Publications by authors named "Neil E Fleshner"

224 Publications

Subpathologies and genomic classifier for treatment individualization of post-prostatectomy radiotherapy.

Urol Oncol 2021 Sep 16. Epub 2021 Sep 16.

Department of Radiation Oncology, University of Toronto; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Techna Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

Purpose/objective: Risk-stratification for post-prostatectomy radiotherapy (PORT) using conventional clinicopathologic indexes leads to substantial over- and under-treatment. Better patient selection could spare unnecessary toxicities and improve outcomes. We investigated the prognostic utility of unfavorable subpathologies intraductal carcinoma and cribriform architecture (IDC/CA), and a 22-gene Decipher genomic classifier (GC) in prostate cancer (PCa) patients receiving PORT.

Material/methods: A cohort of 302 men who received PORT at 2 academic institutions was pooled. PORT was predominately delivered as salvage (62% of cases); 20% received HT+PORT. Specimens were centrally reviewed for IDC/CA presence. In 104 cases, GC scores were determined. Endpoints were biochemical relapse-free (bRFR) and metastasis-free (mFR) rates.

Results: After a median follow-up of 6.49-years, 135 (45%) and 40 (13%) men experienced biochemical relapse and metastasis, respectively. IDC/CA were identified in 160 (53%) of cases. Men harboring IDC/CA experienced inferior bRFR (HR 2.6, 95%CI 1.8-3.2, P<0.001) and mFR (HR 3.1, 95%CI 1.5-6.4, P = 0.0014). Patients with GC scores, 22 (21%) were stratified low-, 30 (29%) intermediate-, and 52 (50%) high-risk. GC low-risk was associated with superior bRFR (HR 0.25, 95%CI 0.1-0.5, P<0.001) and mFR (HR 0.15, 95%CI 0.03-0.8, P = 0.025). On multivariable analyses, IDC/CA and GC independently predicted for bRFR, corresponding to improved discrimination (C-index = 0.737 (95%CI 0.662-0.813)).

Conclusions: IDC/CA subpathologies and GC predict for biochemical relapse and metastasis beyond conventional clinicopathologic indexes in the PORT setting. Patients harboring IDC/CA are at higher risk of relapse after maximal local therapies, thus warranting consideration for treatment intensification strategies. Conversely, for men with absence of IDC/CA and low GC scores, de-intensification strategies could be explored.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.013DOI Listing
September 2021

Genome-wide Meta-analysis Identifies Novel Genes Associated with Recurrence and Progression in Non-muscle-invasive Bladder Cancer.

Eur Urol Oncol 2021 Aug 2. Epub 2021 Aug 2.

Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands.

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed.

Objective: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC.

Design, Setting, And Participants: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation.

Outcome Measurements And Statistical Analysis: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort.

Results And Limitations: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, p = 0.003). Twelve other loci were suggestively associated with RFS (p < 10), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature.

Conclusions: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression.

Patient Summary: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.
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http://dx.doi.org/10.1016/j.euo.2021.07.001DOI Listing
August 2021

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223.

Cancer Med 2021 Sep 13;10(17):5775-5782. Epub 2021 Jul 13.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Background: In men with metastatic castration-resistant prostate cancer (mCRPC) with primarily bone metastases, radium-223 ( Ra) improves overall survival (OS). However, the selection of Ra is not guided by specific validated clinicopathologic factors, and thus outcomes are heterogeneous.

Patients And Methods: This retrospective survival analysis was performed in men with mCRPC treated with Ra at our cancer center. Demographics and disease characteristics were collected. OS was calculated using the Kaplan-Meier method (log-rank). The potential prognostic factors were determined using both univariable (UVA) and multivariable analysis (MVA) (Cox-regression) methods.

Results: In total, 150 patients with a median age of 74 years (52-93) received Ra between May 2015 and July 2018, and 58% had 6-20 bone metastases. Ninety-four (63%) patients received >4 Ra doses, and 56 (37%) received ≤4. The following pre-treatment factors were analyzed (median [range]): eastern cooperative oncology group performance status (ECOG PS), (1 [0-3]); Albumin (ALB), (39 g/L [24-47]); alkaline phosphatase (ALP), (110 U/L [35-1633]); and prostate-specific antigen (PSA), (49 µg/L [0.83-7238]). The median OS for all patients was 14.5 months (95% CI: 11.2-18). These factors were associated with poor survival outcomes in UVA and MVA: ALB <35 g/L, ALP >150 U/L, ECOG PS 2-3, and PSA >80 µg/L. By assigning one point for each of these factors, a prognostic model was developed, wherein three distinct risk groups were identified: good, 0-1 (n = 103); intermediate, 2 (n = 30); and poor risk, 3-4 points (n = 17). The median OS was 19.4, 10.0, and 3.1 months, respectively (p < 0.001).

Conclusions: Pre-treatment ALB, ALP, ECOG, and PSA, were significantly correlated with OS and could guide treatment selection for men with mCRPC by identifying those who are most or least likely to benefit from Ra. Validation in an independent dataset is required prior to widespread clinical utilization.
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http://dx.doi.org/10.1002/cam4.4125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419779PMC
September 2021

Characterization and management of NMIBC recurrences after TMT: a matched cohort analysis.

