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Background and objective: Prostate-specific antigen (PSA) is of limited value as a surrogate marker for overall survival (OS) in prostate cancer (PC). Serum thymidine kinase 1 (sTK1) is an enzyme expressed by actively dividing cells. Our aim was to evaluate the value of sTK1 as prognostic biomarker in metastatic hormone-sensitive PC (mHSPC) and metastatic castration-resistant PC (mCRPC). Methods: sTK1 was examined in three cohorts: (1) 43 men with de novo mHSPC managed with androgen deprivation monotherapy; (2) 99 patients with mCRPC managed with androgen receptor signaling inhibitors (ARSIs); and (3) 98 patients with mCRPC treated with docetaxel. sTK1 levels were determined at treatment initiation. OS was evaluated using Cox regression analysis. Key findings and limitations: In the mHSPC cohort, sTK1 levels in the highest quartile were associated with OS (hazard ratio [HR] 7.77, 95% confidence interval [CI] 2.25–26.9) in comparison to the lowest quartile after multivariable adjustment for age, Gleason score, and PSA. Similarly, sTKI was associated with poor OS in the mCRPC group treated with ARSIs (upper quartile: HR 5.22, 95% CI 2.23–12.2) after multivariable adjustment for age, PSA, and Eastern Cooperative Oncology Group performance status. In the docetaxel-treated mCRPC group the association between OS and sTK1 was lower but still significant (multivariable-adjusted HR 2.28, 95% CI 1.13–4.60). Limitations include the nonrandomized inclusion of patients for different treatments, which could lead to selection bias. Conclusions and clinical implications: sTK1 predicted OS in mHSPC and mCRPC, demonstrating additional value over established clinical risk factors. sTK1 should be measured in randomized clinical trials of treatments for advanced PC to validate its predictive value. Patient summary: We found that for patients with metastatic prostate cancer, high levels of a protein called TK1 that is involved in cell division was linked to higher risk of death. Our findings need to be confirmed in other studies.

Cancer survivorship was recently identified as a prostate cancer (PCa) research priority by PIONEER, a European network of excellence for big data in PCa. Despite being a research priority, cancer survivorship lacks a clear and agreed definition, and there is a distinct paucity of patient-reported outcome (PRO) data available on the subject. Data collection on cancer survivorship depends on the availability and implementation of (validated) routinely collected patient-reported outcome measures (PROMs). There have been recent advances in the availability of such PROMs. For instance, the European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) is developing survivorship questionnaires. This provides an excellent first step in improving the data available on cancer survivorship. However, we propose that an agreed, standardised definition of (prostate) cancer survivorship must first be established. Only then can real-world data on survivorship be collected to strengthen our knowledge base. With more men than ever surviving PCa, this type of research is imperative to ensure that the quality of life of these men is considered as much as their quantity of life. Patient summary: As there are more prostate cancer survivors than ever before, research into cancer survivorship is crucial. We highlight the importance of such research and provide recommendations on how to carry it out. The first step should be establishing agreement on a standardised definition of survivorship. From this, patient-reported outcome measures can then be used to collect important survivorship data.

Abstract Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. Methods We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and distinguish metastatic and non-metastatic subclones. Results In patient GP5, CDK12 inactivation was among the first mutations, leading to a PrCa tandem duplicator phenotype and initiating the cancer around age 50, followed by rapid cancer evolution after age 57, and metastasis around age 59, 5 years prior to prostatectomy. In patient GP12, accelerated cancer progression was detected after age 54, and metastasis occurred around age 56, 3 years prior to prostatectomy. Multiple metastasis-originating events were identified in each patient and tracked anatomically. Metastasis from prostate to lymph nodes occurred strictly ipsilaterally in all 12 detected events. In this pilot, metastatic subclone content analysis appears to substantially enhance the identification of key drivers. Evolutionary analysis’ potential impact on therapy selection appears positive in these pilot cases. Conclusions PrCa evolutionary analysis allows tracking of anatomic site of origin, timing of cancer origin and spread, and distinction of metastatic-capable from non-metastatic subclones. This enables better identification of actionable targets for therapy. If extended to larger cohorts, it appears likely that similar analyses could add substantial biological insight and clinically relevant value.

