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INTRODUCTION AND OBJECTIVE:Controversies exist regarding the risk of cardiovascular events in prostate cancer patients treated with androgen deprivation therapy (ADT). We sought to evaluate the ass...

INTRODUCTION AND OBJECTIVE:Novel hormonal agents (NHAs) such abiraterone acetate (ABI) and enzalutamide (ENZ) are frequently used in metastatic castration-resistant prostate cancer (mCRPC). Despite...

Two recent observational studies have investigated the association between androgen deprivation therapy (ADT) and rheumatoid arthritis (RA), but generated discrepant findings and had important methodological limitations. Thus, the objective of this study was to determine whether the use of ADT is associated with an increased risk of RA in men with prostate cancer. We conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink. The cohort included all men, at least 40 years of age, newly diagnosed with prostate cancer between 1 January 1988 and 31 March 2014, with follow-up until 30 September 2014. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays and latency. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RA, comparing use of ADT with non-use. Secondary analyses were conducted to assess whether the association varied according to ADT type and cumulative duration of use. Finally, we conducted several sensitivity analyses to assess the robustness of our findings. The cohort included 32,302 men followed for a median of 3.3 years. During follow-up, 63 patients were newly diagnosed with RA, generating an incidence rate of 46.5/100,000 person-years. Compared with non-use, the use of ADT was not associated with an increased risk of RA (HR 0.84, 95% CI 0.49–1.45). In secondary analyses, the association did not vary according to ADT type or with cumulative duration of use (p trend = 0.53). The results remained consistent in sensitivity analyses. In this population-based study, the use of ADT was not associated with an increased risk of RA in men with prostate cancer.

PURPOSE: Several new drug therapies have been approved in CRPC in the past decade. However, little is known about their potential overuse at the end of life. Cancer therapy use at the end of life has been considered an indicator of overtreatment. The study objective was to describe CRPC drug use in the last month of life of CRPC patients in Quebec. PATIENTS AND METHODS: Using administrative databases from the province of Quebec in Canada, we identified patients who received medical or surgical castration treatment, received one or more CRPC drugs (chemotherapy, abiraterone, or bone-targeted therapy), and died between 2001 and 2013. CRPC drug use in the last month of life was the primary outcome. RESULTS: The cohort consisted of 1,148 patients with CRPC. A total of 316 men (27.5%) received a CRPC drug in the last month of life. For those who received chemotherapy, abiraterone, and bone-targeted therapy, 10.2%, 27.8%, and 31.8% received them in the last month of life, respectively. In multivariable analyses, age older than 75 years (odds ratio [OR], 0.75; 95% CI, 0.57 to 0.99), and prostate cancer diagnosis received less than 24 months earlier (OR, 0.43; 95% CI, 0.26 to 0.72) were associated with less CRPC drug use. Relative to dying between 2005 and 2011, dying between 2012 and 2013 (OR 1.60; 95% CI, 1.18 to 2.18) was associated with greater CRPC drug use. CONCLUSION: More than one quarter of patients received CRPC drug therapies in the last month of life. Persistent chemotherapy, abiraterone, bone-targeted therapies, and medical castration drugs in the last month of life may be an indicator of inappropriate and expensive end-of-life care.

Androgen deprivation therapy (ADT) plays an important role in the contemporary management of prostate cancer (PCa) across various stages of the disease. While ADT remains a highly effective treatment for PCa, it is not curative, and its use is associated with significant adverse events that span across various organ systems.

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Background Prostate cancer (PCa) is the most common cancer in North American men. Beyond the established contribution of androgens to disease progression, growing evidence suggest that oestrogen-related pathways might also be of clinical importance. The aim of this study was to explore the association of urinary oestrogen levels with clinical outcomes. Methods Urine samples from the prospective multi-institutional PROCURE cohort were collected before RP for discovery (n = 259) and validation (n = 253). Urinary total oestrogens (unconjugated + conjugated), including oestrone and oestradiol, their bioactive and inactive catechol and methyl derivatives (n = 15), were measured using mass spectrometry (MS). Results The median follow-up time for the discovery and replication cohorts was 7.6 and 6.5 years, respectively. Highly significant correlations between urinary oestrogens were observed; however, correlations with circulating oestrogens were modest. Our findings indicate that higher levels of urinary oestriol and 16-ketoestradiol were associated with lower risk of BCR. In contrast, higher levels of 2-methoxyestrone were associated with an increased risk of development of metastasis/deaths. Conclusions Our data suggest that urinary levels of oestriol and 16-ketoestradiol metabolites are associated with a more favourable outcome, whereas those of 2-methoxyestrone are associated with an elevated risk of metastasis after RP. Further studies are required to better understand the impact of oestrogens on disease biology and as easily accessible urine-based risk-stratification markers.

DNA copy number alterations (CNAs) are promising biomarkers to predict prostate cancer (PCa) outcome. However, fluorescence in situ hybridization (FISH) cannot assess complex CNA signatures because of low multiplexing capabilities. Multiplex ligation-dependent probe amplification (MLPA) can detect multiple CNAs in a single PCR assay, but PCa-specific probe mixes available commercially are lacking. Synthetic MLPA probes were designed to target 10 CNAs relevant to PCa: 5q15-21.1 (CHD1), 6q15 (MAP3K7), 8p21.2 (NKX3-1), 8q24.21 (MYC), 10q23.31 (PTEN), 12p13.1 (CDKN1B), 13q14.2 (RB1), 16p13.3 (PDPK1), 16q23.1 (GABARAPL2), and 17p13.1 (TP53), with 9 control probes. In cell lines, CNAs were detected when the cancer genome was as low as 30%. Compared with FISH in radical prostatectomy formalin-fixed, paraffin-embedded samples (n = 18: 15 cancers and 3 matched benign), the MLPA assay showed median sensitivity and specificity of 80% and 93%, respectively, across all CNAs assessed. In the validation set (n = 40: 20 tumors sampled in two areas), the respective sensitivity and specificity of MLPA compared advantageously with FISH and TaqMan droplet digital PCR (ddPCR) when assessing PTEN deletion (FISH: 85% and 100%; ddPCR: 100% and 83%) and PDPK1 gain (FISH: 100% and 92%; ddPCR: 93% and 100%). This new PCa probe mix accurately identifies CNAs by MLPA across multiple genes using low quality and quantities (50 ng) of DNA extracted from clinical formalin-fixed, paraffin-embedded samples.

