The Mitochondrial and Autosomal Mutation Landscapes of Prostate Cancer

Background

Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression.

Objective

To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected.

Design, setting, and participants

Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available.

Outcome measurements and statistical analysis

Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature.

Results and limitations

Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for.

Conclusions

The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology.     

Expression of the Androgen-Regulated Fusion Gene TMPRSS2-ERG Does Not Predict Response to Endocrine Treatment in Hormone-Naïve,Node-Positive Prostate Cancer

Background

Fusion of the androgen-regulated gene transmembrane protease, serine 2, TMPRSS2, to the v-ets erythroblastosis virus E26 oncogene homolog (avian), ERG, of the erythroblast transformation-specific (ETS) family is the most common genetic alteration in prostate cancer (PCa).

Objective

To determine whether expression of androgen-regulated TMPRSS2-ERG predicts response to endocrine treatment in hormone-naïve, node-positive PCa.

Design, setting, and participants

Eighty-five patients with histologically confirmed, node-positive PCa who were without treatment at the moment of lymph node dissection were analysed. RNA was isolated from the paraffin-embedded lymph node metastases and complementary DNA (cDNA) was made. The quality of cDNA was tested by polymerase chain reaction (PCR) analysis of the expression of the housekeeping gene hydroxymethylbilane synthase, HMBS (formerly PBGD). TMPRSS2-ERG expression was analysed by PCR using a forward primer in TMPRSS2 exon 1 and a reverse primer in ERG exon 4.

Measurements

The primary end point was time from start of endocrine therapy to the occurrence of three consecutive rises in prostate-specific antigen (PSA) that were at least 2 wk apart and resulted in two 50% increases over the PSA nadir. Secondary end points were time to PSA nadir after start of endocrine treatment and cancer-specific and overall survival.

Results and limitations

TMPRSS2-ERG was expressed in 59% of the 71 patients who could be analysed. Median duration of response to endocrine therapy was 20.9 mo versus 24.1 mo for gene fusion–positive versus gene fusion–negative patients (95% confidence intervals: 18.6–23.1 vs 18.9–29.4, p = 0.70). Furthermore, no significant differences were seen between the two groups for the secondary end points.

Conclusions

Expression of TMPRSS2-ERG is frequent in lymph node metastases of patients with untreated PCa; however, expression of this androgen-regulated fusion gene did not correspond with duration of response to endocrine therapy. Our results suggest that expression of TMPRSS2-ERG is not a candidate marker to select for metastatic PCa patients who will benefit more from endocrine treatment.     

Prospective Multicentre Evaluation of PCA3 and TMPRSS2-ERG Gene Fusions as Diagnostic and Prognostic Urinary Biomarkers for Prostate Cancer

Background

Prostate cancer antigen 3 (PCA3) and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) gene fusions are promising prostate cancer (PCa) specific biomarkers that can be measured in urine.

Objective

To evaluate the diagnostic and prognostic value of Progensa PCA3 and TMPRSS2-ERG gene fusions (as individual biomarkers and as a panel) for PCa in a prospective multicentre setting.

Design, setting, and participants

At six centres, post–digital rectal examination first-catch urine specimens prior to prostate biopsies were prospectively collected from 497 men. We assessed the predictive value of Progensa PCA3 and TMPRSS2-ERG (quantitative nucleic acid amplification assay to detect TMPRSS2-ERG messenger RNA [mRNA]) for PCa, Gleason score, clinical tumour stage, and PCa significance (individually and as a marker panel). This was compared with serum prostate-specific antigen and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator. In a subgroup (n = 61) we evaluated biomarker association with prostatectomy outcome.

Outcome measurements and statistical analysis

Univariate and multivariate logistic regression analysis and receiver operating curves were used.

Results and limitations

Urine samples of 443 men contained sufficient mRNA for marker analysis. PCa was diagnosed in 196 of 443 men. Both PCA3 and TMPRSS2-ERG had significant additional predictive value to the ERSPC risk calculator parameters in multivariate analysis (p < 0.001 and resp. p = 0.002). The area under the curve (AUC) increased from 0.799 (ERSPC risk calculator), to 0.833 (ERSPC risk calculator plus PCA3), to 0.842 (ERSPC risk calculator plus PCA3 plus TMPRSS2-ERG) to predict PCa. Sensitivity of PCA3 increased from 68% to 76% when combined with TMPRSS2-ERG. TMPRSS2-ERG added significant predictive value to the ERSPC risk calculator to predict biopsy Gleason score (p < 0.001) and clinical tumour stage (p = 0.023), whereas PCA3 did not.