Urol Oncol 2021 Jun 13. Epub 2021 Jun 13.

Division of Urology, Department of Surgery and Surgical Oncology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Canada.

Introduction And Objective: Bladder preservation with trimodal therapy (TMT) has emerged as a feasible alternative strategy to treat localized muscle invasive bladder cancer (MIBC). There is lack of consensus regarding the treatment of local recurrence following TMT. The aim of this paper is to determine whether traditional NMIBC therapies can be applied to the management of NMIBC recurrences following TMT.

Methods: Using our institutional bladder cancer radiotherapy database, all patients with recurrent NMIBC following TMT were identified between 2008-2019. TMT patients were initially treated with maximal TURBT followed by combination chemotherapy/radiotherapy (weekly cisplatin 40 mg/m and 64-66 Gy to the bladder) with localizing Lipiodol injections. We compared NMIBC recurrent patients to a cohort of matched controls with primary NMIBC, hypothesizing that post-TMT patients treated with traditional NMIBC therapies would have outcomes similar to patients with primary NMIBC. Primary NMIBC patients were derived from our local NMIBC database and matching was based on clinical stage and grade in a 5:1 manner (controls:cases). Recurrences in the TMT group were managed according to the standard therapy for NMIBC. A descriptive analysis was performed between patients undergoing TMT with NMIBC recurrence and patients initially diagnosed with de novo NMIBC. Overall survival was calculated for each group and analyzed using the Kaplan-Meier method and Cox proportional hazards modeling. Recurrence-free and cystectomy-free survival were analyzed using competing risk methods.

Results: Twelve patients out of 124 patients in the TMT cohort had NMIBC recurrence and were compared to 60 patients in a control group who were diagnosed with de-novo NMIBC. Median age of the TMT group was 78 [54 - 84] years versus 66 [23 - 88] years for the non-TMT group. Median follow-up for was 3.6 years versus 5.4 years in the non-TMT group. The clinical stage of the TMT NMIBC recurrences was Ta (n = 4), T1 (n = 3), CIS (n = 5). During the follow-up period, 38 (63%) further recurrences occurred in the non-TMT group compared to 2 (17%) in TMT group (P = 0.004). One patient (8%) from the TMT group required a cystectomy compared to 11 (18%) in the non-TMT group (P = 0.68). There were 2 non-cancer deaths (17%) in TMT group compared to one (2%) in the non-TMT group.

Conclusion: Our study demonstrates NMIBC recurrences post TMT can be successfully managed with endoscopic and adjuvant intravesical therapies.
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http://dx.doi.org/10.1016/j.urolonc.2021.05.008DOI Listing
June 2021

Genitourinary Cancer Prevention: Can We Make It a Reality?

Authors:
Neil E Fleshner

Eur Urol Focus 2021 May 3;7(3):497-498. Epub 2021 Jun 3.

Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.euf.2021.05.004DOI Listing
May 2021

Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer.

Sci Rep 2021 03 23;11(1):6630. Epub 2021 Mar 23.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 60 Murray Street, Toronto, ON, M5T 3L9, Canada.

Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.
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http://dx.doi.org/10.1038/s41598-021-85812-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988053PMC
March 2021

Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

Eur Urol 2021 Sep 6;80(3):374-382. Epub 2021 Mar 6.

University of Toronto, Department of Radiation Oncology, 149 College Street, Unit 504, Toronto, Ontario, M5T 1P5, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 700 University Avenue, 7th floor, Toronto, Ontario, M5G 1Z5, Canada; TECHNA Institute, University Health Network, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. Electronic address:

Background: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches.

Objective: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT).

Design/setting/participants: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible.

Interventions: All patients underwent [F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT.

Outcome Measurements/statistical Analysis: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and β of 0.1.

Results: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed.

Conclusions: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa.

Patient Summary: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.
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http://dx.doi.org/10.1016/j.eururo.2021.02.031DOI Listing
September 2021

Benefit of a more extended pelvic lymph node dissection among patients undergoing radical prostatectomy for localized prostate cancer: A causal mediation analysis.

Prostate 2021 04 18;81(5):286-294. Epub 2021 Feb 18.

Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: The therapeutic role of extended (ePLND) versus nonextended pelvic lymph node dissection (nePLND) to remove occult micrometastases in men undergoing radical prostatectomy for localized prostate cancer (PC) is conflicting. Therefore, our aim was to quantify the direct effect of ePLND versus nePLND (removal of occult micrometastases), which is not mediated through the detection of nodal disease and potential adjuvant therapy (indirect effect).

Methods: Retrospective, bi-center cohort study of consecutive patients undergoing radical prostatectomy and PLND for PC (January 2006 and December 2016). Patients were followed until April 2018 for the occurrence of either biochemical recurrence or secondary therapy (composite outcome). ePLND was compared to nePLND by unweighted and weighted survival analysis (total effect) as well as by causal mediation analysis (direct and indirect effect).

