PSA Era Research Articles

Active surveillance of localized disease offers improved survival in the PSA era

Prostate cancer: Active surveillance of localized disease offers improved survival in the PSA era

TMPRSS2–ERG gene fusion status in minute (minimal) prostatic adenocarcinoma

Minute prostatic adenocarcinomas are considered to be of insufficient virulence. Given recent suggestions of TMPRSS2–ERG gene fusion association with aggressive prostatic adenocarcinoma, we evaluated the incidence of TMPRSS2–ERG fusion in minute prostatic adenocarcinomas. A total of 45 consecutive prostatectomies with minute adenocarcinoma were used for tissue microarray construction. A total of 63 consecutive non-minimal, Gleason Score 6 tumors, from a separate PSA Era prostatectomy tissue microarray, were used for comparison. FISH was carried out using ERG break-apart probes. Tumors were assessed for fusion by deletion (Edel) or split (Esplit), duplicated fusions and low-level copy number gain in normal ERG gene locus. Minute adenocarcinomas: Fusion was evaluable in 32/45 tumors (71%). Fifteen out of 32 (47%) tumors were positive for fusion. Six (19%) were of the Edel class and 7 (22%) were classified as combined Edel+Esplit. Non-minute adenocarcinomas (pT2): Fusion was identified in 20/30 tumors (67%). Four (13%) were of Edel class and 5 (17%) were combined Edel+Esplit. Duplicated fusions were encountered in 5 (16%) tumors. Non-minute adenocarcinomas (pT3): Fusion was identified in 19/33 (58%). Fusion was due to a deletion in 6 (18%) tumors. Seven tumors (21%) were classified as combined Edel+Esplit. One tumor showed Esplit alone. Duplicated fusions were encountered in 3 (9%) cases. The incidence of duplicated fusions was higher in non-minute adenocarcinomas (13 vs 0%; P=0.03). A trend for higher incidence of low-level copy number gain in normal ERG gene locus without fusion was noted in non-minute adenocarcinomas (10 vs 0%; P=0.07). We found a TMPRSS2–ERG fusion rate of 47% in minute adenocarcinomas. The latter is not significantly different from that of grade matched non-minute adenocarcinomas. The incidence of duplicated fusion was higher in non-minute adenocarcinomas. Our finding of comparable rate of TMPRSS2–ERG fusion in minute adenocarcinomas may argue against its value as a marker of aggressive prostate carcinoma phenotype.

A Large Proportion of Patients with Prostate Cancer Undergoing Androgen Deprivation Therapy Continue to Die from Non-Cancer Causes in the PSA Era

Objective: This study was conducted to determine the cause of death in patients receiving ADT for PCa in the PSA era. Patients and methods: We followed 618 patients (mean age 73 years) with PCa initiating ADT from October 1999 to October 2007. Patients were recruited from urology clinics. Patients were regularly reviewed in a dedicated PCa clinic. Cause of death was recorded prospectively, after review of medical case notes and biochemical parameters. Results: At median follow-up of 6.7 years, there were 377 deaths (61% mortality). Of these, 176 (47%) were attributable to PCa. Non-cancer deaths ( n = 201) were predominantly cardiovascular ( n = 125) and respiratory ( n = 43). Overall median presenting PSA was 37 ng/ml (range 0.4–5599), significantly higher ( P < 0.001) in those dying from PCa (115 ng/ml) than from other causes (18 ng/ml). PCa specific mortality increased with PSA at presentation (14% for PSA < 50 ng/ml, 45% for 50–100 ng/ml and 69% for > 100 ng/ml). When stratified for presenting age, PCa deaths were 70% (46/66) for men 60–69 years, 47% (85/180) for 70–79 years and 34% (45/131) for >80 years. Conclusions: Many patients with PCa initiating ADT continue to die from non-cancer causes in an era of widespread PSA testing, the proportion increasing with older age at presentation. This may justify deferring hormonal treatment in suitable older asymptomatic men, sparing the burden of long-term ADT. Patients with PCa who require hormonal therapy should be assessed for cardiovascular and respiratory risk factors at the time of presentation.

