M. Andreas Røder

Active surveillance for clinically localized prostate cancer––A systematic review

Active surveillance (AS) has been introduced as an observational strategy to delay or avoid curative treatment without compromising long‐term cancer‐specific survival. The 10 studies included in this review, published between 2008 and 2013, generally agreed upon patients selection for the AS strategy and how they should be managed within the program. However, uncertainties persists concerning optimal patient selection and reliable progression criteria, as well as the long‐term safety of AS. J. Surg. Oncol. 2014 109:830–835.

ERG Protein Expression in Diagnostic Specimens Is Associated with Increased Risk of Progression During Active Surveillance for Prostate Cancer

BACKGROUND Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed. OBJECTIVE To examine the association between ERG expression at diagnosis and the risk of progression during AS. DESIGN, SETTING, AND PARTICIPANTS This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10-12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events. RESULTS AND LIMITATIONS A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p<0.0001) and of the subgroups PSA progression (p<0.0001) and histopathologic progression (p<0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3-29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7-68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62-3.72; p<0.0001). The main limitation of this study is its observational nature. CONCLUSIONS In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes. PATIENT SUMMARY The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.

Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study

BACKGROUND The risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. METHODS Data were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. FINDINGS Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8-8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0-79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7-26·5) versus 50·5% (47·5-53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9-6·5) versus 59·9% (55·2-64·6) for mortality from other causes. In men with PSA concentrations 10 μg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2-1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1-7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7-22·4) and for men with a PSA higher than 20 ng/mL (454 men). INTERPRETATION The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. FUNDING Capital Region of Denmarks Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersens Foundation.

Active surveillance for localized prostate cancer: An analysis of patient contacts and utilization of healthcare resources

Abstract Objective. Evidence supports active surveillance (AS) as a means to reduce overtreatment of low-risk prostate cancer (PCa). The consequences of close and long-standing follow-up with regard to outpatient visits, tests and repeated biopsies are widely unknown. This study investigated the trajectory and costs of AS in patients with localized PCa. Materials and methods. In total, 317 PCa patients were followed in a prospective, single-arm AS cohort. The primary outcomes were number of patient contacts, prostate-specific antigen (PSA) tests, biopsies, hospital admissions due to biopsy complications and patients eventually undergoing curative treatment. The secondary outcome was cost. Results. The 5 year cumulative incidence of discontinued AS in a competing-risk model was 40%. During the first 5 years of AS patients underwent a median of two biopsy sets, and patients were seen in an outpatient clinic including PSA testing three to four times annually. In total, 38 of the 406 biopsy sessions led to hospital admission and 87 of the 317 patients required treatment for bladder outlet obstruction (BOO). With a median of 3.7 years’ follow-up, the total cost of AS was euro (€) 1,240,286. Assuming all patients had otherwise undergone primary radical prostatectomy, the cost difference favoured AS with a net benefit of €662,661 (35% reduction). Conclusions. AS entails a close clinical follow-up with a considerable risk of rebiopsy complication, treatment of BOO and subsequent delayed definitive therapy. This risk should be weighed against a potential economic benefit and reduction in the risk of overtreatment compared to immediate radical treatment.

ERG protein expression over time: from diagnostic biopsies to radical prostatectomy specimens in clinically localised prostate cancer

Aims We evaluated the consistency in ERG protein expression from diagnostic specimens through rebiopsies to radical prostatectomies in patients with clinically localised prostate cancer to investigate the validity of ERG status in biopsies. Methods ERG expression was assessed by immunohistochemistry (IHC) in 625 biopsy sets and 86 radical prostatectomy specimens from 265 patients with prostate cancer managed on active surveillance. For IHC, a rabbit monoclonal primary antibody was used (clone: EPR3864). TMPRSS2-ERG fluorescence in situ hybridisation (FISH) analyses were performed in 74 biopsies using the FISH ZytoLight TriCheck Probe (SPEC ERG/TMPRSS2). FISH results were correlated with IHC findings. Results The concordance between FISH and IHC was 97.3% and IHC demonstrated a sensitivity and specificity for ERG rearrangement of 100% and 95.5%, respectively. Applying IHC, 38.1% of patients were ERG-positive, 53.6% were ERG-negative and 8.3% showed both ERG-positive and negative tumour foci (ERG heterogeneous) at diagnosis. When ERG status was dichotomised (ERG-positive or heterogeneous vs ERG-negative), 95.6%–97.1% of patients did not experience ERG reclassification during the first two rounds of rebiopsies. The concordance in ERG status between biopsies and surgical specimen was 89.5%–94.2% depending on the number of rebiopsies included. Sampling bias was assumed to explain most (81.3%) of the mismatches in ERG status. Conclusions Consistency in ERG status ranged from 90% to 95% for patients undergoing serial biopsies and radical prostatectomy. This indicates that biopsies can be used reliably to investigate ERGs prognostic and predictive value.