Abstract Background Researchers and clinicians using common clinical assessments need to attend to the prevalence of missing data to ensure the validity of the information gathered. The Expanded Prostate Cancer Index Short Form (EPIC-26) is a commonly used measurement scale used for assessing patients’ quality of life, but the measure lacks comprehensive analysis on missing data. We aimed to explore the quantity of missing answers in EPIC-26 and to characterize patterns and possible explanations of missing data in the survey. Methods The survey sample consisted of 625 Finnish prostate cancer patients who participated in a study with a 1-year follow-up with three measurement points (0, 6, and 12 months). Descriptive statistics were used to describe the study population and missingness level. A logistic regression was performed for each EPIC domain to study factors related to missingness during the follow-up. Results Proportions of missing answers in EPIC-26 were low (3.1–3.9%) between survey rounds. As much as 37% of patients left at least one question unanswered during their follow-up. The hormonal domain produced the most missing answers. Questions about breast tenderness/enlargement (question 13.b.), hot flashes (question 13.a.), frequency of erections (question 10.), and ability to reach orgasm (question 8.b.) were most frequently left unanswered. Higher age, lower education level, no relationship, more severe cancer, lower function scores in some EPIC domains, lower treatment satisfaction or self-rated health were associated with missingness. Conclusions Questions 13.b. and 13.a. might be considered female-specific symptoms, thus difficult to comprehend unless patients had already experienced side effects from androgen deprivation therapy. Questions 10. and 8.b. might be difficult to answer if the patient has been sexually inactive. To improve the measure’s validity, the questionnaire’s hormonal section requires additional explanation that the inquired symptoms are common treatment side effects of anti-androgen therapy; questions 8–10 require a not-applicable category for sexually inactive patients.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

ObjectivesTo 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.DesignAnalysis 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.SettingMultiple institutions that were members of international PRACTICAL consortium.ParticipantsAll 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 measuresPrediction with hazard score of age of onset of aggressive cancer in validation set.ResultsIn 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, P98th 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.ConclusionsPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Background: Identification of intervention-related deaths is important for an accurate assessment of the ratio of benefit to harm in screening trials. Objective: To investigate intervention-related deaths by study arm in the European Randomized Study of Prostate Cancer Screening (ERSPC). Design, setting, and participants: ERSPC is a multicenter trial initiated in the 1990s to investigate whether screening on the basis of prostate-specific antigen (PSA) can decrease prostate cancer mortality. The present study included men in the core age group (55–69 yr: screening group n = 112 553, control group n = 128 681) with 16-yr follow-up. Outcome measurements and statistical analysis: Causes of death among men with prostate cancer in ERSPC were predominantly evaluated by independent national committees via review of medical records according to a predefined algorithm. Intervention-related deaths were defined as deaths caused by complications during the screening procedure, treatment, or follow-up. Descriptive statistics were used for the results. Results and limitations: In total, 34 deaths were determined to be intervention-related, of which 21 were in the screening arm and 13 in the control arm. The overall risk of intervention-related death was 1.41 (95% confidence interval 0.99–1.99) per 10 000 randomized men for both arms combined and varied among centers from 0 to 7.0 per 10 000 randomized men. A limitation of this study is that differences in procedures among centers decreased the comparability of the results. Conclusions: Intervention-related deaths were rare in ERSPC. Monitoring of intervention-related deaths in screening trials is important for assessment of harms. Patient summary: We investigated deaths due to screening or treatment to assess harm in a trial of prostate cancer screening. Few such deaths were identified.

Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology. Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials. Design, setting, and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature. Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC. Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression. Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of “skeletal-related events” complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p

Abstract The three oncogenic PIM family kinases have been implicated in the development of prostate cancer (PCa). The aim of this study was to examine the mRNA and protein expression levels of PIM1, PIM2, and PIM3 in PCa and their associations with the MYC and ERG oncogenes. We utilized prostate tissue specimens of normal, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), untreated PCa, and castration‐resistant prostate cancer (CRPC) for immunohistochemical (IHC) analysis. In addition, we analyzed data from publicly available mRNA expression and chromatin immunoprecipitation sequencing (ChIP‐Seq) datasets. Our data demonstrated that PIM expression levels are significantly elevated in PCa compared to benign samples. Strikingly, the expression of both PIM1 and PIM2 was further increased in CRPC compared to PCa. We also demonstrated a significant association between upregulated PIM family members and both the ERG and MYC oncoproteins. Interestingly, ERG directly binds to the regulatory regions of all PIM genes and upregulates their expression. Furthermore, ERG suppression with siRNA reduced the expression of PIM in PCa cells. These results provide evidence for cooperation of PIM and the MYC and ERG oncoproteins in PCa development and progression and may help to stratify suitable patients for PIM‐targeted therapies.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Abstract Background The aim of this study is to investigate the potential impact of prostate magnetic resonance imaging (MRI) -related interreader variability on a population-based randomized prostate cancer screening trial (ProScreen). Methods From January 2014 to January 2018, 100 men aged 50–63 years with clinical suspicion of prostate cancer (PCa) in Helsinki University Hospital underwent MRI. Nine radiologists individually reviewed the pseudonymized MRI scans of all 100 men in two ProScreen trial centers. All 100 men were biopsied according to a histological composite variable comprising radical prostatectomy histology (N = 38) or biopsy result within 1 year from the imaging (N = 62). Fleiss’ kappa (κ) was used to estimate the combined agreement between all individual radiologists. Sample data were subsequently extrapolated to 1000-men subgroups of the ProScreen cohort. Results Altogether 89% men of the 100-men sample were diagnosed with PCa within a median of 2.4 years of follow-up. Clinically significant PCa (csPCa) was identified in 76% men. For all PCa, mean sensitivity was 79% (SD ±10%, range 62–96%), and mean specificity 60% (SD ±22%, range 27–82%). For csPCa (Gleason Grade 2–5) MRI was equally sensitive (mean 82%, SD ±9%, range 67–97%) but less specific (mean 47%, SD ±20%, range 21–75%). Interreader agreement for any lesion was fair (κ 0.40) and for PI-RADS 4–5 lesions it was moderate (κ 0.60). Upon extrapolating these data, the average sensitivity and specificity to a screening positive subgroup of 1000 men from ProScreen with a 30% prevalence of csPCa, 639 would be biopsied. Of these, 244 men would be true positive, and 395 false positive. Moreover, 361 men would not be referred to biopsy and among these, 56 csPCas would be missed. The variation among the radiologists was broad as the least sensitive radiologist would have twice as many men biopsied and almost three times more men would undergo unnecessary biopsies. Although the most sensitive radiologist would miss only 2.6% of csPCa (false negatives), the least sensitive radiologist would miss every third. Conclusions Interreader agreement was fair to moderate. The role of MRI in the ongoing ProScreen trial is crucial and has a substantial impact on the screening process.

Abstract Background The long‐term health‐related quality of life (HRQOL) impacts of PCa screening have not been adequately evaluated. We aimed to compare the generic and disease‐specific health‐related quality of life (HRQOL) among men with prostate cancer in the screening arm with the control arm of the PSA‐based prostate cancer screening trial in up to 15 years of follow‐up. Materials and methods This study was conducted within population‐based Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). During 1996‐1999 80,458 men were randomized to the serum prostate‐specific antigen (PSA) screening arm (SA, N = 32 000) and the control arm (CA, N = 48 458). Men in the screening arm were screened at 4‐year intervals until 2007. HRQOL questionnaires were delivered to newly diagnosed prostate cancer patients in the screening and control arm 1996‐2006 (N = 5128) at the time of diagnosis (baseline), at 3‐month, 12‐month and 5, 10, and 15‐year follow‐up. Validated UCLA Prostate Cancer Index (UCLA‐PCI) and RAND 36‐Item Health Survey were used for HRQOL assessment. The data were analyzed with a random effects model for repeated measures. Results At baseline, men with prostate cancer in the screening arm reported better Sexual Function, as well as less Sexual and Urinary Bother. Long‐term follow‐up revealed slightly higher HRQOL scores in the screening arm in prostate cancer specific measures at 10‐year post diagnosis, but the differences were statistically significant only in Urinary Bother (UCLA‐PCI score 77.9; 95% CI 75.2 to 80.5 vs. 70.9; 95% CI 66.8 to 74.9 P = .005). The generic HRQOL scores were comparable between the trial arms. The overall differences in disease‐specific or generic HRQOL scores by trial arm did not vary during the follow‐up. Conclusion No major differences were observed in HRQOL in men with prostate cancer between the prostate cancer screening and control arms during five to 15‐year follow‐up.

Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa. Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms. Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value

ContextAlthough prostate cancer (PCa) screening reduces the incidence of advanced disease and mortality, trade-offs include overdiagnosis and resultant overtreatment.ObjectiveTo review primary data on PCa overdiagnosis and overtreatment.Evidence acquisitionElectronic searches were conducted in Cochrane Central Register of Controlled Trials, PubMed, and Embase from inception to July 2013 for original articles on PCa overdiagnosis and overtreatment. Supplemental articles were identified through hand searches.Evidence synthesisThe lead-time and excess-incidence approaches are the main ways used to estimate overdiagnosis in epidemiological studies, with estimates varying widely. The estimated number of PCa cases needed to be diagnosed to save a life has ranged from 48 down to 5 with increasing follow-up. In clinical studies, generally lower rates of overdiagnosis have been reported based on the frequency of low-grade minimal tumors at radical prostatectomy (1.7-46.8%). Autopsy studies have reported PCa in 18.5-38.5%, although not all are low grade or low volume. Factors influencing overdiagnosis include the study population, screening protocol, and background incidence, limiting generalizability between settings. Reported rates of overtreatment vary widely in the literature, although contemporary international studies suggest increasing use of conservative management.ConclusionsEpidemiological, clinical, and autopsy studies have been used to examine PCa overdiagnosis, with estimates ranging widely from 1.7% to 67%. Correspondingly, estimates of overtreatment vary widely based on patient features and may be declining internationally. Careful patient selection for screening and reducing overtreatment are important to preserve the benefits and reduce the downstream harms of prostate-specific antigen testing. Because all of these estimates are extremely population and context specific, this must be considered when using these data to inform policy.Patient summaryScreening reduces spread and death from prostate cancer (PCa) but overdiagnoses some low-risk tumors that may not have caused harm. Because treatment has potential side effects, it is critical that not all patients with PCa receive aggressive treatment.

Abstract Background Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. Methods The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. Results In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant non-users, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1.13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. Conclusions We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.

Purpose Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but leads to over diagnosis of indolent prostate cancer. The use of 5α-reductase inhibitors lowers prostate specific antigen and in theory could affect the performance of prostate specific antigen based screening. We evaluated the outcomes of prostate cancer screening in 5α-reductase inhibitors users. Materials and Methods The study was performed in FinRSPC (Finnish Randomized Study of Screening for Prostate Cancer). Of 80,454 men 31,866 were randomized to be screened at 4-year intervals during 1996 to 2004. Information on 5α-reductase inhibitors reimbursements before prostate cancer during 1995 to 2009 was collected from the national prescription database for 78,615 men. We evaluated the effect of screening on prostate cancer risk and mortality by 5α-reductase inhibitors using Cox regression. Results Men receiving 5α-reductase inhibitors had higher median prostate specific antigen and were more often screen positive than nonusers. Despite this, screening did not significantly affect prostate cancer detection (HR 0.89, 95% CI 0.79–1.01) or mortality (HR 0.82, 95% CI 0.51–1.32) compared to findings in the control arm among men on 5α-reductase inhibitors. On ROC analysis prostate specific antigen and age did not predict Gleason 7-10 prostate cancer as accurately in 5α-reductase inhibitors users as it did among nonusers (first screening round AUC 0.79 vs 0.88). Conclusions Prostate specific antigen based screening among men receiving 5α-reductase inhibitors did not improve the detection of high grade or metastatic prostate cancer, or prevent prostate cancer death. [ABSTRACT FROM AUTHOR]