Results: Positive nodal disease was detected in 71 (7%) out of 1008 patients undergoing radical prostatectomy and PLND for PC (ePLND: 368 [36.5%]; nePLND: 640 [63.5%]). Survival analysis demonstrated results in favor of ePLND (unweighted hazard ratio: 0.77 [95% confidence interval: 0.59-1.01], p = .056; weighted hazard ratio: 0.75 [0.56-0.99], p = .044). The causal mediation analysis confirmed the total effect of 0.77 (0.71-0.82). After disentangling this total effect into an indirect effect (via detection of nodal disease and potential adjuvant therapy) and a direct effect (via removal of occult micrometastases), we identified an even more protective direct effect of 0.69 (0.63-0.75).

Conclusions: Our results not only indicate the utility of ePLND but also that its impact is not restricted to a staging benefit and probably involves a therapeutic benefit mediated through the removal of occult micrometastases.
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http://dx.doi.org/10.1002/pros.24105DOI Listing
April 2021

Quantitative Prostate MRI Analysis Following Fluvastatin Therapy for Localized Prostate Cancer - A Pilot Study.

Can Assoc Radiol J 2021 Feb 10:846537120988262. Epub 2021 Feb 10.

Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.

Purpose: To assess the role of multi-parametric MRI (mpMRI) in assessment of tumor response to fluvastatin administered prior to radical prostatectomy.

Methods: Men with MRI-visible, clinically significant prostate cancer and due to be treated with radical prostatectomy were prospectively enrolled. mpMRI was performed at baseline and following 6-7 week of neoadjuvant oral statin therapy (40 mg fluvastatin, twice daily), prior to prostatectomy. MRI assessment included tumor size, T2 relaxation time, ADC value, K-trans (volume transfer constant), Kep (reflux constant), and Ve (fractional volume) parameters at the 2 time points. Initial prostate needle biopsy cores, prior to starting oral statin therapy, corresponding to site of tumor on radical prostatectomy specimens were selected for analysis. The effect of fluvastatin on tumor proliferation (marker Ki67) and on tumor cell apoptosis (marker cleaved Caspase-3, CC3) were analyzed and correlated with MRI findings.

Results: Nine men with paired MRI studies were included in the study. Binary histopathological data was available for 6 of the participants. No significant change in tumor size ( = 0.898), T2 relaxation time ( = 0.213), ADC value ( = 0.455), K-trans ( = 0.613), Kep ( = 0.547) or Ve ( = 0.883) between the time of biopsy and prostatectomy were observed. No significant change in tumor proliferation (%Ki67-positive cells, = 0.766) was observed by immunohistochemistry analysis. However, there was a significant increase in tumor cell apoptosis (%CC3-positive cells, = 0.047).

Conclusion: mpMRI techniques may not be sufficiently sensitive to detect the types (or magnitude) of tumor cell changes observed following 6-7 weeks of fluvastatin therapy for prostate cancer.
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http://dx.doi.org/10.1177/0846537120988262DOI Listing
February 2021

Adherence to Mediterranean Diet, Physical Activity and Survival after Prostate Cancer Diagnosis.

Nutrients 2021 Jan 16;13(1). Epub 2021 Jan 16.

Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano IRCCS, via F. Gallini 2, 33081 Aviano, Italy.

Despite the considerable number of studies investigating the Mediterranean diet in prostate cancer (PCa) etiology, very few focused on cancer survival. We assessed the pre-diagnostic diet and physical activity in a cohort of 777 men with PCa diagnosed between 1995 and 2002 in north-eastern Italy; adherence to the Mediterranean diet was evaluated through the Mediterranean Diet Score (MDS). Hazard ratios (HR) of death with confidence intervals (CI) were estimated using the Cox model, adjusting for potential confounders. During 10 years of follow-up, 208 patients (26.8%) died, 75 (9.7%) due to PCa. Patients reporting MDS ≥ 5 showed a higher overall survival than those with MDS < 5 (HR = 0.74; 95% CI: 0.56-0.99). Although high physical activity was not significantly associated with overall survival (HR = 0.79; 95% CI: 0.59-1.07), the HR for all-cause death was the lowest (HR = 0.58; 95% CI: 0.38-0.90) for men reporting MDS ≥ 5 and high physical activity compared to those reporting MDS < 5 and low/moderate physical activity. No association emerged for PCa specific survival. Study findings support the beneficial impact of pre-diagnostic adherence to the Mediterranean diet and physical activity on overall survival; they are mainly driven by risk reduction in non-prostate cancer mortality, which however accounts for about 80% of death in men with PCa.
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http://dx.doi.org/10.3390/nu13010243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829941PMC
January 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Is there an association between a history of military service and cancer diagnosis? Results from a US national-level study of self-reported outcomes.

Cancer Causes Control 2021 Jan 16;32(1):47-55. Epub 2020 Oct 16.

Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.

Purpose: To examine cancer prevalence in men with and without military service history, using national-level self-reported outcomes.

Methods: A cross-sectional survey-based US study, including men aged 18 and above from the Health Information National Trends Survey database between 2011 and 2014. The primary endpoint was self-reported cancer prevalence. Multivariable logistic regression analyses assessed the association of various covariates with the prevalence of cancer.