Background: Inaccurate risk classification and the burden of unnecessary biopsies are a challenge due to the limited ability of current risk assessment tools and modalities to diagnose prostate cancer (PCa) and distinguish indolent from aggressive disease. This systematic review assesses newly developed tests and interventions with high evidence of clinical utility that might be adopted in clinical practice during PCa management before initial and repeat biopsy, after positive biopsy, and after radical treatment. Methods: The Cochrane, Embase, MEDLINE, and Web of Science databases were searched for studies pertaining to the clinical utility of PCa diagnostic tests. Outcomes of interest were (1) a measure of the percentage of altered decision-making, (2) decrease in number of unnecessary biopsies, (3) decrease or increase in treatment intensity, and (4) risk reclassification after test results. Results: The search yielded 2,940 articles, of which 46 met the inclusion criteria. We found clinical utility evidence on the Prostate Health Index (PHI), 4Kscore test, MRI, OncotypeDX, Decipher test, Prolaris, ConfirmMDx, Progensa PCA3, NADiA ProsVue, and ProMark. No evidence was identified for Prostarix, ProstaVysion, Prostate Core Mitomic Test, and Mi-Prostate Score. The interventions demonstrated their clinical utility in terms of change in treatment recommendations, decrease/increase in interventional treatment, decrease in biopsy, and risk reclassification. At diagnosis after a positive biopsy, ProMark, OncotypeDX, Prolaris, and MRI guided the use of active surveillance. Use of NADiA ProsVue, Decipher, and Prolaris aided in the decision to add adjuvant therapy post-prostatectomy. PHI, 4Kscore, and MRI used prior initial and repeat biopsies, and ConfirmMDx and Progensa PCA3 used prior repeat biopsies to improve prediction of biopsy outcome, allowing a decrease in unnecessary biopsies. Conclusions: This systematic review suggests that implementation of these tests in clinical practice could effectuate personalized treatment of PCa. Further clinical and economic evaluation studies of long-term PCa outcomes are warranted to provide further guidance.

To test the agreement between high-grade PCa at RP and TMA, and the ability of TMA to predict BCR. Validation of concordance between tissue microarray (TMA) and radical prostatectomy (RP) high-grade prostate cancer (PCa) is crucial because latter determines the treated natural history of PCa. We hypothesized that TMA Gleason score is in agreement with RP pathology and capable of accurately predicting biochemical recurrence (BCR). Data were provided from a multi-institutional Canadian sample of 1333 TMA and RP specimens with complete clinicopathological data. First, rate of agreement between TMA and high-grade Gleason at RP or biopsy and RP was tested. Second, ability of RP, TMA and biopsy to predict BCR was compared. Multivariable (MVA) Cox regression models were fitted and BCR rates were illustrated with Kaplan-Meier plots. Agreement between RP and TMA and between RP and biopsy was 72.6% (95% CI:69.7-75.5) and 60.4% (95% CI:57.2-63.6), respectively. In MVA predicting BCR, the accuracy for RP, TMA and biopsy was 0.73, 0.72 and 0.68, respectively. TMA added discriminatory ability among exclusively low-grade Gleason RP patients (p = 0.02), but did not improve BCR discrimination in exclusive high-grade PCa RP patients (p = 0.8). TMA Gleason grade accurately reflects presence of high-grade Gleason in RP specimen, accurately predicts BCR rates after RP and improves prediction of BCR in low-grade Gleason patients at RP.

To characterize testosterone profile changes over time in a cohort of prostate cancer (PCa) patients managed with active surveillance (AS) and to assess its correlation with the initial disease characteristics and further progression. We conducted retrospective chart review of PCa patients managed with AS. Patients were followed with PSA, total, free and bioavailable testosterone measurements, physical examination, and by repeat biopsies or periodic magnetic resonance imaging. Disease progression was identified by follow-up biopsy changes or by imaging. A Cox proportional hazard regression models were used to assess the association between testosterone profile at baseline and the risk of progression. For the 122 patients included in analyses, the mean age at diagnosis was 65.8 years; the mean follow-up time was 7.8 years. At baseline, 108 (88.5%) patients had a Gleason score of ≤ 6. In all, 45 (36.8%) patients had disease progression, with a mean time to progression of 4.6 years. During follow-up, PSA levels showed a rising trend, while testosterone profile levels showed a trend of decrease over time. There was no significant correlation between PSA and testosterone profile (total, free, and bioavailable) level changes over time (ρ = − 0.14, − 0.11 and − 0.16, P = 0.16, 0.34, and 0.20, respectively). In addition, multivariable analysis showed that serum-free testosterone was an independent predictor of disease progression (HR 0.93, 95% CI 0.88–0.99, P = 0.029). Our study results showed that testosterone profile measurements tended to decrease over time in PCa patients managed with AS. Free testosterone was a significant independent variable of disease progression.

Preclinical studies suggest statins may help prevent prostate cancer (PC), but epidemiologic results are mixed. Many epidemiological studies have relatively short prediagnosis drug exposure data, which may miss some statin use. We completed a nested case-control study investigating the impact of statin use on PC diagnosis and clinically significant PC using data from men aged ≥40 years in the Canadian province of Saskatchewan between 1990 and 2010. Drug exposure histories were derived from a population-based prescription drug database. We used conditional logistic regression to model use of statins as a class and stratified analyses for groups defined by lipophilicity. Clinically significant PC was defined as Gleason score 8-10 OR stage C or D or III or IV at diagnosis. 12,745 cases of PC were risk-set matched on age and geographic location to 50,979 controls. Greater than 90% of subjects had prediagnosis drug exposure histories >15 years. 2,064 (16.2%) cases and 7,956 (15.6%) controls were dispensed one or more statin prescriptions. In multivariable models, ever prescription of statins was not associated with PC diagnosis (OR 0.97; 95% CI 0.90-1.05). Neither lipophilic statins (OR 0.96, 95% CI 0.88-1.04) nor hydrophilic statins (OR 1.06, 95% CI 0.95-1.20) impacted PC diagnosis. There was no effect of the dose or duration of statin use. Diagnosis of clinically significant PC decreased with statin use (OR 0.84, 95% CI 0.73-0.97). Statin use is not associated with overall PC risk, regardless of duration or dose of statin exposure. Statin use is associated with a decreased risk of clinically significant PC.

Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases. Patient selection was based on death from a pca-related cause or therapy used according to the Canadian Urological Association guidelines on mcrpc management. Treatments included chemotherapy (mitoxantrone before 2005 and docetaxel after 2005), abiraterone, bone-targeted therapy (zoledronic acid or denosumab, or both), and palliative radiation therapy (rt). During the study period, neither enzalutamide nor cabazitaxel was publicly reimbursed in Quebec, and as a result, no capture of their use was possible for this study. Multivariate logistic regression was used to identify factors associated with the probability of receiving chemotherapy, bone-targeted therapies, and palliative rt before death from pca. Overall, the database search identified 3106 patients who died of pca between January 2001 and December 2013. Median age of death was 78 years. Of those 3106 patients, just 2568 (83%) received mcrpc-specific treatments: chemotherapy, abiraterone, palliative rt, or bone-targeted therapy, the other 17% of the patients were managed solely with maximum androgen blockade (androgen deprivation therapy plus anti-androgens) despite a record of pca-related death. Logistic regression analyses indicate that patients dying after 2005 were more likely to have received chemotherapy [odds ratio (or): 1.51, 95% ci: 1.22 to 1.85] and bone-targeted therapy (or: 1.97, 95% ci: 1.64 to 2.37). Age was a significant predictor for the use of chemotherapy, bone-targeted therapy, and palliative rt (ors in the range 0.96&ndash, 0.98, p < 0.05). Patient age seems to be a strong determinant in the of selection mcrpc therapy, affecting the probability of the use of chemotherapy, bone-targeted therapy, or palliative rt. Although chemotherapy is still used only in a small percentage of patients, the introduction of new therapies&mdash, such as bone-targeted therapy, docetaxel, and abiraterone&mdash, affected treatment selection over time. The availability of enzalutamide since February 2014 will likely produce additional changes in mcrpc management.