Conclusions

TMPRSS2-ERG had independent additional predictive value to PCA3 and the ERSPC risk calculator parameters for predicting PCa. TMPRSS2-ERG had prognostic value, whereas PCA3 did not. Implementing the novel urinary biomarker panel PCA3 and TMPRSS2-ERG into clinical practice would lead to a considerable reduction of the number of prostate biopsies.     

A 36-gene Signature Predicts Clinical Progression in a Subgroup of ERG-positive Prostate Cancers

Background

The molecular basis of the clinical heterogeneity of prostate cancer (PCa) is not well understood.

Objective

The purpose of our study was to identify and characterize genes in a clinically relevant gene expression signature in a subgroup of primary PCa positive for transmembrane protease, serine 2 (TMPRSS2)–v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG).

Design, setting, and participants

We studied gene expression profiles by unsupervised hierarchical clustering in 48 primary PCas from patients with a long clinical follow-up. Results were correlated with clinical outcome and validated in an independent patient cohort. Selected genes from a defined classifier were tested in vitro for biologic properties.

Intervention

Initial treatment of primary tumors was radical prostatectomy.

Outcome measurements and statistical analysis

Associations between clinical and histopathologic variables were evaluated by the Pearson χ² test, Mann-Whitney U test, or Kruskal-Wallis test, where appropriate. The log-rank test or Breslow method was used for statistical analysis of Kaplan-Meier survival curves.

Results and limitations

Most tumors that overexpressed ERG clustered separately from other primary PCas. No differences in any clinical end points between ERG-positive and ERG-negative cancers were detected. Importantly, within the ERG-positive samples, two subgroups were identified, which differed significantly in prostate-specific antigen recurrence-free survival, and cancer-specific and overall survival. From our findings, we defined a gene expression classifier of 36 genes. In a second, completely independent tumor set, the classifier also distinguished ERG-positive subgroups with different clinical outcome. In both patient cohorts, the classifier was not predictive in ERG-negative tumors. Biologic processes regulated by genes in the classifier included cell adhesion and bone remodeling. Tumor growth factor-β signaling was indicated as the main differing signaling pathway between the two ERG subgroups. In vitro biologic assays of two selected genes from the classifier (inhibin, beta A [INHBA] and cadherin 11, type 2, OB-cadherin (osteoblast) [CDH11]) supported a functional role in PCa progression. Possible multifocality and limited number of PCa samples can be limitations of the study.

Conclusions

The classifier identified can contribute to prediction of tumor progression in ERG-positive primary prostate tumors and might be instrumental in therapy decisions.     

Prostate Cancer Gene 3 (PCA3): Development and Internal Validation of a Novel Biopsy Nomogram

Background

Urinary prostate cancer gene 3 (PCA3) represents a promising novel marker of prostate cancer detection.

Objective

To test whether urinary PCA3 assay improves prostate cancer (PCa) risk assessment and to construct a decision-making aid in a multi-institutional cohort with pre–prostate biopsy data.

Design, setting, and participants

PCA3 assay cut-off threshold analyses were followed by logistic regression models which used established predictors to assess PCa-risk at biopsy in a large multi-institutional data set of 809 men at risk of harboring PCa.

Measurements

Regression coefficients were used to construct four sets of nomograms. Predictive accuracy (PA) estimates of biopsy outcome predictions were quantified using the area under the curve of the receiver operator characteristic analysis in models with and without PCA3. Bootstrap resamples were used for internal validation and to reduce overfit bias. The extent of overestimation or underestimation of the observed PCa rate at biopsy was explored graphically using nonparametric loss-calibration plots. Differences in PA were tested using the Mantel-Haenszel test. Finally, nomogram-derived probability cut-offs were tested to assess the ability to identify patients with or without PCa.

Results and limitations

PCA3 was identified as a statistically independent risk factor of PCa at biopsy. Addition of a PCA3 assay improved bootstrap-corrected multivariate PA of the base model between 2% and 5%. The highest increment in PA resulted from a PCA3 assay cut-off threshold of 17, where a 5% gain in PA (from 0.68 to 0.73, p = 0.04) was recorded. Nomogram probability–derived risk cut-off analyses further corroborate the superiority of the PCA3 nomogram over the base model.

Conclusions

PCA3 fulfills the criteria for a novel marker capable of increasing PA of multivariate biopsy models. This novel PCA3-based nomogram better identifies men at risk of harboring PCa and assists in deciding whether further evaluation is necessary.     

