Margit Fisch

Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging.

BACKGROUND Knowledge about the staging significance of the prostate cancer antigen 3 (PCA3) score to better identify pathologic features after radical prostatectomy (RP) is limited and controversial. OBJECTIVE Our aim was to study the clinical staging significance of PCA3 to identify pathologic favorable and/or unfavorable features in the RP specimen. DESIGN, SETTING, AND PARTICIPANTS Complete retrospective clinical and pathologic data of consecutive men who had undergone RP from three tertiary referral centers including preoperative PCA3 scores (n=305) and computer-assisted planimetrically measured tumor volume data (n=160) were available. INTERVENTION All patients were treated with RP. MEASUREMENTS PCA3 scores were assessed using the PROGENSA assay (Gen-Probe, San Diego, CA, USA). Beyond standard risk factors (age, digital rectal examination, prostate-specific antigen, prostate volume, biopsy Gleason score, percentage of positive cores), five different PCA3 codings were used in logistic regression models to identify five distinct pathologic end points: (1) low-volume disease (<0.5 ml), (2) insignificant prostate cancer (PCa) according to the Epstein criteria, (3) extracapsular extension (ECE), (4) seminal vesicle invasion (SVI), and (5) aggressive disease defined as Gleason sum ≥7. Accuracy estimates of each end point were quantified using the area under the curve (AUC) of the receiver operator characteristic analysis in models with and without PCA3. RESULTS AND LIMITATIONS PCA3 scores were significantly lower in low-volume disease and insignificant PCa (p ≤ 0.001). AUC of multivariable low-volume disease (+2.4 to +5.5%) and insignificant PCa models (+3 to +3.9%) increased when PCA3 was added to standard clinical risk factors. In contradistinction, regardless of its coding, PCA3 scores were not significantly elevated in pathologically confirmed ECE (p=0.4) or SVI (p=0.5), respectively. Higher PCA3 scores were associated with aggressive disease (p<0.001). Importantly, the addition of PCA3 to multivariable intermediate- and high-grade models did not improve prediction. Despite reporting the largest pathologic PCA3 study, the main limitation resides in its small sample size. CONCLUSIONS PCA3 was confirmed as a valuable predictor of pathologically confirmed low-volume disease and insignificant PCa. Further exploration of its role as an additional marker to select patients for active surveillance may be warranted. In contradistinction, assessment of pathologically advanced or aggressive PCa is not improved using PCA3.

Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer

Purpose: The HER2 oncogene is involved in the biology of many different tumor types and serves as a prognostic marker and a therapeutic target in breast cancer. In contrast to breast cancer, studies on Her2 overexpression and gene amplification in prostate cancer have yielded different results. The purpose of this study was to learn more on the prevalence and clinical significance of HER2 amplification and overexpression in prostate cancer. Experimental Design: A tissue microarray containing >2,000 prostate cancers with follow-up data was used. Tissue microarray sections were analyzed on protein and DNA level using two different antibodies (HercepTest, DAKO; Novocastra NCL-CB11) and fluorescence in situ hybridization. Results: Immunohistochemical analyses showed highly similar results for both antibodies. Detectable Her2 immunostaining was observed in 17.2% for the HercepTest and in 22.5% for the Novocastra antibody with the vast majority of cases showing 1+ or 2+ staining. For both antibodies (HercepTest/Novocastra), significant associations were found between positive staining and high Gleason grade (P < 0.0001, both), advanced pT stage (P < 0.0001/P = 0.0015), rapid tumor cell proliferation (P = 0.0004/P = 0.0071), and tumor recurrence (P < 0.0001, both). HER2 amplification was only found in 1 of 2,525 analyzable cases (0.04%). Conclusions: Low-level Her2 overexpression occurs at relevant frequency in prostate cancer and in the absence of gene amplification. Increased Her2 expression may potentially lead to an aggressive behavior of tumor cells through the stimulation of tumor cell proliferation because Her2 staining was shown to be significantly associated with Ki67 labeling index. These data argue for reconsidering anti-Her2 therapy, possibly with modified approaches. Clin Cancer Res; 16(5); 1553–60

Inverse stage migration in patients undergoing radical prostatectomy: results of 8916 European patients treated within the last decade

Study Type – Therapy (case series)

Radical prostatectomy improves progression‐free and cancer‐specific survival in men with lymph node positive prostate cancer in the prostate‐specific antigen era: a confirmatory study

Study Type – Therapy (outcomes research)
Level of Evidence 2b

Chromosome 8p deletions and 8q gains are associated with tumor progression and poor prognosis in prostate cancer.