Editorial Comment

The authors evaluate the impact of bilateral nerve-sparing technique on pathologic and functional outcomes of a large cohort of men who underwent robotic radical prostatectomy by 3 experienced surgeons. Some limitations of this study, as discussed by the authors, are the retrospective nature of the analysis, and the fact that the “extrafascial dissection” was initiated in 2006; therefore, by their own criteria, 10.4% of the patients in the IF group would have had EF dissection if they had undergone surgery after 2006. Also, the series is sequential, so the most recent patients have the benefit of increased surgeon experience and probably a slightly lower risk of disease because of stage migration in the PSA era, and the questionnaire data are absent in 25% of the cohort. The most significant limitation, however, is that multivariate analysis to examine the independent effect of nerve-sparing technique on positive margins and sexual function is not performed. Results that appear positive in univariate analysis may be affected by subtle prostate cancer risk, age, or era of treatment differences. 1 Nelles J.L. Freedland S.J. Presti Jr, J.C. et al. Impact of nerve sparing on surgical margins and biochemical recurrence: results from the SEARCH database. Prostate Cancer Prostatic Dis. 2009; 12: 172-176 Crossref PubMed Scopus (22) Google Scholar We congratulate the authors for the prospective data collection, validated quality of life data, and the comprehensive reporting of their pathologic information. Extrafascial Versus Interfascial Nerve-sparing Technique for Robotic-assisted Laparoscopic Prostatectomy: Comparison of Functional Outcomes and Positive Surgical Margins CharacteristicsUrologyVol. 74Issue 3PreviewTo evaluate the pathologic and functional outcomes of patients with bilateral interfascial (IF) or extrafascial nerve-sparing (EF-NSP) techniques. It is believed that the IF-NSP technique used during robotic-assisted radical prostatectomy (RARP) spares more nerve fibers, while EF dissection may lower the risk for positive surgical margins (PSM). Full-Text PDF Editorial CommentUrologyVol. 74Issue 3PreviewIn this issue of Urology, Shikanov et al report the results of nerve-sparing radical prostatectomy in a large, prospective cohort.1 Three experienced surgeons used a partial extrafascial approach for moderately aggressive cancer and an interfascial approach for less aggressive cancer. Full-Text PDF ReplyUrologyVol. 74Issue 3PreviewWe appreciate the thoughtful and valid editorial comments. However, some issues have to be considered and reiterated. Full-Text PDF Editorial CommentUrologyVol. 74Issue 3PreviewThe introduction of robotic procedures for prostate cancer surgery is an unquestionably exciting development for the field of urology, much as that for any scientific discovery or innovative biotechnology brought to this field. However, for this application to be considered a major advancement, it must undergo proper and responsible evaluation of its merits. The touted advantages of robotic radical prostatectomy include reduced surgical blood loss and improved visualization during surgery, and claims have also been put forward that the surgery affords equivalent, if not heightened, outcomes of oncologic control and functional recovery of erectile function and urinary continence, when compared to the conventional open surgical approaches. Full-Text PDF

Use of an inhibitor of differentiation-1 (Id1) expression (exp) to discriminate good prognosis (GP) from poor prognosis (PP) prostate cancer (PCa)

e16128 Background: In the PSA era a significant proportion of PCa patients (pts) at onset have potential indolent tumors that will not impact their life expectancy or quality of life. Most of them will be radically treated and suffer its consequences. Thus, PCa overtreatment is a great concern among clinicians. Pre-treatment molecular factors may help differentiate indolent from aggressive PCa. Id1, involved in cell differentiation and angiogenesis, has recently showed to mediate lung metastasis (mts) from breast cancer. Its role in PCa endothelial (end) cells is well established but its exp and role in PCa cells is controversial. Using a new monoclonal antibody (MoAb) (195–14) for immunohistochemistry (IHC), Id1 exp is limited to some PP breast and bladder tumors. Whether Id1 exp is relevant in PCa prognosis is unknown. We tested 195–14 in PP and GP PCa samples and matched mts where available. Methods: 52 PCa pts were studied, 20 GP + 32 PP. All formalin-fixed and paraffin-embedded primary biopsies and matched mts of 16 of them were stained for tumor and end cell Id1 exp. 195–14 (1:500), (Biocheck), was used for IHC. Results: GP group: median age 65, all pts T2N0M0, median Gleason score 6 (6–9), median PSA at onset 5,5 ng/ml. After a median follow-up of 38 months (ms) 1 pt showed radiological and PSA progression (P); other PSA P. All but one remain alive. PP group: median age was 70, T3-T4 (70%), Gleason 8–10 (61%), median PSA at onset 58 ng/ml, 2 or more mts locations (79%), 94% showed P to docetaxel, median time-to- progression and overall survival after chemotherapy were 18 weeks and 7 ms. Among PP, 39% of primary PCa and 38% of mts showed Id1 tumor cell exp and 79% of primary tumors and 81% of mts showed end Id1 exp. In the GP group 0% showed Id1 tumor cell exp, and 50% showed end Id1 exp. The unexpected Id1 exp difference in tumor cells in PP compared to GP pts predicted clinical outcome. Consistently with other reports end Id1 exp is high in both groups. PP showed higher levels. Conclusions: Id1 exp discriminated GP from PP in our PCa cohort. These novel results highlight Id1 as a prognostic marker in PCa. Whether Id1 exp in the diagnostic biopsy can impact PCa therapeutic decision-making needs further investigation. No significant financial relationships to disclose.