Purpose Screening for prostate cancer remains controversial, although ERSPC (European Randomized Study of Screening for Prostate Cancer) showed a 21% relative reduction in prostate cancer mortality. The Finnish Randomized Study of Screening for Prostate Cancer, which is the largest component of ERSPC, demonstrated a statistically nonsignificant 16% mortality benefit in a separate analysis. The purpose of this study was to estimate the degree of contamination in the control arm of the Finnish trial. Materials and Methods Altogether 48,295 and 31,872 men were randomized to the control and screening arms, respectively. The screening period was 1996 to 2007. The extent of prostate specific antigen testing was analyzed retrospectively using laboratory databases. The incidence of T1c prostate cancer (impalpable prostate cancer detected by elevated prostate specific antigen) was determined from the national Finnish Cancer Registry. Results Approximately 1.4% of men had undergone prostate specific antigen testing 1 to 3 years before randomization. By the first 4, 8 and 12 years of followup 18.1%, 47.7% and 62.7% of men in the control arm had undergone prostate specific antigen testing at least once and in the screening arm the proportions were 69.8%, 81.1% and 85.2%, respectively. The cumulative incidence of T1c prostate cancer was 6.1% in the screening arm and 4.5% in the control arm (RR 1.21, 95% CI 1.13–1.30). Conclusions A large proportion of men in the control arm had undergone a prostate specific antigen test during the 15-year followup. Contamination is likely to dilute differences in prostate cancer mortality between the arms in the Finnish screening trial. [ABSTRACT FROM AUTHOR]

Purpose: We evaluate the ability of an electronic nose to discriminate prostate cancer from benign prostatic hyperplasia using urine headspace, potentially offering a clinically applicable noninvasive and rapid diagnostic method. Materials and Methods: The ChemPro® 100-eNose was used to discriminate prostate cancer from benign prostatic hyperplasia using urine sample headspace. Its performance was tested with 50 patients with confirmed prostate cancer and 24 samples from 15 patients with benign prostatic hyperplasia (15 patients provided urine preoperatively and 9 patients provided samples 3 months postoperatively) scheduled to undergo robotic assisted laparoscopic radical prostatectomy or transurethral resection of prostate, respectively. The patients provided urine sample preoperatively and those with benign prostatic hyperplasia also provided samples 3 months postoperatively to be used as a pooled control sample population. A discrimination classifier was identified for eNose and subsequently, sensitivity and specificity values were determined. Leave-one-out cross-validation was performed. Results: Using leave-one-out cross-validation the eNose reached a sensitivity of 78%, a specificity of 67% and AUC 0.77. Conclusions: The electronic nose is capable of rapidly and noninvasively discriminating prostate cancer and benign prostatic hyperplasia using urine headspace in patients undergoing surgery. [ABSTRACT FROM AUTHOR]

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Other Research Unit

Purpose: We conducted a randomized trial to compare intermittent and continuous androgen deprivation in patients with advanced prostate cancer. We studied time to progression, overall and prostate cancer specific survival, and time to treatment failure. Materials and Methods: Between May 1997 and February 2003, 852 men with locally advanced or metastatic prostate cancer were enrolled to receive androgen deprivation therapy for 24 weeks. Patients in whom prostate specific antigen decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to intermittent or continuous androgen deprivation. In the intermittent therapy arm androgen deprivation therapy was withdrawn and resumed again for at least 24 weeks based mainly on prostate specific antigen decrease and increase. Results: There were 298 patients who did not meet the randomization criteria. The remaining 554 patients were randomized, with 274 (49.5%) to intermittent androgen deprivation and 280 (50.5%) to the continuous androgen deprivation arm. Median followup was 65.0 months. Of these patients 392 (71%) died, including 186 (68%) in the intermittent androgen deprivation arm and 206 (74%) in the continuous androgen deprivation arm (p = 0.12). There were 248 prostate cancer deaths, comprised of 117 (43%) in the intermittent androgen deprivation and 131 (47%) in the continuous androgen deprivation arm (p = 0.29). Median times from randomization to progression were 34.5 and 30.2 months in the intermittent androgen deprivation and continuous androgen deprivation arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. Conclusions: Intermittent androgen deprivation is a feasible, efficient and safe method to treat advanced prostate cancer compared with continuous androgen deprivation. [ABSTRACT FROM AUTHOR]