Alcohol Intake Increases High-grade Prostate Cancer Risk Among Men Taking Dutasteride in the REDUCE Trial

Background

Although most studies found no association between alcohol intake and prostate cancer (PCa) risk, an analysis of the Prostate Cancer Prevention Trial found that high alcohol intake significantly increased PCa risk among men randomized to the 5α-reductase inhibitor (5-ARI) finasteride.

Objective

Determine whether alcohol affects PCa risk among men taking the 5-ARI dutasteride.

Design, settings, and participants

Reduction by Dutasteride of Prostate Cancer Events was a 4-yr, multicenter, randomized, double-blind, placebo-controlled trial to compare PCa after dutasteride administration (0.5 mg/d) with placebo. Participants had a baseline prostate-specific antigen between 2.5 and 10.0 ng/ml and a recent negative prostate biopsy. Alcohol intake was determined by baseline questionnaire, and participants underwent a prostate biopsy to determine PCa status at 2 yr and 4 yr of follow-up.

Outcome measurements and statistical analysis

Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between alcohol intake and low-grade (Gleason <7) and high-grade (Gleason >7) PCa.

Results and limitations

Of 6374 participants in our analysis, approximately 25% reported no alcohol consumption, 49% were moderate drinkers (one to seven drinks per week), and 26% were heavy drinkers (more than seven drinks per week). Alcohol intake was not associated with low- or high-grade PCa in the placebo arm and was not associated with low-grade PCa among men taking dutasteride. In contrast, men randomized to dutasteride and reporting more than seven drinks per week were 86% more likely to be diagnosed with high-grade PCa (p = 0.01). Among alcohol abstainers, dutasteride was associated with significantly reduced risk of high-grade PCa (OR: 0.59; 95% CI, 0.38–0.90), but dutasteride was no longer associated with reduced high-grade PCa among men reporting high alcohol intake (OR: 0.99; 95% CI, 0.67–1.45).

Conclusions

Alcohol consumption negated a protective association between dutasteride and high-grade PCa.

Patient summary

We confirmed a prior study that alcohol affects PCa prevention in patients taking 5-ARIs. Patients taking 5-ARIs may wish to eliminate alcohol intake if they are concerned about PCa.     

Dutasteride Treatment Over 2 Years Delays Prostate-specific Antigen Progression in Patients with Biochemical Failure After Radical Therapy for Prostate Cancer: Results from the Randomised,Placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS)

Background

Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial.

Objective

To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy.

Design, setting, and participants

Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries.

Intervention

The 5α-reductase inhibitor, dutasteride.

Outcome measurements and statistical analysis

The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression.

Results and limitations

Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p < 0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35–76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p < 0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53–75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study.

Conclusions

Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience.

Clinical trial registry

ClinicalTrials.gov, NCT00558363.     

Performance of the Prostate Cancer Antigen 3 (PCA3) Gene and Prostate-Specific Antigen in Prescreened Men: Exploring the Value of PCA3 for a First-line Diagnostic Test

Background

The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene as a primary diagnostic is unknown.

Objective

Assess the value of PCA3 as a first-line diagnostic test.

Design, setting and participants

Participants included men aged 63–75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section.

Interventions

Lateral sextant biopsies were performed if the serum PSA value was ≥3.0 ng/ml and/or the PCA3 score was ≥10.

Measurements

Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0 ng/ml.

Results and limitations

In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ = 0.14; p < 0.0001). A PSA ≥3.0 ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade ≥4, n = 19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 ≥35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve [AUC]: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers.

Conclusions

PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population.     

Risk assessment of prostatic pathology in patients undergoing radical cystoprostatectomy

Objectives

To determine the incidence and location of prostate adenocarcinoma (PCa) and prostatic urothelial carcinoma (PUC) for patients undergoing radical cystoprostatectomy (RCP) for bladder cancer and to ascertain what preoperative information may be useful in predicting PUC or PCa in patients who may be candidates for prostate-sparing cystectomy.

Methods

Between 2001 and 2004, 235 consecutive patients underwent RCP and had whole-mount sections of the prostate. We reviewed our prospective radical cystectomy database for preoperative clinicopathological information associated with each patient. The bladder and whole-mount prostate sections were re-reviewed to determine the location and depth of the bladder tumor as well as the presence of any associated PCa and PUC.