Indications and timing for prostate biopsy, diagnosis of early stage prostate cancer and its definitive treatment: A clinical conundrum in the PSA era

The use of PSA for prostate cancer screening has led to a large increase in the number of men undergoing transrectal ultrasonography (TRUS) - guided biopsy of the prostate to determine the presence of prostate cancer. Recently, the indications for prostate biopsy based on PSA level have been questioned and new prostate cancer risk calculators that consider other factors related to prostate cancer have been proposed. Also, there have been significant changes over the years regarding the protocols used to sample the prostate. Most protocols recommend more extensive sampling of the prostate with more laterally directed biopsies of the peripheral zone for both initial and subsequent biopsies. There is still much controversy over the appropriate number and location of biopsy cores, and timing to optimize the diagnosis of prostate cancer on initial and repeat biopsy. Finally, discovery of a new molecular marker independent of the PSA level will be very important in the diagnosis and prognosis of prostate cancer.

The Role of Prostate Specific Membrane Antigen and Pepsinogen C Tissue Expression as an Adjunctive Method to Prostate Cancer Diagnosis

The diagnosis of prostate cancer in men with persistently increased prostate specific antigen after a negative prostate biopsy has become a great challenge for urologists and pathologists. We analyzed the diagnostic value of 6 genes in the tissue of patients with prostate cancer. The study was comprised of 50 patients with localized disease who underwent radical prostatectomy. Gene selection was based on a previous microarray analysis. Among 4,147 genes with different expressions between 2 pools of patients 6 genes (PSMA, TMEFF2, GREB1, TH1L, IgH3 and PGC) were selected. These genes were tested for diagnostic value using the quantitative reverse transcription polymerase chain reaction method. Initially malignant tissue samples from 33 patients were analyzed and in the second part of the study we analyzed benign tissue samples from the other 17 patients with prostate cancer. The control group was comprised of tissue samples of patients with benign prostatic hyperplasia. Analysis of malignant prostatic tissue demonstrated that prostate specific membrane antigen was over expressed (mean 9 times) and pepsinogen C was under expressed (mean 1.3 x 10(-4) times) in all cases compared to benign prostatic hyperplasia. The other 4 tested genes showed a variable expression pattern not allowing for differentiation between benign and malignant cases. When we tested these results in the benign prostate tissues from patients with cancer, pepsinogen C maintained the expression pattern. In terms of prostate specific membrane antigen, despite over expression in most cases (mean 12 times), 2 cases (12%) presented with under expression. Pepsinogen C tissue expression may constitute a powerful adjunctive method to prostate biopsy in the diagnosis of prostate cancer cases.

The Specific Definition of High Risk Prostate Cancer Has Minimal Impact on Biochemical Relapse-Free Survival

Accurate categorization of high risk prostate cancer cases remains elusive. Various schemes based on clincopathological criteria have been proposed to stratify cases by presumed recurrence risk. We determined whether survival outcomes are dependent on the specific definition. The study population included men who underwent radical prostatectomy from 1987 to 1995 (708) and 1996 to 2007 (3,351). Patients who received adjuvant therapy or had no postoperative prostate specific antigen were excluded from analysis. High risk patients were identified based on 6 commonly used definitions. Biochemical failure was defined as a prostate specific antigen of 0.4 ng/ml or greater and increasing or initiation of salvage therapy. Estimates of biochemical relapse-free survival were generated with the Kaplan-Meier method. Hazard ratios for disease recurrence were estimated using Cox proportional hazards analysis. High risk patients determined by the 6 definitions demonstrated a 2.7 to 5.3-fold increased hazard of biochemical relapse, and 5 and 10-year biochemical relapse-free survival rates were 36% to 58% and 25% to 43%, respectively. When stratified by date of treatment high risk patients from 1987 to 1995 generally had worse biochemical relapse-free survival compared to those treated after 1996. Within each era the variation in biochemical relapse-free survival among various high risk definitions was not substantial. Biochemical relapse-free survival after radical prostatectomy does not vary substantially based on the specific definition of high risk prostate cancer. There is a trend toward improved biochemical relapse-free survival in patients treated more recently, perhaps reflecting stage migration or changes in surgical technique. The data suggest that high risk prostate cancer may represent a relatively homogeneous population.