Background: Prostate cancer shows considerable heterogeneity in disease progression and we propose that markers expressed in tumour stroma may be reliable predictors of aggressive tumour subtypes. Methods: We have used Kaplan–Meier, univariate and multivariate analysis to correlate the expression of Asporin (ASPN) mRNA and protein with prostate cancer progression in independent cohorts. We used immunohistochemistry and H scoring to document stromal localisation of ASPN in a tissue microarray and mouse prostate cancer model, and correlated expression with reactive stroma, defined using Masson Trichrome staining. We used cell cultures of primary prostate cancer fibroblasts treated with serum-free conditioned media from prostate cancer cell lines to examine regulation of ASPN mRNA in tumour stromal cells. Results: We observed increased expression of ASPN mRNA in a data set derived from benign vs tumour microdissected tissue, and a correlation with biochemical recurrence using Kaplan–Meier and Cox proportional hazard analysis. ASPN protein localised to tumour stroma and elevated expression of ASPN was correlated with decreased time to biochemical recurrence, in a cohort of 326 patients with a median follow up of 9.6 years. Univariate and multivariate analysis demonstrated that ASPN was correlated with progression, as were Gleason score, and clinical stage. Additionally, ASPN expression correlated with the presence of reactive stroma, suggesting that it may be a stromal marker expressed in response to the presence of tumour cells and particularly with aggressive tumour subtypes. We observed expression of ASPN in the stroma of tumours induced by p53 inhibition in a mouse model of prostate cancer, and correlation with neuroendocrine marker expression. Finally, we demonstrated that ASPN transcript expression in normal and cancer fibroblasts was regulated by conditioned media derived from the PC3, but not LNCaP, prostate cancer cell lines. Conclusions: Our results suggest that ASPN is a stromally expressed biomarker that correlates with disease progression, and is observed in reactive stroma. ASPN expression in stroma may be part of a stromal response to aggressive tumour subtypes.

Publisher's version (útgefin grein)., Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40–69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Patient summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening. © 2019 The Authors We demonstrate that after 3 yr of prostate-specific-antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., We demonstrate that, after four annual PSA screening rounds, BRCA2 mutation carriers have a higher incidence of PrCa, are diagnosed at a younger age, and present with more clinically significant tumours than BRCA2 noncarriers. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Therefore, these data support the use of systematic PSA screening in male BRCA2 carriers. Author contributions : Rosalind A. Eeles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Aaronson, Ardern-Jones, Bancroft, Bangma, Castro, Dearnaley, Eccles, Evans, Eyfjord, Falconer, Foster, Gronberg, Hamdy, Johannsson, Khoo, Kote-Jarai, Lilja, Lindeman, Lubinski, Mahle, Mikropoulos, Mitra, Moynihan, Page, Rennert, Suri. Acquisition of data: All authors. Analysis and interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis : Page, Bancroft, Brook, Assel, Vickers, Lilja. Obtaining funding : Eeles and all IMPACT collaborating sites obtained their own funding for running the study at their site. Administrative, technical, or material support: All authors. Supervision: Eeles. Other : None. Financial disclosures: Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker $1000. The remaining authors have no other conflict of interest to declare.000. The remaining authors have no other conflict of interest to declare. Funding/Support and role of the sponsor : This research is coordinated by the Institute of Cancer Research, London, UK, and is supported by grants from Cancer Research UK (grant references C5047/A21332, C5047/A13232, and C5047/A17528) and the Ronald and Rita McAulay Foundation. Judith Offman is supported by Cancer Research UK Programme Grant reference C8161/A16892. Mr. and Mrs. Jack Baker are acknowledged for supporting the study in NorthShore University HealthSystem, Evanston, IL, USA and Myriad Genetics Laboratory, Salt Lake City, UT, USA, for providing research BRCA testing rates for NorthShore University HealthSystem patients. We acknowledge funding from the National Institute for Health Research (NIHR) to the Biomedical Research Center at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, at Manchester University Foundation Trust (IS-BRC-1215-20007), the Oxford Biomedical Research Centre Program, and the Cambridge Clinical Research Centre, NIHR Cambridge Biomedical Research Centre. We acknowledge that in Australia, this project was cofunded by Cancer Council Tasmania and Cancer Australia (grant number 1006349 [2011–2013]), Prostate Cancer Foundation of Australia (grant number PCFA PRO4 [2008]), Cancer Councils of Victoria and South Australia (grant number 400048 [2006–2008]), the Victorian Cancer Agency Clinical Trial Capacity CTCB08_14, Cancer Australia and Prostate Cancer Foundation of Australia (2014–2016; grant number 1059423), and Translational grants EOI09_50. The Association of International Cancer Research funded data collection in The Netherlands (AICR 10-0596). We acknowledge funding from the Basser Center for BRCA (to Susan Domchek). This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation. This work was also supported in part by the NIHR Oxford Biomedical Research Centre Program in UK, the Swedish Cancer Society (CAN 2017/559), the Swedish Research Council (VR-MH project no. 2016-02974), and General Hospital in Malmö Foundation for Combating Cancer. We acknowledge funding from the Slovenian Research Agency, Research programme P3-0352. We thank CERCA Program/Generalitat de Catalunya for their institutional support. Elena Castro acknowledges funding from Prostate Cancer Foundation. We acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad), “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI16/00563, JR18/00011 and CIBERONC), and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). We acknowledge funding support from Fundação para a Ciência e a Tecnologia to the IPO Porto study (project grant PTDC/DTP-PIC/1308/2014 to Manuel R. Teixeira and fellowship grant SFRH/BD/116557/2016 to Marta Cardoso).

