-, and high-risk groups were 79.8%, 82.6%, and 46.8%, respectively (P 0.0001 at low and intermediate risk vs. high risk). There was no statistically significant difference in BRFS between low-and intermediate-group in any risk stratifications. CONCLUSIONS: The present risk stratification systems applied for biochemical recurrence after surgery could not discriminate Lowand Int-risk group in Japanese population. A new risk stratification is necessary for Asian population.