Summary: We performed dual-color immunostaining with a 3-antibody cocktail (α-methylacyl coenzyme-A racemase, CK34betaE12, and p63) on prostate biopsies from 200 patients. Current practice (hematoxylin and eosin staining followed by dual-color immunostaining on selected cases) was compared with a protocol in which routine dual-color immunostaining was provided in all cases. In the original pathology reports, adenocarcinoma was diagnosed in 87/200 (43%) patients. Small foci interpreted as putative cancers were detected with dual-color immunostaining in 14/113 patients who were originally diagnosed with a nonmalignant lesion. All of the suggested cancerous foci were independently reevaluated by 5 pathologists. A diagnosis of adenocarcinoma was assessed by consensus in 8 cases, and atypical small acinar proliferation was diagnosed in 1 case. Consensus was not reached in 5 cases. Six of the foci reclassified as cancer were of Gleason score 3 + 3 = 6, while 2 were graded as Gleason score 4 + 4 = 8. The feasibility of routine dual-color immunostaining was also tested by analyzing the time spent on microscopic assessment. Because small, atypical lesions expressing α-methylacyl coenzyme-A racemase (blue chromogen) were easy to detect using dual-color immunostaining, the microscopic analysis of dual-color immunostaining and hematoxylin-eosin staining was faster than that of hematoxylin-eosin staining alone that was later followed by dual-color immunostaining in selected cases (median 251 seconds versus 299 seconds, P < .0001). We concluded that routine dual-color immunostaining of all prostate biopsies would produce better diagnostic sensitivity with a smaller microscopy workload for the pathologist. However, minute foci interpreted as cancer with dual-color immunostaining need to be confirmed with hematoxylin-eosin staining, and minimal criteria for a definitive diagnosis of cancer are still lacking. [ABSTRACT FROM AUTHOR]

Purpose: We assessed whether dutasteride enhances the usefulness of total prostate specific antigen for diagnosing clinically significant prostate cancer. Materials and Methods: The 4-year REDUCE study evaluated the efficacy and safety of 0.5 mg dutasteride daily for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative prostate biopsy. Specificity, sensitivity, and positive and negative predictive values of prostate specific antigen for the diagnosis of prostate cancer were assessed. Results: Final prostate specific antigen before biopsy and change from month 6 to final prostate specific antigen performed better for the diagnosis of Gleason score 7–10 tumors in men who received dutasteride vs placebo as assessed by the area under the ROC curves (0.700 vs 0.650, p = 0.0491; and 0.699 vs 0.593, p = 0.0001, respectively). Increases in prostate specific antigen were associated with a higher likelihood of biopsy detectable, Gleason score 7–10 and clinically significant (modified Epstein criteria) prostate cancer. Percentage decreases in prostate specific antigen from baseline to month 6 in the dutasteride arm did not predict prostate cancer overall or Gleason score 7–10 cancer. Conclusions: In men with a previously negative prostate biopsy, prostate specific antigen performed better during the 4-year study as a marker of prostate cancer in men who received dutasteride vs placebo. The degree of prostate specific antigen increase after 6 months was a better indicator of clinically significant cancer in the dutasteride arm than in the placebo arm. Conversely, the initial decrease in prostate specific antigen in men taking dutasteride did not predict the likelihood of prostate cancer. [ABSTRACT FROM AUTHOR]