Improvement in Clinical Outcomes with Prostate Radiotherapy at a Single Institution in the PSA Era

Improvement in Clinical Outcomes with Prostate Radiotherapy at a Single Institution in the PSA Era

Predictive Significance of Surgical Margin Status After Prostatectomy for Prostate Cancer During PSA Era

The presence of positive surgical margins (PSMs) after prostatectomy for prostate cancer has long been an indicator of poor survival outcomes. However, with the downstaging of cancer occurring in the prostate-specific antigen testing era, we sought to determine whether the risk associated with PSMs retains the same effect on prognosis as before the prostate-specific antigen testing era. Of the 3460 patients in the Columbia University Urologic Oncology database, 2215 (64%) were identified who had undergone radical prostatectomy from 1991 to 2005 and had sufficient pathologic data to be analyzed and >or=1 year of follow-up. Three epochs were chosen: 1991-1995, 1996-2000, and 2001-2005. The median age, preoperative prostate-specific antigen, and Gleason score was 61.6 years, 6 ng/mL, and 7, respectively, and >50% of patients had pathologic Stage T2 disease. On multivariate analysis, PSMs were a risk factor for biochemical failure for each epoch (P < .01). The Wald's test indicated that the significance of PSMs had not changed over time (P = .8). The contribution of PSMs to the accuracy of predicting biochemical failure in a multivariate model was found only for the earliest epoch, because it improved the model by 0.15 (95% confidence interval 0.03-0.27). In the second epoch, it was 0.13 (95% confidence interval -0.01 to 0.27), and it was 0.13 for the third (95% confidence interval -0.06 to 0.32). The results of this study suggest that the predictive contribution of PSMs to the accuracy of a multivariate model or nomogram used to predict the outcomes after prostatectomy has decreased during the past 15 years.

Family history of prostate and breast cancer and the risk of prostate cancer in the PSA era

A family history of prostate cancer (PCa) or breast cancer (BCa) has been associated with the risk of PCa, but the risks were inconsistent in terms of the affected family members, and data in the PSA era are limited. This study included a subcohort of the Health Professionals Follow-Up Study composed of a highly PSA screened population from 1986 to 2004 with 3,695 PCa cases identified. Questionnaires and a food frequency questionnaire were administered every other and every 4 years, respectively. Family history of PCa and BCa was ascertained in 1990, 1992, and 1996. All statistics were two-sided. A family history of PCa in both a father and brother(s) was associated with a 2.3-fold increased risk of PCa [95% confidence interval (CI) = 1.76-3.12]. Men with a father or brother(s) with a PCa diagnosis at age<60 and >or=60 had 2.16- and 1.95-fold increased risk of PCa, respectively. A family history of PCa was related to early-onset PCa (<65 years: RR = 2.25, 95% CI = 1.95-2.60) and weakly to late-onset PCa (>or=65 years: RR = 1.67, 95% CI = 1.52-1.85). History of BCa in a mother or a sister was associated with a 1.22-fold increased risk of PCa (95% CI = 1.08-1.38). A family history of PCa or BCa significantly increases PCa risk. These associations are evident in a population with widespread PSA screening.

Association between plasma cholesterol and prostate cancer in the PSA era.

We previously found that statin users had a lower risk of advanced and possibly high-grade prostate cancer compared with nonusers. We hypothesize that statins' effects on cholesterol synthesis may explain those findings because prostate cancer cells exhibit cholesterol dysregulation. Thus, we investigated whether low plasma cholesterol is associated with prostate cancer overall and by stage and grade. Participants were drawn from the 18,018 members of the Health Professionals Follow-Up Study who provided blood in 1993-1995. We ascertained 698 incident cases through January 2000. Controls were 698 men who had a PSA test and were matched to cases. Plasma cholesterol was measured enzymatically. Conditional logistic regression was used to estimate multivariable ORs and 95% CIs of total, clinically organ-confined (n = 518), advanced (T3b or worse; n = 61), low-grade (Gleason sum < 7; n = 386) and high-grade (Gleason sum > or = 7, n = 247) disease. Low cholesterol (<25th percentile vs. > or =25th percentile) was not associated with total (OR = 0.93, 95% CI: 0.72-1.20), organ-confined (OR = 0.87, 95% CI: 0.64-1.18) or low-grade (OR = 1.06, 95% CI: 0.75-1.51) disease. However, men with low cholesterol had a lower risk of high-grade disease (OR = 0.61, 95% CI: 0.39-0.98), especially if organ-confined (OR = 0.54, 95% CI: 0.29-0.99). The association for advanced disease appeared inverse, but number of cases was small (OR = 0.42, 95% CI: 0.13-1.36). Associations remained after excluding cholesterol-lowering drug users. These results coupled with prior statin findings suggest that mechanistic studies on cholesterol metabolism should be pursued to understand a possible target for preventing poorly differentiated prostate cancers.