Results

We identified 113 of 235 (48%) and 77 of 235 (33%) men with PCa and PUC, respectively. Among patients with PCa, 33 (29%) had Gleason score of ≥ 7, 25 (22%) had PCa tumor volume > 0.5 cc, and 15 (13%) had extracapsular extension. On multivariable analysis, only increasing age was significantly associated with PCa (odds ratio = 1.3, p = 0.046). Of the 77 with PUC, 28 (36%) had in situ disease only, while 49 (64%) had prostatic stromal invasion. Bladder tumor location in the trigone/bladder neck (p < 0.001) and bladder carcinoma in situ (p < 0.001) was strongly associated with PUC in the final specimen. Overall, 158 (67%) had either PCa or PUC in the prostate.

Conclusions

PCa and/or PUC is present in a majority of RCP specimens. Current preoperative staging and tumor characteristics are not adequate for determining who can safely be selected for prostate-sparing cystectomy.     

Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial

Background

Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa).

Objective

To assess outcomes following AS of men with screen-detected PCa.

Design, setting, and participants

Of the 968 men who were diagnosed with screen-detected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis.

Intervention

The study participants were followed at intervals of 3–12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage.

Outcome measurements and statistical analysis

The end points—overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival—were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS.

Results and limitations

Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failure-free survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 (p = 0.09), 3.6 (p = 0.002), and 4.6 (p = 0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up.

Conclusions

A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa.     

High-risk prostate cancer: from definition to contemporary management

Context

High-risk prostate cancer (PCa) is a potentially lethal disease. It is clinically important to identify patients with high-risk PCa early on because they stand to benefit the most from curative therapy. Because of recent advances in PCa management, a multimodal approach may be advantageous.

Objective

Define high-risk PCa, and identify the best diagnostic and treatment patterns for patients with clinically localized and locally advanced disease. A critical analysis of published results following monomodal and/or multimodal therapy for high-risk PCa patients was also performed.

Evidence acquisition

A review of the literature was performed using the Medline, Embase, Scopus, and Web of Science databases as well as the Cochrane Database of Systematic Reviews.

Evidence synthesis

High-risk PCa accounts for ≤15% of all new diagnoses. Compared with patients with low- and intermediate-risk PCa, patients with high-risk PCa are at increased risk of treatment failure. Unfortunately, no contemporary randomized controlled trials comparing different treatment modalities exist. Evaluation of the results published to date shows that no single treatment can be universally recommended. Most often, a multimodal approach is warranted to optimize patient outcomes.

Conclusions

A significant minority of patients continue to present with high-risk PCa, which remains lethal in some cases. Outcomes following treatment of men with high-risk tumors have not substantially improved over time. However, not all high-risk patients are at the same risk of PCa progression and death. At present, a multimodal approach seems the best way to achieve acceptable outcomes for high-risk PCa patients.     

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 man's 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.     

Assessment of Prostate Cancer Aggressiveness Using Dynamic Contrast-enhanced Magnetic Resonance Imaging at 3 T

Background

A challenge in the diagnosis of prostate cancer (PCa) is the accurate assessment of aggressiveness.

Objective

To validate the performance of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of the prostate at 3 tesla (T) for the assessment of PCa aggressiveness, with prostatectomy specimens as the reference standard.

Design, settings, and participants

A total of 45 patients with PCa scheduled for prostatectomy were included. This study was approved by the institutional review board; the need for informed consent was waived.

Outcome measurements and statistical analysis

Subjects underwent a clinical MRI protocol including DCE-MRI. Blinded to DCE-images, PCa was indicated on T2-weighted images based on histopathology results from prostatectomy specimens with the use of anatomical landmarks for the precise localization of the tumor. PCa was classified as low-, intermediate-, or high-grade, according to Gleason score. DCE-images were used as an overlay on T2-weighted images; mean and quartile values from semi-quantitative and pharmacokinetic model parameters were extracted per tumor region. Statistical analysis included Spearman's ρ, the Kruskal-Wallis test, and a receiver operating characteristics (ROC) analysis.

Results and limitations

Significant differences were seen for the mean and 75th percentile (p75) values of wash-in (p = 0.024 and p = 0.017, respectively), mean wash-out (p = 0.044), and p75 of transfer constant (K^trans) (p = 0.035), all between low-grade and high-grade PCa in the peripheral zone. ROC analysis revealed the best discriminating performance between low-grade versus intermediate-grade plus high-grade PCa in the peripheral zone for p75 of wash-in, K^trans, and rate constant (K_ep) (area under the curve: 0.72). Due to a limited number of tumors in the transition zone, a definitive conclusion for this region of the prostate could not be drawn.

Conclusions

Quantitative parameters (K^trans and K_ep) and semi-quantitative parameters (wash-in and wash-out) derived from DCE-MRI at 3 T have the potential to assess the aggressiveness of PCa in the peripheral zone. P75 of wash-in, K^trans, and K_ep offer the best possibility to discriminate low-grade from intermediate-grade plus high-grade PCa.     