Results: A total of 4,527 men were analyzed, with 1,352 (29.9%) reporting a history of military service. Compared to men with no military service history, men with a military service history were older (median of 65 [IQR 56, 74] vs. 53 [IQR 41, 62] years, p < 0.0001), more commonly Caucasian (71.4% vs. 61.4%, p < 0.0001), born in the US (95.6% vs. 79.5%, p < 0.0001), attained higher education level and annual household income (p < 0.0001), and consisted of more smokers(58.3% vs. 44.5%, p < 0.0001). The age-adjusted comparison demonstrated a higher cancer prevalence in men with military service history (20.5% vs. 7.6%, p < 0.0001). Specifically, genitourinary, dermatological, gastrointestinal, and hematological cancers were generally more prevalent. Adjusting for all available confounders, multivariable models showed that military service history was associated with 1.56 (95% CI 1.20-2.03), and 1.57 (95% CI 1.07-2.31) increased odds of having any cancer, and specifically genitourinary cancer, respectively.

Conclusions: Further research is needed to ascertain whether the association between military service and increased cancer diagnosis results from better screening programs or increased exposure to risk factors during military service.
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http://dx.doi.org/10.1007/s10552-020-01355-4DOI Listing
January 2021

A 38-gene model comprised of key TET2-associated genes shows additive utility to high-risk prostate cancer cases in the prognostication of biochemical recurrence.

BMC Cancer 2020 Oct 2;20(1):953. Epub 2020 Oct 2.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, M5T 3L9, Canada.

Background: Early treatment of patients at risk for developing aggressive prostate cancer is able to delay metastasis and reduce mortality; as such, up-front identification of these patients is critical. Several risk classification systems, including CAPRA-S, are currently used for disease prognostication. However, high-risk patients identified by these systems can still exhibit wide-ranging disease outcomes, leading to overtreatment of some patients in this group.

Methods: The master methylation regulator TET2 is downregulated in prostate cancer, where its loss is linked to aggressive disease and poor outcome. Using a random forest strategy, we developed a model based on the expression of 38 genes associated with TET2 utilizing 100 radical prostatectomy samples (training cohort) with a 49% biochemical recurrence rate. This 38-gene model was comprised of both upregulated and downregulated TET2-associated genes with a binary outcome, and was further assessed in an independent validation (n = 423) dataset for association with biochemical recurrence.

Results: 38-gene model status was able to correctly identify patients exhibiting recurrence with 81.4% sensitivity in the validation cohort, and added significant prognostic utility to the high-risk CAPRA-S classification group. Patients considered high-risk by CAPRA-S with negative 38-gene model status exhibited no statistically significant difference in time to recurrence from low-risk CAPRA-S patients, indicating that the expression of TET2-associated genes is able to separate truly high-risk cases from those which have a more benign disease course.

Conclusions: The 38-gene model may hold potential in determining which patients would truly benefit from aggressive treatment course, demonstrating a novel role for genes linked to TET2 in the prognostication of PCa and indicating the importance of TET2 dysregulation among high-risk patient groups.
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http://dx.doi.org/10.1186/s12885-020-07438-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530956PMC
October 2020

Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.

JAMA Oncol 2020 Nov;6(11):1751-1758

Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, Ontario, Canada.

Importance: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial.

Objectives: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC.

Design, Setting, And Participants: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function.

Interventions: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS).

Results: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life.

Conclusions And Relevance: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting.

Trial Registration: ClinicalTrials.gov Identifier: NCT02033993.
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http://dx.doi.org/10.1001/jamaoncol.2020.3927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499236PMC
November 2020

Can post-treatment free PSA ratio be used to predict adverse outcomes in recurrent prostate cancer?

BJU Int 2021 06 26;127(6):654-664. Epub 2020 Sep 26.

Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, ON, Canada.

Objectives: To assess whether free PSA ratio (FPSAR) at biochemical recurrence (BCR) can predict metastasis, castrate-resistant prostate cancer (CRPC), and cancer-specific survival (CSS), following therapy for localised disease.

Patients And Methods: A single-centre retrospective cohort study (NCT03927287) including a discovery cohort composed of patients with an FPSAR after radical prostatectomy (RP) or radiotherapy (RT) between 2000 and 2017. For validation, an independent Biobank cohort of patients with BCR after RP was tested. Using a defined FPSAR cut-off, the metastasis-free-survival (MFS), CRPC-free survival, and CSS were compared. Multivariable Cox models determined the association between post-treatment FPSAR, metastases, and CRPC.

Results: Overall, 822 patients (305 RP- and 363 RT-treated patients and 154 Biobank patients) were analysed. In the RP cohort, a total of 272/305 (89.1%) and 33/305 (10.9%) had a FPSAR test incidentally and reflexively, respectively. In the RT cohort, 155/363 (42.7%) and 208/263 (57.3%) had a FPSAR test incidentally and reflexively, respectively. However, in the prospective Biobank RP cohort, FPSAR testing was done on all samples of patients diagnosed with BCR. A FPSAR cut-off of 0.10 was determined using receiver operating characteristic analyses in both the RP and RT cohorts. A FPSAR of <0.10 resulted in longer median MFS (14.8 vs 9.3 years and 14.8 vs 13 years, respectively), and longer median CRPC-free survival (median not reached vs 9.9 years and 20.7 vs 13.8 years, respectively). Multivariable analyses showed that a FPSAR of ≥0.10 was associated with increased metastasis in the RP cohort (hazard ratio [HR] 1.915, 95% confidence interval [CI] 1.241-2.955) and RT cohort (HR 1.754, 95% CI 1.112-2.769), and increased CRPC in the RP cohort (HR 2.470, 95% CI 1.493-4.088). Findings were validated in the Biobank cohort.