Purpose: Deletions of 8p and gains of 8q belong to the most frequent cytogenetic alterations in prostate cancer. The target genes of these alterations and their biological significance are unknown. Experimental Design: To determine the relationship between chromosome 8 changes, and prostate cancer phenotype and prognosis, a set of 1.954 fully annotated prostate cancers were analyzed in a tissue microarray format by fluorescence in situ hybridization. Results: Both 8p deletions and 8q gains increased in number during different stages of prostate cancer progression. 8p deletions/8q gains were found in 26.1%/4.8% of 1,239 pT2 cancers, 38.5%/9.8% of 379 pT3a cancers, 43.5%/8.9% of 237 pT3b cancers, 40.7%/14.8% of 27 pT4 cancers, 39.1%/34.8% of 23 nodal metastases, 51.9%/33.3% of 27 bone metastases, and 45.5%/59.9% of 22 hormone refractory cancers (P < 0.0001 each). Both 8p deletions and 8q gains were also significantly associated with high Gleason grade and with each other (P < 0.0001 each). In primary tumors, 8p deletions were seen in only 27.3% of 1,882 cancers without 8q gain but in 57.4% of 122 tumors with 8q gain (P < 0.0001). Among cancers treated with radical prostatectomy, 8p deletions (P = 0.003) and 8q gains (P = 0.02) were associated with biochemical tumor recurrence. However, multivariate analysis (including prostate-specific antigen, pT/pN stage, Gleason score, and surgical margin status) did not reveal any statistically independent effect of 8p or 8q alterations on biochemical tumor recurrence. Conclusions: 8p deletions and 8q gains are relatively rare in early stage prostate cancer but often develop during tumor progression. The prognostic effect does not seem to be strong enough to warrant clinical application. Clin Cancer Res; 16(1); 56–64

External Validation of Urinary PCA3-Based Nomograms to Individually Predict Prostate Biopsy Outcome

BACKGROUND Prior to safely adopting risk stratification tools, their performance must be tested in an external patient cohort. OBJECTIVE To assess accuracy and generalizability of previously reported, internally validated, prebiopsy prostate cancer antigen 3 (PCA3) gene-based nomograms when applied to a large, external, European cohort of men at risk of prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS Biopsy data, including urinary PCA3 score, were available for 621 men at risk of PCa who were participating in a European multi-institutional study. INTERVENTION All patients underwent a ≥10-core prostate biopsy. Biopsy indication was based on suspicious digital rectal examination, persistently elevated prostate-specific antigen level (2.5-10 ng/ml) and/or suspicious histology (atypical small acinar proliferation of the prostate, >/= two cores affected by high-grade prostatic intraepithelial neoplasia in first set of biopsies). MEASUREMENTS PCA3 scores were assessed using the Progensa assay (Gen-Probe Inc, San Diego, CA, USA). According to the previously reported nomograms, different PCA3 score codings were used. The probability of a positive biopsy was calculated using previously published logistic regression coefficients. Predicted outcomes were compared to the actual biopsy results. Accuracy was calculated using the area under the curve as a measure of discrimination; calibration was explored graphically. RESULTS AND LIMITATIONS Biopsy-confirmed PCa was detected in 255 (41.1%) men. Median PCA3 score of biopsy-negative versus biopsy-positive men was 20 versus 48 in the total cohort, 17 versus 47 at initial biopsy, and 37 versus 53 at repeat biopsy (all p≤0.002). External validation of all four previously reported PCA3-based nomograms demonstrated equally high accuracy (0.73-0.75) and excellent calibration. The main limitations of the study reside in its early detection setting, referral scenario, and participation of only tertiary-care centers. CONCLUSIONS In accordance with the original publication, previously developed PCA3-based nomograms achieved high accuracy and sufficient calibration. These novel nomograms represent robust tools and are thus generalizable to European men at risk of harboring PCa. Consequently, in presence of a PCA3 score, these nomograms may be safely used to assist clinicians when prostate biopsy is contemplated.