Background: Androgen deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer (PCa); however, it accelerates the loss of bone mineral density (BMD), which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to assess baseline fracture risk properly. The objective of this study was to examine the proportion of BMD testing in men initiating ADT in Quebec and to identify factors associated with receipt of this testing. Methods: The study cohort consisted of men extracted from Quebec public healthcare insurance administrative databases who initiated continuous ADT from 2000 to 2015 for >12 months. The primary study outcome was receipt of BMD testing in the period from 6 months before through 12 months after ADT initiation. Multivariable generalized linear mixed regression modeling with a logit link was performed to identify variables associated with BMD testing. Results: We identified 22,033 patients, of whom 3,910 (17.8%) underwent BMD testing. Rates of BMD testing increased from 4.1% in 2000 to 23.4% in 2015. After multivariable analyses, prior history of osteoporosis (odds ratio [OR], 1.84; 95% CI, 1.32–2.57; PP=.006), use of bisphosphonates (OR, 1.47; 95% CI, 1.25–1.73; PP=.006) were associated with higher odds of BMD testing. Patient age >80 years (OR, 0.67; 95% CI, 0.59–0.76; PPPPConclusions: In our study population, BMD testing rates in men initiating ADT were low, although they increased over the years especially in the years after the publication of recommendations for BMD testing in these patients. Potential gaps identified include being older, more comorbid, and rural areas. Overall, additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.

Castration-resistant prostate cancer (CRPC) is defined by disease progression despite castrate levels of testosterone and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases. Advanced prostate cancer has been known under a few names over the years, including hormone-resistant prostate cancer (HRPC) and androgen-insensitive prostate cancer (AIPC). Most recently, the terms castration-resistant prostate cancer or castration-recurrent prostate cancer were introduced with the realization that extra-testicular androgen production plays a significant role in the resistance of prostate cancer cells to medical or surgical castration therapy.1 In their second publication, the Prostate Cancer Working Group defined CRPC as a continuum on the basis of whether metastases are detectable (clinically or by imaging) and whether the serum testosterone is in the castrate range by surgical orchidectomy or medical therapy.2 This definition creates a clinical-states model, where patients can be classified. The rising PSA states (castrate and non-castrate) signify that no detectable (measurable or non-measurable) disease has ever been found. The clinical metastases states (castrate and non-castrate) signify that disease was detectable at some point in the past, regardless of whether it is detectable now.3 Prognosis is associated with several factors that go beyond PSA levels. These include performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, and serum lactate dehydrogenase and alkaline phosphatase levels. Bone metastases will occur in 90% of men with CRPC and can produce significant morbidity, including pain, pathological fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection, are also common. CRPC includes patients without metastases or symptoms with rising PSA levels despite androgen-deprivation therapy (ADT) to patients with metastases and significant debilitation due to cancer symptoms.

Background The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients. Methods and findings In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan–Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00–1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09–1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05–3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30–5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow. Conclusions We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression., Fred Saad and colleagues reveal the prognostic association between nuclear NF-κB p65 expression and prostate cancer outcomes., Author summary Why was this study done? In Canada and the US, prostate cancer is the most commonly diagnosed cancer in men. Identifying patients with aggressive prostate cancer is crucial for the choice of treatment to increase survival. Previously, we and others showed that the localization of a biomarker, nuclear factor kappa B (NF-κB) p65, in the nucleus of prostate cancer cells allows the identification of patients with aggressive prostate cancer. More specifically, the nuclear expression of NF-κB p65 is associated with cancer recurrence. What did the researchers do and find? To further validate our findings in a larger, multi-centre cohort of patients, we took advantage of the Canadian Prostate Cancer Biomarker Network (CPCBN) tissue microarrays that include a test (n = 250) and a validation (n = 1,262) series built with radical prostatectomy specimens from prostate cancer patients. We showed that NF-κB p65 in the nucleus of prostate cancer cells was associated with all evaluated prostate cancer endpoints (biochemical recurrence, development of bone metastases, and prostate-cancer-specific death). What do these findings mean? We validated the association between NF-κB p65 nuclear frequency and more aggressive prostate cancer. Nuclear frequency of NF-κB p65 should help to better identify patients with a higher risk of disease progression, and this could impact patient management. For the implementation of this biomarker in the clinical workflow, the investigation of nuclear frequency of NF-κB p65 in whole diagnostic samples will be important.

Background Docetaxel-based chemotherapy has been the cornerstone of the management of symptomatic metastatic castration-resistant prostate cancer (mCRPC) since 2004. This study aimed to describe how real-world clinical practice was changed with the public funding of novel hormonal agents (abiraterone and enzalutamide) in Quebec. Methods We conducted a retrospective cohort study in two McGill University hospitals. Hospital-based cancer registries were used to select mCRPC patients in medical oncology departments from January 2010 to June 2014. Two groups according to mCRPC diagnosis year were built, with 2012 chosen as the cut-off year, corresponding to the year abiraterone was approved for public reimbursement in second-line in Quebec. Kaplan–Meier analysis was used to estimate time to first docetaxel prescription since mCRPC diagnosis before and after 2012. Cox regression was used to identify predictive factors of docetaxel and novel hormonal agent use. Results In our cohort, 308 patients diagnosed with mCRPC were selected with 162 patients in the pre-2012 group and 146 patients in the post-2012 group. The median age at mCRPC was 74.0 years old. At 12 months from diagnosis, 69% of patients received a prescription for docetaxel in the pre-2012 group comparatively to 53% in the post-2012 group. Factors that decreased the likelihood of docetaxel utilization were: age older than 80 at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3–0.7), mCRPC diagnosis after 2012 (HR: 0.6; 95%CI: 0.4–0.8), and asymptomatic disease at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3–0.7). Conclusion The introduction of novel hormonal agents reduced first-line and overall docetaxel utilization and delayed time to its initiation.

INTRODUCTION AND OBJECTIVES:Prostate cancer (PCa) accounts for 10% of all cancers diagnosed in Canada and 21% (21,300 new cases) of cancers among males. Androgen deprivation therapy (ADT) is a very...

62 Background: Novel hormonal agents (NHAs) such abiraterone (ABI) and enzalutamide (ENZA) have demonstrated similar survival benefits against placebo groups in their respective clinical trials leading to their regulatory approval in both the pre- and post-chemotherapy settings in metastatic castration-resistant prostate cancer (mCRPC). Despite the overall tolerable risk profile, certain signals of cardiovascular toxicity were reported for these agents in clinical trials but little is known about their incidence in clinical practice. The objective was to assess the comparative cardiovascular safety of ABI and ENZA in patients with mCRPC in the real-world. Methods: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. Patients were selected on the basis of having received androgen deprivation therapy prior to initiating a novel hormonal agent (ABI or ENZA) between 2012 and 2016. The primary outcome of interest was cardiovascular-related hospitalization (composite outcome that included acute coronary disease, cerebrovascular disease, heart failure, arrhythmia and other cardiovascular causes). Inverse probability of treatment weighting (IPTW) with the propensity score was used to adjust for measured baseline confounders including pre-existing cardiovascular disease. Results: The cohort comprises 2,183 patients, with 1,773 (81.2%) in the ABI group and 410 (18.8%) in the ENZA group. Before IPTW, mean age of the ENZA group was higher than the ABI group (78 vs 76). There were more ENZA patients with pre-existing arrythmia (ABI: 10.7%, ENZA: 15.1%) and diabetes (ABI: 21.5%, ENZA: 25.1%). Crude incidence rates of cardiovascular-related hospitalization were of 10 events per 100 person-years (PYs) and of 7 events per 100 PYs for the ABI and ENZA groups, respectively. After applying IPTW, all baseline variables were well balanced across both groups with standardized differences < 0.05. The ABI group was at greater risk of cardiovascular-related hospitalization compared to the ENZA group (IPTW-hazard ratio (HR): 1.79, 95% confidence interval (95%CI): 1.04-3.09). The risk of hospitalization for heart failure was greater in ABI (IPTW-HR: 3.02, 95%CI: 1.17-7.78). Conclusions: In our study population, there was a greater risk of cardiovascular-related hospitalizations for ABI users relative to ENZA users, in particular for hospitalization for heart failure. Given the lack of evidence from randomized head-to-head comparisons of both agents, these results provide clinicians with additional insight on the cardiovascular risks of mCRPC patients treated with NHAs in the real-world and further large studies are required to corroborate these findings.