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts

Abstract Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main outcome measures Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10−16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

A genetic risk score to guide age-specific, personalized prostate cancer screening

Background Prostate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to a high false-positive rate, among other concerns, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient’s risk. Genetic risk may provide key information to guide the decisions of whether and at what age to screen an individual man for PCa. Methods Genotype, PCa status, and age from 34,444 men of European ancestry from the PRACTICAL consortium database were analyzed to select single-nucleotide polymorphisms (SNPs) associated with prostate cancer diagnosis. These SNPs were then incorporated into a survival analysis to estimate their effects on age at PCa diagnosis. The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was validated in an independent dataset comprised of 6,417 men with screening PSA and genotype data. PHS was calculated for these men to test for prediction of PCa-free survival. PHS was also combined with age-specific PCa incidence data from the U.S. population to generate a PCa-Risk (PCaR) age that relates a given man’s risk to that of the population average. PHS and PCaR age were evaluated for prediction of positive predictive value (PPV) of PSA screening. Findings PHS calculated from 54 SNPs was very highly predictive of age at PCa diagnosis for men in the validation set (p =10−53). PPV of PSA screening varied from 0.18 to 0.52 for men with low and high genetic risk, respectively. PHS modulates PCa-free survival curves by an estimated 20 years between men in the 1st or 99th percentiles of genetic risk. Interpretation Polygenic hazard scores give personalized genetic risk estimates and can inform the decisions of whether and at what age to screen a man for PCa. Funding Department of Defense #W81XWH-13-1-0391

PD26-01 CHANGES IN CLINICO-PATHOLOGICAL CHARACTERISTICS AT PROSTATE CANCER DIAGNOSIS DETECTED ON PROSTATE BIOPSIES IN DANISH MEN FROM 1995 TO 2011

INTRODUCTION AND OBJECTIVES: The incidence of prostate cancer (PCa) in Denmark has increased dramatically during the past two decades. PCa now accounts for 25% of all male cancers in Denmark, a change that parallels an increased use of PSA testing among healthy men. We hypothesized that this development has had a tremendous impact on clinico-pathological parameters at diagnosis of PCa over time, due to lead time bias. METHODS: We analyzed data from the Danish Prostate Cancer Registry (DaPCaR) created at our institution, which includes all Danish men who have undergone histopathological examination of prostate tissue in the period 1995-2011. We identified all diagnostic biopsies, defined as the first needle core biopsy containing PCa, and described changes in age at diagnosis, biopsy Gleason score (GS) and clinical T-category. RESULTS: A total of 37,723 diagnostic biopsy-sets were identified. In 1995, a total of 343 men were diagnosed with PCa on needle core biopsy vs 3958 men in 2011. Median age at diagnosis decreased from 72 years in 2005 to 69 years in 2011 (p<0,0001). The percentage of patients aged 65 years or younger at the time of diagnosis was 21.9% in 1995 compared to 32.9% in 2011. We observed several changes in the distribution of biopsy GS. The most prominent changes in GS were seen from 2005 and onwards, where the total number of patients diagnosed with PCa GS 6 decreased from 34.8% to 28.2% with a concurrent increment in men with GS1⁄47 from 27.7% to 36.8%(p<0,0001). Biopsy GS 8 increased only very slightly from 33.4% to 33,6% from 2005 to 2011 (p<0,0001). Also, a change in tumor stage at diagnosis was observed with 31.7% classified with localized disease in 1995 compared to 66.8% in 2011 (p<0.0001). CONCLUSIONS: The number of patients diagnosed with PCa on needle core biopsies increased more than ten-fold during the investigated time period. Significant changes in all primary diagnostic clinico-pathological characteristics were observed. The number of men with low and intermediate risk features of PCa increased dramatically which can be speculated to be a result of PSA based detection even though PSA screening has not been recommended in Denmark. A lead time on diagnosis is supported by the fact that the median age at diagnosis decreased with 3 years during a 16-year time span. The increment in men diagnosed with GS1⁄47 from 2005 is suspected to be a consequence of revised international consensus guidelines and is unlikely to reflect changes in tumor biology. Source of Funding: The Capitol Region of Denmarks Fund for Science and Innovation

Urokinase plasminogen activator receptor (uPAR) as a novel biomarker in prostate cancer.

183 Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated...

994 STANDARDIZED RELATIVE SURVIVAL AND MORTALITY AFTER RADICAL PROSTATECTOMY FOR CLINICALLY LOCALIZED PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Survival remains the most valuable endpoint for description of efficacy after radical prostatectomy (RP) for prostate cancer (PCa). Survival is typically reported as overall and cancer-specific. The objective of this study was to investigate standardised relative survival and mortality ratio in patients undergoing RP for localized PCa at our institution during the past 15 years. METHODS: Between 1995-2010, 1350 consecutive patients underwent RP for clinically localized PCa. Patients have been followed prospectively per protocol. No patients were lost to follow-up. Overall and cause-specific survival was described using Kaplan-Meier estimation. Standardized relative survival and mortality ratio was calculated based on expected survival in the age-matched Danish population using the methods and macros described by Dickmann. The countryspecific population mortality rates used for calculating the expected survival were based on the data from The Human Mortality Database. Standadized mortality was calculated as observed mortality in the cohort / expected mortality in Denmark. RESULTS: Median follow-up was 3.4 years (range: 0-14.3 years). Fifty-nine (4.4%) patients died during follow-up. Seven-teen (1.3%) patients died of PCa. Estimated ten-year overall survival was 89.3%. Cancer-specific survival was estimated to 96.6% after 10 years. Relative survival following 5 and 10 years was 1.04 and 1.14. Standardized mortality ratio was 0.61 and 0.39 at 5and 10 years. CONCLUSIONS: Overall and cancer-specific survival in a consecutive series of patients in a non-screened Danish population after ten years is 90%. Survival and mortality ratio is significantly better than expected in the age-matched background population. This finding is likely explained by selection bias. Although the results indicate an excellent outcome in terms of cancer control the efficacy of prostatectomy as treatment of localized PCa remains at debate.