Location of the Primary Tumor is Not an Independent Predictor of Cancer Specific Mortality in Patients With Upper Urinary Tract Urothelial Carcinoma

PURPOSE The prognostic significance of renal pelvis vs ureteral upper urinary tract urothelial carcinoma tumor location is controversial. We assessed the prognostic significance of upper urinary tract urothelial carcinoma tumor location in a large, population based data set. MATERIALS AND METHODS Our analyses relied on 2,824 patients treated with nephroureterectomy for upper urinary tract urothelial carcinoma within 9 SEER registries between 1988 and 2004. Univariable and multivariable models tested the effect of tumor location on cancer specific mortality rates. Covariates consisted of age, race, SEER registry, gender, type of surgery (nephroureterectomy with vs without bladder cuff removal), pT stage, pN stage, grade and year of surgery. RESULTS Relative to ureteral tumors renal pelvis tumors were of higher stage (T3/T4 disease 38.4% vs 57.9%, p <0.001) and had a higher rate of lymph node metastases (6.0% vs 9.8%, p = 0.003) at nephroureterectomy. The respective 5-year cancer specific mortality-free survival estimates were 81.0% vs 75.5% (p = 0.007). However, after multivariable adjustment tumor location failed to reach independent predictor status of cancer specific mortality (p = 0.8). CONCLUSIONS To our knowledge this is the largest cohort in which the impact of upper urinary tract urothelial carcinoma tumor location on cancer specific mortality was examined. At nephroureterectomy renal pelvis tumors had significantly more advanced T and N stages compared to ureteral tumors. However, after adjustment for stage, grade and other covariates tumor location did not independently predict cancer specific mortality. Thus, the biological behavior of renal pelvis vs ureteral tumors is the same after nephroureterectomy as long as stage, grade, and other patient and tumor characteristics are accounted for.

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.

Prognostic Role and HER2 Expression of Circulating Tumor Cells in Peripheral Blood of Patients Prior to Radical Cystectomy: A Prospective Study

BACKGROUND Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB). OBJECTIVE Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB. DESIGN, SETTING, AND PARTICIPANTS Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization. INTERVENTION Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy. MEASUREMENTS Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis. RESULTS AND LIMITATIONS CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1-100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤ 0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤ 0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size. CONCLUSIONS Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials.

Penile Implantation in Europe: Successes and Complications with 253 Implants in Italy and Germany

INTRODUCTION Results for prosthesis implantation from everyday clinical practice within Europe are few. This report provides data on the most commonly used penile prostheses (the American Medical Systems [AMS] series). AIM The study aimed to assess, retrospectively, complications and patient satisfaction with AMS penile implants in 253 consecutive patients with erectile dysfunction from three European centers. METHODS Pre, intra- and postoperative data were obtained from chart review, with a mean follow-up of 60 months; 200 patients were available for evaluation. Patient satisfaction data were collected using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire. MAIN OUTCOME MEASURE Complications and patient satisfaction were assessed. Patient satisfaction was evaluated using a standardized assessment tool (the modified EDITS questionnaire). RESULTS Major postoperative complications occurred in 40 (20%) patients, including 9 (22.5%) prosthesis infections, 18 (45%) mechanical failures, and 13 (32.5%) erosions. Patient satisfaction with the AMS 700CX, AMS Ambicor, and AMS 600-650 was 97%, 81%, and 75%, respectively; dissatisfaction was 0%, 5%, and 6%, respectively. Partner satisfaction with the AMS 700CX, AMS Ambicor, and AMS 600-650 was 91%, 91%, and 75%, respectively; dissatisfaction was 0%, 5%, and 6%, respectively. Erections were more natural (harder) than before with the AMS 700CX, AMS Ambicor, and AMS 600-650 in 91%, 85%, and 88%, respectively; hardness was the same as before in 9%, 15%, and 13%, respectively; no erections were less hard than before. CONCLUSIONS Postoperative complications differed from those reported in the literature, while patient satisfaction rates were roughly similar. The reporting of specific data for different implant types, plus the use of standardized assessment tools for patient satisfaction is significant as in the future, it will allow comparison of data between centers performing penile prosthesis implants using these devices.