BACKGROUND Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo steroids, we examined the expression of key enzymes and proteins involved in steroid biosynthesis and metabolism. METHODS Using TissueScan™ Cancer qPCR Arrays and quantitative RT-PCR, we performed comparative gene expression analyses between various prostate cell lines and biopsies, including normal, hyperplastic, cancerous, and androgen-deprived prostate cells lines, as well as normal, benign prostate hyperplasia (BPH), PCa, and CRPC human specimens. These studies were complemented with steroid biosynthesis studies in normal and BPH cells. RESULTS Normal human prostate WPMY-1 and WPE1-NA22, benign prostate hyperplasia BPH-1, and cancer PC-3, LNCaP, and VCaP cell lines, as well as normal, BPH, PCa, and CRPC specimens, were used. Although all cell lines express mRNA encoding for hydroxymethylglutaryl-CoA reductase (HMGCR), the mitochondrial translocator protein TSPO and cholesterol side chain cleavage enzyme CYP11A1 were only observed in WPMY-1, BPH-1, and LNCaP cells. HSD3B1, HSD3B2, and CYP17A1 are involved in androgen formation and were not found in most cell lines. WPE1-NA22 and BPH-1 cells were unable to synthesize de novo steroids from mevalonate. Moreover, androgen-deprived cells did not have alterations in the expression of enzymes that could lead to de novo steroid formation. All prostate specimens expressed TSPO and CYP11A1. HSD3B1/2, CYP17A1, HSD17B5, and CYP19A1 mRNA expression was distinct to the profile observed in cells lines. The majority of BPH (90.9%) and PCa (83.1%) specimens contained CYP17A1, compared to control (normal) specimens (46.7%). BPH (82%), PCa (59%), normal (40%), and CRPC (34%) specimens expressed the four key enzymes that metabolize cholesterol to androgens. CONCLUSION These studies question the use of prostate cell lines to study steroid biosynthesis and demonstrate that human prostate samples contain transcripts encoding for key steroidogenic enzymes and proteins indicating that they have the potential to synthesize de novo steroids. We propose CYP17A1 as a candidate enzyme that can be used for patient stratification and treatment in BPH and PCa. Prostate 76:575–587, 2016. © 2016 Wiley Periodicals, Inc.

5530 Background: The accuracy of the extracellular vesicle-fingerprint score (EV-FPS) test to predict clinically significant prostate cancer (PCa; Gleason grade (GG) ≥ 3) from indolent disease (GG ≤ 2) and avoid unnecessary prostate biopsies was determined at the point of prostate biopsy decision. Methods: Clinical data, health information, and blood samples were collected from a prospective validation cohort of 415 men, without prior PCa diagnosis, referred to urology clinics for prostate biopsy or transurethral prostate surgery (June 2014-Dec 2016). The patient’s EV-FPS risk score was calculated by combining machine learning model-analyzed microflow cytometry data from EV biomarkers with logistic regression-analyzed patient-centric clinical features. The plasma-derived EV biomarkers were prostate-specific membrane antigen, polysialic acid and ghrelin-growth hormone receptor. The patient clinical features were; age, ethnicity, PCa family history, PSA levels, abnormal digital rectal examination (DRE) and prior negative prostate biopsy. Together, the biomarkers and clinical features provided specificity for clinically significant PCa. Results: The EV-FPS test identified clinically significant PCa patients with high accuracy (0.81 area under curve) at 95% sensitivity and 97% negative predictive value. Using a 7.85% probability cut-off after test validation; 95% of the patients with GG ≥ 3 would have been found before biopsy, 35% biopsies would have been avoided and diagnosis of GG ≥ 3 PCa would have been missed in only 5% of the cohort. Conclusions: This minimally invasive EV-FPS test accurately predicted clinically significant PCa in men with high EV-FPS risk scores, high PSA level and/or abnormal DRE. Therefore, men with low EV-FPS risk scores could potentially avoid unnecessary prostate biopsies. Clinical care cut-offs to calculate the number of biopsies that could have been avoided, and the percentage of GG ≥ 1 to GG ≥ 3 PCa that could have had a delayed diagnosis. [Table: see text]

Introduction: Prostate cancer (PCa) is the second most frequent cancer in men and a leading cause of cancer-related mortality. Despite major advances in immunotherapy, PCa remains a poor responder. Metastatic PCa is responsible for the majority of PCa-associated mortality. Most PCa metastases are multifocal and display a strong bones tropism (91.1% of cases), but PCa metastases can also spread to the lymph nodes (8.7%), lungs (5.7%), liver (4.5%) and brain (1.8%). Liver metastases are associated with worse prognosis but due to their multifocal nature and frequent spreading to other sites, PCa metastases are rarely resected. Therefore, immunologic characterization of these lesions concomitant with generation of research tools derived from these lesions are urgently needed to understand how to intercept disease progression. Methods: A 62-year-old male who previously underwent radical prostatectomy in 2016 was diagnosed in July 2018 with a single liver metastasis (5.3 cm) by MRI. The tumor was surgically resected and tumor tissue along with peripheral blood was collected and processed for in-depth immunologic/molecular characterization and generation of tumor models. The study was done in accordance with the guidelines approved by MUHC IRB. Prior written informed consent was obtained from the subject to participate in the study (protocol: SDR-11-066). Results: The prostatic origin of the tumor mass was confirmed by positivity for PSMA and NKX3.1 expression. Patient-derived xenografts, 2D cell and organoid cultures were generated and immunophenotyping of the innate and adaptive peripheral and tumor-infiltrating immune cells subsets was performed. Genomic alterations are currently being characterized by multiplex ligation-dependent probe amplification (MLPA). Additionally, chromatin accessibility-based characterization of the gene regulatory network of tumor luminal cells (CD49-CD26+) using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) together with RNA-seq is presently under way. Conclusions: Our collaborative effort will provide the much-needed research tools required to model and understand the processes leading to the rare, but lethal, progression from a localized PCa lesion to liver metastases. Combined with other ongoing research efforts, we believe this case will help us understand the molecular basis to the liver tropism of a subset of PCa metastases and ultimately provide biomarkers for early identification of patients with increased metastatic potential as well as a basis to determine the appropriate immunotherapy modality for metastatic patients. Citation Format: Aurélie Y. Le Page, Anna de Polo, K-P Guérard, A. Lazaris, S.K. Petrillo, W. Ebrahimizadeh, S. Tabariès, S. Shinde-Jadhav, A. Feldiorean, N. Boufaeid, W. Kassouf, C. Piccirillo, P.M. Siegel, A. Aprikian, A. Gregorieff, J. Lapointe, P. Metrakos, D.P. Labbé. Immune profiling and organoids generation of a rare case of prostate cancer liver metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A26.