Probability of finding T1a and T1b (Incidental) prostate cancer during TURP has decreased in the PSA era

The purpose of this study is to assess the likelihood of detecting stage T1a and T1b cancer in transurethral prostatectomy specimens during the PSA era. Comparison was made of transurethral resection of prostate (TURP) cohorts in the pre-PSA era (1986-1987) and the PSA era (1994-2000), excluding patients with known PCa. A total of 228 men without a known history of prostate cancer underwent TURP during the pre-PSA era time frame and 501 underwent the procedure during the PSA era time frame. Malignancy diagnosed at the time of TURP decreased from 14.9 to 5.2% of patients in the pre-PSA and PSA eras, respectively. Stage T1a decreased from 4.4 to 2.4% and Stage T1b decreased from 10.5 to 2.8% of patients in the pre-PSA and PSA eras, respectively (P<0.001, Fisher's exact test). Prostate cancer newly identified during TURP has decreased significantly in the era of PSA screening in our study population, with the most significant drop being in clinically significant stage T1b. The decrease in TURP rates reduces the overall incidence of T1a/b cancer but cannot explain the lower risk of detecting previously unsuspected cancer at the time of any given TURP. Identification of many men with occult prostate cancer before TURP through screening and early detection is the most likely cause of this finding. These data suggest that men considering surgical or medical management of benign prostatic hyperplasia may be informed that it should be infrequent that men properly evaluated for prostate cancer will harbor clinically significant undetected malignancy.

Lower Mortality After Prostatectomy in ‘PSA Era’

Lower Mortality After Prostatectomy in ‘PSA Era’

Improved 10-year outcomes for prostate cancer patients with Gleason 7-10 treated with high-dose-rate brachytherapy boost in the PSA era

Improved 10-year outcomes for prostate cancer patients with Gleason 7-10 treated with high-dose-rate brachytherapy boost in the PSA era

Prostate Cancer Prognosis Favorable in PSA Era

Prostate Cancer Prognosis Favorable in PSA Era

Detection of Prostate Cancer via Biopsy in the Medicare–SEER Population During the PSA Era

Detection of Prostate Cancer via Biopsy in the Medicare–SEER Population During the PSA Era

Improved 10-year Outcomes for Prostate Cancer Patients With Gleason 8–10 Treated With Intensity Modulated High Dose Rate Brachytherapy Boost in the PSA Era

Improved 10-year Outcomes for Prostate Cancer Patients With Gleason 8–10 Treated With Intensity Modulated High Dose Rate Brachytherapy Boost in the PSA Era

Changes in Prognostic Significance and Predictive Accuracy of Gleason Grading System Throughout PSA Era: Impact of Grade Migration in Prostate Cancer

To describe the changes in the Gleason grading system over time and evaluate how a shift in Gleason grading has affected the overall predictive accuracy of the system in predicting biochemical disease-free survival after radical prostatectomy. The Columbia University Urologic Oncology Database was reviewed, and 1515 patients who met the inclusion criteria were identified who had undergone radical prostatectomy from 1988 to 2004. The patients were divided into two time cohorts (1988 to 1997 and 1998 to 2004). To determine whether a shift in the Gleason sum distribution has occurred, a chi-square test was performed. Survival curves and log-rank tests were used to compare the biochemical disease-free survival between cohorts stratified by the Gleason sum. To estimate the predictive ability of the Gleason system over time, concordance indexes were calculated. A shift toward greater Gleason sums over time was confirmed using the chi-square test (P <0.001). A significant difference was observed in biochemical disease-free survival between the two time cohorts for those with Gleason sum 6 cancer (P <0.01). The concordance indexes corresponding to Gleason sum alone for each time cohort were 0.71 and 0.87, demonstrating that the Gleason sum's predictive ability improved significantly over time. After adjusting for other variables, the Gleason sum continued to demonstrate a significantly improved predictive ability in the more recent time cohort. We found a trend toward the assignment of increasing Gleason sums over time in our data set. This shift in Gleason sum distribution between the two time cohorts has resulted in a significant improvement in the predictive ability of the Gleason system.

Editorial Comment on: Predictive Factors for Progression in Patients with Clinical Stage T1a Prostate Cancer in the PSA Era

Editorial Comment on: Predictive Factors for Progression in Patients with Clinical Stage T1a Prostate Cancer in the PSA Era