Conclusions: A post-treatment FPSAR of ≥0.10 is associated with more aggressive disease, suggesting a potentially novel role for this biomarker.
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http://dx.doi.org/10.1111/bju.15236DOI Listing
June 2021

Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment.

Epigenomics 2020 08 1;12(15):1317-1332. Epub 2020 Sep 1.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, M5G 1X5, Canada.

We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC) during treatment. Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Alterations in methylation states of genes previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression. Importantly, we also report that markers associated with a highly aggressive form of the disease, neuroendocrine-CRPC, were associated with a faster time to clinical progression. Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.
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http://dx.doi.org/10.2217/epi-2020-0173DOI Listing
August 2020

Diagnostic utility of axial imaging in the evaluation of hematuria: A systematic review and critical appraisal of the literature.

Can Urol Assoc J 2021 Feb;15(2):48-55

Section of Urology, Department of Surgery, Medical College of Georgia-Augusta University, Augusta, GA, United States.

Introduction: Increasing severity of hematuria is instinctively associated with higher likelihood of urological malignancy. However, the robustness of the evidentiary base for this assertion is unclear, particularly as it relates to the likelihood of upper urinary tract pathology. Thus, the value of axial imaging in the diagnostic workup of hematuria is unclear due to differences in the underlying patient populations, raising concern for sampling bias. We performed a systematic review to characterize the literature and association between severity of hematuria and likelihood of upper urinary tract cancer based on axial imaging.

Methods: MEDLINE, EMBASE, and Cochrane were systematically searched for all studies reporting on adult patients presenting with hematuria. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for reporting of this systematic review and meta-analysis and the Newcastle-Ottawa Scale for risk of bias assessment. Degree of hematuria was classified as "microscopic," "gross," or "unspecified." Three urological malignancies (bladder, upper tract urothelial, and renal cancer) were considered both individually and in aggregate. Random-effects model with pairwise comparisons was employed to arrive at the axial imaging diagnostic yields.

Results: Twenty-nine studies were included, of which six (20.7%) reported on patients with gross hematuria only, four (13.8%) reported on patients with microscopic hematuria only, seven (24.1%) included both, and 12 (41.4%) did not define or specify the severity of hematuria. Of 29 studies, two (6.9%) were at high-risk of bias, 21 (72.4%) at intermediate-risk, and six (20.7%) at low-risk of bias using the Newcastle-Ottawa criteria. Based on axial imaging, rates of diagnoses of renal, upper tract urothelial, and bladder cancers differed with differing severity of hematuria. Notably, rates of renal and upper tract urothelial carcinoma were higher in studies of patients with unspecified hematuria severity (3.6% and 10.4%, respectively) than among patients with gross hematuria (1.5% and 1.3%, respectively). When all urological malignancies were pooled, patients with unspecified hematuria were diagnosed more frequently (19.5%) compared to those with gross (15.3%) and microscopic hematuria (4.5%, difference=1.51%, 99% confidence interval 3.6-26.5%).

Conclusions: Lack of granularity in the available literature, particularly with regards to patients with unspecified hematuria severity, limits the generalizability of these results and highlights the need for future studies that provide sufficient baseline information, allowing for firmer conclusions to be drawn.
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http://dx.doi.org/10.5489/cuaj.6522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864718PMC
February 2021

Sequential administration of Bacillus Calmette-Guerin (BCG) and Electromotive Drug Administration (EMDA) of mitomycin C (MMC) for the treatment of high-grade nonmuscle invasive bladder cancer after BCG failure.

Urol Oncol 2020 11 23;38(11):850.e9-850.e15. Epub 2020 Jul 23.

Department of Surgical Oncology, Urology. University Health Network, Toronto, ON, Canada; Department of Surgery, Urology, Sinai Health System, Mount Sinai Hospital, Toronto, ON, Canada. Electronic address:

Background: There is a need for effective nonsurgical treatment options in patients with nonmuscle invasive bladder cancer (NMIBC) in whom Bacillus Calmette-Guerin (BCG) therapy has failed.

Objective: We aimed to determine the efficacy of Electromotive Drug Administration (EMDA) of mitomycin C (MMC) with NMIBC after BCG failure.

Design, Setting, And Participants: A retrospective review of 26 NMIBC patients in whom BCG therapy failed who received BCG/EMDA-MMC between 2013 and 2017 was performed. All but 4 patients fulfilled the FDA criteria for BCG unresponsive disease. Progression and recurrence-free survival (RFS)were calculated using Kaplan-Meier curves. Progression was defined as development of muscle invasive disease, presence of metastasis on imaging or treatment. We used FDA-defined criteria as complete response (CR) for single-arm trials of BCG-unresponsive patients.