OBJECTIVE The psychosocial impact of a prostate cancer diagnosis significantly affects a patient's quality of life. We studied patient communication at the time of diagnosis and its impact on psychosocial adjustment of patients. METHODS This is a cross-sectional data analysis from self-administered questionnaires in the PROCURE biobank study, consisting of a cohort of patients with localized prostate cancer undergoing radical prostatectomy in Quebec (Canada), 2006 to 2013. Odds ratios (OR) and their respective 95% confidence intervals (95% CI) were calculated using binary or ordered logistic regression models. RESULTS Data from 1841 patients were analyzed. The median age of patients was 62 years (range 41-80 years), the majority was French-Canadian (68.3%) and married (79.6%). Most patients (90.1%) considered conversations with their treating physician a useful information source. Patients were dissatisfied on the communication when receiving their diagnosis by telephone (OR = 0.19, 95% CI, 0.11-0.33). Younger patients were also more dissatisfied. Most patients preferred to receive information on prostate cancer (89.5%) and radical prostatectomy (88.0%) at the time of diagnosis, while only 58.8% and 52.4% of patients received this information at this stage. Patients who were dissatisfied with the communication of the diagnosis had more negative responses, such as increased worries and fear (P

Background: Refinement of parameters defining prostate cancer (PC) prognosis are urgently needed to identify patients with indolent versus aggressive disease. The Canadian Prostate Cancer Biomaker Network (CPCBN) consists of researchers from four Canadian provinces to create a validation cohort to address issues dealing with PC diagnosis and management. Methods: A total of 1512 radical prostatectomy (RP) specimens from five different biorepositories affiliated with teaching hospitals were selected to constitute the cohort. Tumoral and adjacent benign tissues were arrayed on tissue microarrays (TMAs). A patient clinical database was developed and includes data on diagnosis, treatment and clinical outcome. Results: Mean age at diagnosis of patients in the cohort was 61 years. Of these patients, 31% had a low grade (≤6) Gleason score (GS), 55% had GS 7 (40% of 3 + 4 and 15% of 4 + 3) and 14% had high GS (≥8) PC. The median follow-up of the cohort was 113 months. A total of 34% had a biochemical relapse, 4% developed bone metastasis and 3% of patients died from PC while 9% died of other causes. Pathological review of the TMAs confirmed the presence of tumor and benign tissue cores for > 94% of patients. Immunohistochemistry and FISH analyses, performed on a small set of specimens, showed high quality results and no biorepository-specific bias. Conclusions: The CPCBN RP cohort is representative of real world PC disease observed in the Canadian population. The frequency of biochemical relapse and bone metastasis as events allows for a precise assessment of the prognostic value of biomarkers. This resource is available, in a step-wise manner, for researchers who intend to validate prognostic biomarkers in PC. Combining multiple biomarkers with clinical and pathologic parameters that are predictive of outcome will aid in clinical decision-making for patients treated for PC.

Background: In men with localized prostate cancer who are undergoing radical prostatectomy (RP), it is uncertain whether their systemic hormonal environment is associated with outcomes. The objective of the study was to examine the association between the circulating steroid metabolome with prognostic factors and progression. Methods: The prospective PROCURE cohort was recruited from 2007 to 2012, and comprises 1,766 patients with localized prostate cancer who provided blood samples prior to RP. The levels of 15 steroids were measured in plasma using mass spectrometry, and their association with prognostic factors and disease-free survival (DFS) was established with logistic regression and multivariable Cox proportional hazard models. Results: The median follow-up time after surgery was 73.2 months. Overall, 524 patients experienced biochemical failure and 75 developed metastatic disease. Testosterone and androsterone levels were higher in low-risk disease. Associations were observed between adrenal precursors and risk of cancer progression. In high-risk patients, a one-unit increment in log-transformed androstenediol (A5diol) and dehydroepiandrosterone-sulfate (DHEA-S) levels were linked to DFS with HR of 1.47 (P = 0.0017; q = 0.026) and 1.24 (P = 0.043; q = 0.323), respectively. Although the number of metastatic events was limited, trends with metastasis-free survival were observed for A5diol (HR = 1.51; P = 0.057) and DHEA-S levels (HR = 1.43; P = 0.054). Conclusions: In men with localized prostate cancer, our data suggest that the preoperative steroid metabolome is associated with the risk of recurrence of high-risk disease. Impact: The associations of adrenal androgens with progression of localized high-risk disease could help refine hormonal strategies for these patients.

To evaluate the five-tier Gleason grade group (GG) scoring of prostate cancers adopted by the International Society of Urology Pathology (ISUP) in 2014, and to propose modifications to optimize its performance.Data were obtained from PROCURE, a prospective cohort of patients with localized prostate cancer undergoing radical prostatectomy in Québec, 2006-2013. Surgical specimens were evaluated by genitourinary pathologists using 2014 ISUP criteria. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy. Analyses were conducted using Kaplan-Meier methods, log-rank tests, Cox proportional hazards models and Harrell's concordance indices.A total of 1 917 patients were included, with a median follow-up of 69 months. The 5-year treatment failure rates were 9.6%, 23.5%, 43.1%, 52.6% and 84.3% in GG1-5, respectively (P 0.001 when comparing GG2 with GG3). Treatment failure rates for patients in GG2 and GG3 with tertiary Gleason 5 pattern were higher than patients in the same group without a tertiary pattern (P 0.001), but were similar to rates for patients in GGs 3 or 4 without a tertiary pattern (P 0.3). Primary Gleason pattern (4/5) predicted treatment failure in GG5 (5-year failure rates 82.3% vs 97.1%, respectively; P = 0.001). The five-tier GG system had greater accuracy as a prognostic indicator compared with the four-tier system (Harrell's concordance index 0.716 vs 0.676). When upgrading patients in GG2/3 with tertiary Gleason 5 pattern to patients in GG3/4, and separating patients in GG5 by primary Gleason pattern, the Harrell's concordance index increased to 0.730.The five-tier GG system increased accuracy for predicting treatment failure compared with the previous grading systems, but can be further improved.