A panel of TMPRSS2:ERG fusion transcript markers for urine-based prostate cancer detection with high specificity and sensitivity

Background

The TMPRSS2:ERG fusion is both prevalent and unique to prostate cancer (PCa) and has great potential for noninvasive diagnosis of PCa in bodily fluids.

Objectives

To evaluate the specificity and sensitivity of the TMPRSS2:ERG fusion in urine from diverse clinical contexts and to explore potential clinical applications.

Design, setting, and participants

A total of 101 subjects were enrolled in 2008 from urologic oncology clinics to form three study groups: 44 PCa free, 46 confirmed PCa, and 11 negative prostate biopsies. The PCa-free group included females, healthy young men, and post–radical prostatectomy (RP) patients. The confirmed PCa group was composed of patients under active surveillance, scheduled for treatment, or with metastatic disease.

Measurements

Urine was collected after attentive digital rectal exam (DRE) and coded to blind group allocation for laboratory test. RNA from urine sediments was analyzed using a panel of four TMPRSS2:ERG fusion markers with quantitative polymerase chain reaction (qPCR).

Results and limitations

Our fusion markers demonstrated very high technical specificity and sensitivity for detecting a single fusion-positive cancer cell (VCaP) in the presence of at least 3000 cells in urine sediments. In clinical analysis, there were no fusion-positive samples in the PCa-free group (0 of 44 samples), while there were 16 of 46 (34.8%) fusion-positive samples in the confirmed PCa group. The fusion incidence varied significantly among the three PCa subgroups. The clinical sensitivity increased to 45.4% in cancer patients prior to treatments. The fusion markers were detected in 2 of 11 (18.2%) biopsy-negative patients, suggesting potentially false negative biopsies. This study is not prospective and is limited in sample sizes.

Conclusions

Our novel panel of TMPRSS2:ERG fusion markers provided a very specific and sensitive tool for urine-based detection of PCa. Theses markers can potentially be used to diagnose patients with PCa who have negative biopsies.     

Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

Background

Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM).

Objective

To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM.

Design, setting, and participants

We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred.

Outcome measurements and statistical analysis

The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls.

Results and limitations

Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only.

Conclusions

Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa.

Patient summary

In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction.     

Long-Term Follow-up of Patients with Prostate Cancer and Nodal Metastases Treated by Pelvic Lymphadenectomy and Radical Prostatectomy: The Positive Impact of Adjuvant Radiotherapy

Background

Recent large, prospective, randomised studies have demonstrated that adjuvant radiotherapy (RT) is a safe and effective procedure for preventing disease recurrence in locally advanced prostate cancer (PCa) patients. However, no study has ever tested the role of adjuvant RT in node-positive patients after radical prostatectomy (RP).

Objective

We hypothesised that adjuvant RT with early hormone therapy (HT) might improve long-term outcomes of patients with PCa and nodal metastases treated with RP and extended pelvic lymph node dissection (ePLND).

Design, setting, and participants

This retrospective study included 250 consecutive patients with pathologic lymph node invasion. We assessed factors predicting long-term biochemical recurrence (BCR)–free and cancer-specific survival (CSS) in node-positive PCa patients treated with RP, ePLND, and adjuvant treatments between 1988 and 2002 in a tertiary academic centre.

Intervention

All patients received adjuvant treatments according to the treating physician after detailed patient information: 129 patients (51.6%) were treated with a combination of RT and HT, while 121 patients (48.4%) received adjuvant HT alone.

Measurements

BCR-free survival and CSS in patients with node-positive PCa.

Results and limitations

Mean follow-up was 95.9 mo (median: 91.2). BCR-free survival and CSS rates at 5, 8, and 10 yr were 72%, 61%, 53% and 89%, 83%, 80%, respectively. In multivariable Cox regression models, adjuvant RT and the number of positive nodes were independent predictors of BCR-free survival (p = 0.002 and p = 0.003, respectively) as well as of CSS (p = 0.009 and p = 0.01, respectively). Moreover, there was significant gain in predictive accuracy when adjuvant RT was included in multivariable models predicting BCR-free survival and CSS (gain: 3.3% and 3%, respectively; all p < 0.001).

Conclusions

Our data showed excellent long-term outcome for node-positive PCa patients treated with radical surgery plus adjuvant treatments. This study is the first to report a significant protective role for adjuvant RT in BCR-free survival and CSS of node-positive patients.