Results And Limitations: Twenty-six patients were included. Initial pathology was carcinoma in situ (CIS) in 53.8% (14/26), pT1 in 34.6% (9/26), and pTa HG disease in 11.6% (3/26). Twelve of 26 patients progressed (46.2%). Following BCG/EMDA-MMC treatment, progression-free survival rates were 58.3% (95% confidence interval [CI] 41.1-82.1) at 1 year and 48.9% (95% CI 48.9) at 2 years from the date of induction of BCG/EMDA-MMC, respectively. RFS was 41.9% (95% CI 25.9-67.8) at 1 year and 27.2% (95% CI 13.6-54.4) at 2 years. CR at 6, 12, and 18 months was observed in 16 (61.5%), 11 (44.0%), and 7 patients (30.4%), respectively. Side effects included dysuria (19.2%), hematuria (19.2%), and frequency (11.5%). Three patients were admitted for side effects but managed conservatively. Four patients (15.4%) died of bladder cancer over the course of the study.

Conclusions: EMDA-MMC BCG represents a viable option in patients with BCG unresponsive NMIBC with close to 50% progression-free survival at 2 years. However, these patients have a high risk of death from bladder cancer (15% in our cohort at 2 years) thus warranting extremely close surveillance.
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http://dx.doi.org/10.1016/j.urolonc.2020.06.031DOI Listing
November 2020

Small Renal Mass Surveillance: Histology-specific Growth Rates in a Biopsy-characterized Cohort.

Eur Urol 2020 09 14;78(3):460-467. Epub 2020 Jul 14.

Division of Urology, Department of Surgery, Princess Margaret Cancer Centre and the University Health Network, University of Toronto, Toronto, ON, Canada.

Background: Most reports of active surveillance (AS) of small renal masses (SRMs) lack biopsy confirmation, and therefore include benign tumors and different subtypes of renal cell carcinoma (RCC).

Objective: We compared the growth rates and progression of different histologic subtypes of RCC SRMs (SRM) in the largest cohort of patients with biopsy-characterized SRMs on AS.

Design, Setting, And Participants: Data from patients in a multicenter Canadian trial and a Princess Margaret cohort were combined to include 136 biopsy-proven SRM lesions managed by AS, with treatment deferred until progression or patient/surgeon decision.

Outcome Measurements And Statistical Analysis: Growth curves were estimated from serial tumor size measures. Tumor progression was defined by sustained size ≥4 cm or volume doubling within 1 yr.

Results And Limitations: Median follow-up for patients who remained on AS was 5.8 yr (interquartile range 3.4-7.5 yr). Clear cell RCC SRMs (SRM) grew faster than papillary type 1 SRMs (0.25 and 0.02 cm/yr on average, respectively, p =  0.0003). Overall, 60 SRM lesions progressed: 49 (82%) by rapid growth (volume doubling), seven (12%) increasing to ≥4 cm, and four (6.7%) by both criteria. Six patients developed metastases, and all were of clear cell RCC histology. Limitations include the use of different imaging modalities and a lack of central imaging review.

Conclusions: Tumor growth varies between histologic subtypes of SRM and among SRM, which likely reflects individual host and tumor biology. Without validated biomarkers that predict this variation, initial follow-up of histologically characterized SRMs can inform personalized treatment for patients on AS.

Patient Summary: Many small kidney cancers are suitable for surveillance and can be monitored over time for change. We demonstrate that different types of kidney cancers grow at different rates and are at different risks of progression. These results may guide better personalized treatment.
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http://dx.doi.org/10.1016/j.eururo.2020.06.053DOI Listing
September 2020

Re: Reconsidering Prostate Cancer Mortality - The Future of PSA Screening: Against increasing PSA threshold to 10 ng/ml.

Eur Urol 2020 12 2;78(6):927-929. Epub 2020 Jul 2.

Department of Surgical Oncology, Urology, University Health Network, Toronto, Canada.

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http://dx.doi.org/10.1016/j.eururo.2020.06.026DOI Listing
December 2020

Determining the Impact of Spatial Heterogeneity on Genomic Prognostic Biomarkers for Localized Prostate Cancer.

Eur Urol Oncol 2020 Jun 27. Epub 2020 Jun 27.

Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada; Techna Institute, University Health Network, Toronto, ON, Canada. Electronic address:

Localized prostate tumors show remarkably diverse clinical courses, with some being cured by local therapy alone, while others rapidly relapse and have a lethal course despite precision surgery or radiotherapy. Many genomic biomarkers have been developed to predict this clinical behavior, but these are confounded by the extreme spatial heterogeneity of prostate tumors: most are multifocal and harbor multiple subclonal populations. To quantify the influence of spatial heterogeneity on genomic prognostic biomarkers, we developed a case-control high-risk cohort (n = 42) using a prospective registry, risk matched by clinicopathologic prognostic indices. Half of the cohort had early biochemical recurrence (BCR; ie, ≤18 mo), while half remained without evidence of disease for at least 48 mo after radical prostatectomy. We then genomically profiled multiple tumor foci per patient, analyzing 119 total specimens. These data allowed us to validate three published genomic prognostic biomarkers and quantify their sensitivity to tumor spatial heterogeneity. Remarkably, all three biomarkers robustly predicted early BCR, and all three were robust to spatiogenomic variability. These data suggest that DNA-based genomic biomarkers can overcome intratumoral heterogeneity: single biopsies may be sufficient to estimate the risk of early BCR after radical treatment in patients with high-risk disease. PATIENT SUMMARY: We investigated whether heterogeneity between tumor regions within the prostate affects the accuracy of DNA-based biomarkers predicting early relapse after prostatectomy. We observed persistent accuracy in predicting disease relapse, suggesting that spatial heterogeneity may not hinder biomarker performance.
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http://dx.doi.org/10.1016/j.euo.2020.06.005DOI Listing
June 2020

Canadian experience of neoadjuvant chemotherapy on bladder recurrences in patients managed with trimodal therapy for muscle-invasive bladder cancer.