We evaluated whether an increased body-mass index (BMI) and decreased physical activity increase the risk of locally advanced or high-risk prostate cancer (PCa) at radical prostatectomy (RP), and treatment failure after surgery.Data were collected from the PROCURE Biobank, a prospective cohort of patients with localized PCa undergoing RP in four academic centers in Québec between 2006 and 2013. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy, and analyzed using the Kaplan-Meier method, log-rank tests, and Cox proportional-hazards models. Uni- and multivariate (ordered) logistic regression was used for time-independent variables.1813 patients were included. Median follow-up time was 69 months. Patients who reported a lower BMI were generally older, of Asian descent, and physically more active (p 0.05). Younger, black, and overweight/obese patients reported less physical activity (p 0.05). In multivariate analyses, a higher BMI increased the risk for locally advanced, high-risk PCa (defined as a pT3, N1 and/or Gleason 8-10 tumor; odds ratio 1.33, p 0.001), but increased physical activity did not predict high-risk disease (odds ratio 0.84, p = 0.39). Patients with a higher BMI also had a larger prostate at surgery (odds ratio 1.13, p = 0.03). BMI and physical activity were not associated with positive surgical margins or time to treatment failure (p 0.05).BMI was an independent predictor for locally advanced, high-risk disease in this cohort of PCa patients undergoing RP, but was unrelated to treatment failure. Physical activity was not related to locally advanced, high-risk PCa or treatment failure.

Prostate cancer is a clinically heterogeneous disease and accurately risk-stratifying patients is a key clinical challenge. We hypothesized that the concurrent identification of the DNA copy number alterations 10q23.3 (PTEN) deletion and 16p13.3 (PDPK1) gain, related to the PI3K/AKT survival pathway, would improve prognostication. We assessed PTEN deletion status using fluorescence in situ hybridization (FISH) and evaluated its clinical significance in combination with the 16p13.3 gain in a set of 332 primary radical prostatectomy cases on a tissue microarray with clinical follow-up. The PTEN deletion was detected in 34% (97/287) of the evaluable tumors and was significantly associated with high Gleason grade group (P

Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

Identifying tumors with high metastatic potential is key to improving the clinical management of prostate cancer. Recently, we characterized a chromosome 16p13.3 gain frequently observed in prostate cancer metastases and now demonstrate the prognostic value of this genomic alteration in surgically treated prostate cancer. Dual-color FISH was used to detect 16p13.3 gain on a human tissue microarray representing 304 primary radical prostatectomy (RP) cases with clinical follow-up data. The results were validated in an external dataset. The 16p13.3 gain was detected in 42% (113/267) of the specimens scorable by FISH and was significantly associated with clinicopathologic features of aggressive prostate cancer, including high preoperative PSA (P = 0.03) levels, high Gleason score (GS, P < 0.0001), advanced pathologic tumor stage (P < 0.0001), and positive surgical margins (P = 0.009). The 16p13.3 gain predicted biochemical recurrence (BCR) in the overall cohort (log-rank P = 0.0005), and in subsets of patients with PSA ≤10 or GS ≤7 (log-rank P = 0.02 and P = 0.006, respectively). Moreover, combining the 16p13.3 gain status with standard prognostic markers improved BCR risk stratification and identified a subgroup of patients with high probability of recurrence. The 16p13.3 gain status was also associated with an increased risk of developing distant metastases (log-rank P = 0.03) further substantiating its role in prostate cancer progression. Implications: This study demonstrates the prognostic significance of the 16p13.3 genomic gain in primary prostate tumors, suggesting potential utility in the clinical management of the disease by identifying patients at high risk of recurrence who may benefit from adjuvant therapies. Mol Cancer Res; 16(1); 115–23. ©2017 AACR.

Background Abiraterone acetate was introduced in Quebec in 2012 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who had received chemotherapy with docetaxel. This study describes abiraterone use in the early postapproval period and its clinical effectiveness in Quebec, for both patients who had received docetaxel chemotherapy and those who could not receive docetaxel therapy owing to medical reasons. Methods A retrospective cohort study was conducted using Quebec public health care administrative databases. Our cohort consisted of patients with mCRPC who received abiraterone between January 2012 and June 2013. Treatment groups were defined as patients who received abiraterone following docetaxel chemotherapy and those who received abiraterone without having had chemotherapy, under the "exception patient" measure. Study outcomes included overall survival, duration of abiraterone therapy and number of hospital days. Cox proportional hazard regression was used to estimate the effectiveness of abiraterone adjusted for several covariates. Results Our cohort consisted of 303 patients with mCRPC treated with abiraterone (99 after chemotherapy and 204 as exception patients). The median age at initiation of abiraterone therapy was 75.0 for the postchemotherapy group and 80.0 for the exception patient group. The corresponding median survival values were 12 and 14 months (log-rank test p = 0.8). Risk of death was similar in the 2 groups (adjusted hazard ratio 0.89 [95% confidence interval 0.57-1.38]). Interpretation The effectiveness of abiraterone in older patients who were ineligible for chemotherapy was similar to that of patients with prior docetaxel exposure. Overall, the real-world survival benefits of abiraterone were similar to those in the COU-AA-301 trial.

Active surveillance (AS) is commonly recommended for men with localized low-intermediate-risk prostate cancer (PCa). The aim of our study was to assess the probability that patients with PCa would develop unfavorable disease features (UDF) while under AS for the purpose of evaluating whether immediate hemiablation therapy (HAT) could bring clinical benefit to selected patients. In our cohort of AS patients, 157 were diagnosed with unilateral PCa. Using five different definitions of UDF, patients’ data were used to simulate the theoretical outcome whether these patients were managed by immediate unilateral HAT or remained on AS. The mean age at the time of diagnosis was 67 years (range 47–81). The median follow-up was 5.4 years [interquartile range (IQR) 3.4–8]. Baseline characteristics included a median PSA value of 5.5 ng/ml (IQR 4.5–7), median number of biopsy taken of 10 (IQR 6–10), and maximum cancer percentage on any core of 10 (IQR 5–20). Of the 157 patients, 144 (92 %) had a Gleason score (GS) of ≤6. Using the whole range of definition for UDF, 10–47 % of patients developed UDF while under AS. Using baseline GS, maximum percentage of cancer on any core, and PSA density, we found significant trends for higher development of UDF for patients under AS. The majority of our patients did not develop UDF while under AS. Our study, thus, suggests that careful patient selection for focal therapy should be performed to avoid subjecting patients to unnecessary treatment.