Can Urol Assoc J 2020 Dec;14(12):404-410

Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Introduction: Bladder preservation with trimodal therapy (TMT) has emerged as a feasible alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Neoadjuvant chemotherapy (NAC) was proven to cause pathological downstaging. For this reason, we evaluated whether receipt of NAC decreases local bladder recurrences in TMT patients.

Methods: We retrospectively analyzed our TMT database for all patients treated between 2003 and 2017. Patients were treated with maximal transurethral resection of bladder tumor (TURBT) followed by chemotherapy/radiotherapy with or without NAC. Baseline demographic and tumor characteristics were recorded. Rates of local and systemic recurrence were analyzed per receipt of NAC. Overall recurrence-free survival (RFS) and bladder (b)RFS were analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.

Results: Median age and followup periods were 72 years and 3.6 years, respectively. Fifty-four patients had NAC and concurrent chemoradiation (NAC-TMT) vs. 70 patients who had concurrent chemoradiation only (TMT). Carcinoma in situ (CIS) was present in 31% of the patients in NAC-TMT group compared to 24% in TMT group (p=0.40). After treatment, 24 (44%) and 31 (44%) patients in NAC-TMT and TMT groups, respectively, had bladder tumor recurrence. Overall RFS at three years was 46% and 50% in NAC-TMT and TMT groups, respectively (p=0.70). BRFS at three years was 55% and 69% in NAC-TMT and TMT groups, respectively (p=0.27). Multivariable analyses found that the presence of concomitant CIS (hazard ratio [HR] 2.13; 95% confidence interval CI 1.06-4.27; p=0.0036) was the primary factor associated with local bladder recurrence.

Conclusions: Receipt of NAC does not obviate the risk of bladder recurrence post-TMT. Patients with CIS should be monitored especially closely for local recurrence.
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http://dx.doi.org/10.5489/cuaj.6459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704086PMC
December 2020

Use of combined androgen deprivation therapy with postoperative radiation treatment for prostate cancer: Impact of randomized trials on clinical practice.

Urol Oncol 2020 11 16;38(11):848.e1-848.e7. Epub 2020 Jun 16.

Department of Radiation Oncology, University of Toronto, Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Canada; Techna Institute, University Health Network, Canada. Electronic address:

Purpose: To assess the impact of RTOG-9601 and GETUG-AFU-16 on the routine use of combination androgen deprivation therapy (ADT) with postoperative radiotherapy (PORT) for prostate cancer (CaP).

Material And Methods: Patients with localized CaP treated with radical prostatectomy (RP) and PORT with or without ADT at a comprehensive cancer center from January 2006 to June 2007 (Period 1 = P1), July 2011 to December 2012 (Period 2 = P2), and January 2017 to June 2018 (Period 3 = P3) were included. Clinicopathologic features and treatment characteristics were analyzed and compared. Multivariable logistic regression was used to assess prognostic factors and association with ADT use. Statistical tests were two-sided and a P value <0.05 was considered significant. To validate the findings, United States National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results (SEER) data were collected to assess rates of combined ADT and PORT from 2004 to 2015.

Results: Five hundred and two patients were included: 152 (P1), 185 (P2), and 165 (P3). PORT was most commonly delivered as early SRT (delivered >1 year post-RP with undetectable PSA or PSA >0.05 and ≤0.5 ng/ml) in all periods. The use of combination PORT and ADT increased over time: 14.5% (P1), 32% (P2), and 41% (P3) (P < 0.001). The proportion of patients that met eligibility criteria for either GETUG-AFU-16 or RTOG-9601 decreased from 47% (P1) to 35% (P3) (P = 0.04). International Society of Urological Pathology grade ≥4 (P < 0.002) and pre-PORT PSA >0.5 ng/ml (P < 0.001) were associated with use of ADT. Positive surgical margin status had a negative association (RR 0.5, P < 0.002). The NCDB demonstrated similar trends for use of combined ADT with PORT, increasing from 37% to 49% from 2004 to 2015.

Conclusion: The use of combined ADT with PORT increased over time. However, only a third of contemporary patients undergoing PORT are represented in the major trials supporting the evidence for combination treatment, highlighting the need to characterize the modern impact of this intensification strategy.
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http://dx.doi.org/10.1016/j.urolonc.2020.04.019DOI Listing
November 2020

Predictors of prostate-specific antigen testing in men aged ≥55 years: A cross-sectional study based on patient-reported outcomes.