Objective To evaluate the clinical and pathological factors influencing the risk of disease progression in a cohort of patients with low–intermediate risk prostate cancer under active surveillance (AS). Patients and Methods We studied 300 patients diagnosed between 1992 and 2012 with prostate adenocarcinoma with favourable parameters or who refused treatment and were managed with AS. Of those, 155 patients with at least one repeat biopsy and no progression criteria at the time of the diagnosis were included for statistical analyses. Patients were followed every 3–6 months for prostate-specific antigen (PSA) measurement and physical examination. Patients were offered repeat prostatic biopsy every year. Disease progression was defined as the presence of one or more of the following criteria: ≥3 positive cores, >50% of cancer in at least one core, and a predominant Gleason pattern of 4. Results For the 155 patients, the mean (sd) age at diagnosis was 67 (7) years; the median (interquartile range) follow-up was 5.4 (3.6–9.5) years. Of these, 67, 25, six, and two patients had two, three, four, and five repeat biopsies, respectively. At baseline, 11 (7%) patients had a Gleason score of 3+4, while the remaining 144 (93%) patients had a Gleason score of ≤6. In all, 50 (32.3%) patients had disease progression on repeat biopsies, with a median progression-free survival time of 7 years. The rate of disease progression decreased after the second repeat biopsy. The 5-year overall survival rate was 100%. Having a PSA density (PSAD) of >0.15 ng/mL/mL, >1 positive core, and Gleason score >6 at the time of the diagnosis was associated with a significantly higher rate of disease progression on univariate analysis (P 10% showed a trend toward significance for a higher progression rate (P = 0.054). On multivariate analysis, only the presence of a PSAD of >0.15 ng/mL/mL remained significant for a higher progression rate (P < 0.05). Of the 155 patients, five (3.2%) subsequently received radiotherapy, 13 (8.4%) received hormonal therapy, and 13 (8.4%) underwent radical prostatectomy. Conclusion AS is a suitable management option for patients with clinically low-risk prostate cancer. A PSAD of >0.15 ng/mL/mL is an important predictor for disease progression.

40 Background: The approval of novel hormonal agents (NHAs), abiraterone and enzalutamide, have increased the therapeutic arsenal available in metastatic castration-resistant prostate cancer (mCRPC). However, the use of chemotherapy and other antineoplastics at the end of life has been suggested as an indicator of poor quality of care. In this study, we report the use of NHAs at the end of life in men with mCRPC in the province of Quebec, Canada. Methods: Using Quebec public healthcare administrative databases, we identified patients with prostate cancer who used an NHA (abiraterone or enzalutamide) after androgen deprivation therapy and who died between 2012 and 2016. The primary outcome was the use of an NHA in the 30 days before death. Use of an NHA in the 60 and 90 days before dying, and initiation (first prescription) of an NHA in the 30 days before death were evaluated as secondary outcomes. Multivariable analysis of the primary outcome was performed with logistic regression with results reported as odds ratios (OR) with 95% confidence intervals (95%CI). Results: The cohort consists of 1316 patients who used an NHA over the course of their disease and died at a median age of 78 years old, with 292 (22.2%), 464 (35.3%), and 575 (43.7%) having used an NHA in the 30, 60 and 90 days of life, respectively. Use of NHA 30 days before dying decreased over the study period, from 44.8% in 2012 to 17.0% in 2016 (Cochran-Armitage test p-value < 0.001). On multivariable analyses, later years of death remained associated with lower odds of NHA use 30 days before death (OR 0.74, 95%CI 0.66 to 0.81, p < 0.001). Fifty-eight (4.4%) patients initiated a NHA 30 days before dying. Conclusions: Rates of NHA use 30 days before dying were high initially but decreased over the study period. Further assessment of NHA use at the end of life is warranted to examine if the trend will be maintained given the recent approval of additional oral NHAs for prostate cancer.

38 Background: Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) treatment, however several side-effects are associated with its long-term use. Notably, loss of bone mineral density (BMD) is accelerated which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to properly assess baseline fracture risk. The objective was to examine the proportion of BMD testing in men initiating long-term ADT in Quebec. Methods: The cohort consists of men extracted from Quebec public healthcare insurance administrative databases who were diagnosed with PCa from 2001-2012 and treated by ADT for at least one continuous year. The primary study outcome was the receipt of baseline BMD testing (defined as a BMD test identified in the period from 6 months prior to and up to 12 months after ADT initiation). Multivariable generalized linear mixed with a logit link was performed to identify variables associated with baseline BMD testing accounting for physician clustering. Results: We identified 7,069 patients, of which 887 (12.6%) underwent baseline BMD testing. Baseline BMD testing varied by year of ADT initiation, from 7.7% in 2001-2003 to 12.3% in 2013-2012. Following multivariable analyses, later years of ADT initiation (2004-2006, 2007-2009, 2010-2012, 2013-2015) remained associated with higher odds of baseline BMD testing compared to the earlier years (2001-2003) (ORs ranging from 1.43-1.88; p < 0.001). Conversely, age > 80 (OR 0.73; 95% CI 0.57-0.94; p = 0.001), greater Charlson comorbidity score (OR 0.51; 95%CI 0.34-0.75; p = 0.001), and rural residence (OR 0.60; 95%CI 0.48-0.75; p < 0.001) were associated with lower odds of baseline BMD testing. Conclusions: In our study population, rates of baseline BMD testing in men initiating ADT are low, although the rates increased over the course of the study period. Potential gaps identified in baseline BMD testing include older, more comorbid patients, and rural residence. Additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.

161 Background: Canadian Urological Association guidelines outline the scheduling of imaging modalities based on prostate-specific antigen doubling time (PSADT) to screen for mets in pts with nonmetastatic (M0) CRPC and to manage pts with metastatic (M1) CRPC. Data describing guideline adoption and real-world timing of bone scans and treatment patterns in Canadian CRPC pts are limited. Methods: A retrospective chart review conducted at 13 Canadian urology practices included pts with CRPC (PSA ≥2 ng/mL despite androgen deprivation therapy) sequentially identified in reverse chronological order starting July 30, 2015. Pts had no mets at CRPC diagnosis (index date). Data were abstracted from the index date to the chart review date. Coprimary objectives were to describe CRPC management in terms of timing of the 1st and repeat bone scans in M0 and treatment patterns when pts became metastatic. Secondary objectives described nonbone imaging. Results: 232 pts enrolled. Over the observation period 109 remained nonmetastatic (M0 cohort); 123 developed mets (M1 cohort). Median index PSADT was ~1.5x greater for the M0 cohort than the M1 cohort. 68 pts (71.6%) in M0 and 117 pts (95.1%) in M1 had ≥1 bone scan. Median (95% CI) months from CRPC diagnosis to 1st bone scan was 7.5 (5.6–9.6) for pts in M1 and 15.7 (10.0–23.0) for pts in M0. Median (95% CI) months from identification of mets to start of treatment for the M1 cohort was 3.2 (2.3–5.7). The most common therapies were abiraterone (55%) and enzalutamide (42%), with respective median (95% CI) durations of 12.7 (8.7–23.3) and 15.7 months (10.4–NE). 25% of pts received a bone-targeted agent. Conclusions: In CRPC, time to first bone scan was shorter for pts who subsequently developed mets or had rapid PSADT. Abiraterone and enzalutamide were the most common therapies in pts with mets. [Table: see text]