Int J Urol 2020 Sep 31;27(9):711-718. Epub 2020 May 31.

Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

Objectives: To examine the predictors of prostate-specific antigen discussion with a physician and prostate-specific antigen testing in men aged ≥55 years.

Methods: Utilizing the USA Health Information National Trends Survey, 4th Ed., a cross-sectional study from 2011 to 2014 was carried out to analyze the factors predicting prostate-specific antigen testing and discussion in men ≥55 years. Associations between each covariate and prostate-specific antigen discussion/testing were determined. Multivariable logistic regression models were used to determine clinically relevant predictors of prostate-specific antigen discussion/testing. Due to multiple comparisons, the Bonferroni correction was used.

Results: A total of 2731 men included in the Health Information National Trends Survey were analyzed. Several socioeconomic parameters were found to increase the likelihood of men aged ≥55 years to undergo prostate-specific antigen testing: living with a spouse, a higher level of education (college graduate or above), a higher income (>$50 000 annually) and previous history of any cancer. In contrast, current smokers were less likely to undergo prostate-specific antigen testing. Having a prostate-specific antigen discussion with a physician was more likely for men surveyed in 2014, for men who were living with a spouse, who had a higher annual income (>$50 000 annually) and those with a history of any cancer.

Conclusions: Significant inequalities in prostate-specific antigen testing and discussion exist among men in the USA, mainly driven by socioeconomic factors. Ideally, prostate-specific antigen testing and discussion should be based on relevant clinical factors with a shared decision-making approach for every man. Therefore, a better understanding of the socioeconomic factors influencing prostate-specific antigen testing/discussions can inform strategies to reduce existing gaps in care.
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http://dx.doi.org/10.1111/iju.14276DOI Listing
September 2020

Association between metformin medication, genetic variation and prostate cancer risk.

Prostate Cancer Prostatic Dis 2021 03 18;24(1):96-105. Epub 2020 May 18.

Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: The relationship between metformin use and prostate cancer risk remains controversial. Genetic variation in metformin metabolism pathways appears to modify metformin glycemic control and the protective association with some cancers. However, no studies to date have examined this pharmacogenetic interaction and prostate cancer chemoprevention.

Methods: Clinical data and germline DNA were collected from our prostate biopsy database between 1996 and 2014. In addition to a genome-wide association study (GWAS), 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism were included on a custom SNP array. Associations between metformin use and risk of high-grade (Grade Group ≥ 2) and overall prostate cancer were explored using a case-control design. Interaction between the candidate/GWAS SNPs and the metformin-cancer association was explored using a case-only design.

Results: Among 3481 men, 132 (4%) were taking metformin at diagnosis. Metformin users were older, more likely non-Caucasian, and had higher body mass index, Gleason score, and number of positive cores. Overall, 2061 (59%) were diagnosed with prostate cancer, of which 922 (45%) were high-grade. After adjusting for baseline characteristics, metformin use was associated with higher risk of high-grade prostate cancer (OR = 1.76, 95% CI 1.1-2.9, p = 0.02) and overall prostate cancer (OR = 1.77, 95% CI 1.1-2.9, p = 0.03). None of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer association. Among the GWAS SNPs, one SNP (rs149137006) had genome-wide significant interaction with metformin for high-grade prostate cancer, and another, rs115071742, for overall prostate cancer. They were intronic and intergenic SNPs, respectively, with largely uncharacterized roles in prostate cancer chemoprevention.

Conclusions: In our cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer. While SNPs involved in metformin metabolism did not have modifying effects on the association with disease risk, one intronic and one intergenic SNP from the GWAS study did, and these require further study.
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http://dx.doi.org/10.1038/s41391-020-0238-yDOI Listing
March 2021

A Prospective Randomized Controlled Trial of Irrigation "Bag Squeeze" to Manage Pain for Patients Undergoing Flexible Cystoscopy.

J Urol 2020 Nov 12;204(5):1012-1018. Epub 2020 May 12.

Division of Urology, Department of Surgical Oncology, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Purpose: We determined if the "bag squeeze" technique decreases pain during flexible cystoscopy in men.

Materials And Methods: This single center, prospective, double-blind, randomized controlled trial recruited 200 consenting participants who were ambulatory, outpatient males who had undergone prior cystoscopy and were not expected to require any secondary procedures. Men with prior urethral stricture or bladder neck contracture were excluded from study. Once eligibility was assessed and consent obtained, participants were randomized to undergo cystoscopy with the bag squeeze (group A) or the sham bag squeeze procedure (group B). Following cystoscopy, participants completed a pain questionnaire (visual analogue scale). Differences in mean pain score between groups were evaluated using Students' t-test with a 2-sided alpha of 0.05.

Results: A total of 200 patients were randomized and underwent flexible cystoscopy. Ten participants were ineligible because they required secondary procedures. Among the 190 eligible patients 97 were randomized to bag squeeze (group A) and 93 to sham bag squeeze (group B) with mean pain scores of 1.91 and 3.39, respectively (p <0.005).

Conclusions: This study demonstrated a clinically meaningful decrease in pain for men undergoing flexible cystoscopy when the irrigation bag squeeze technique was used vs placebo bag squeeze. Accordingly, this useful, simple and free method to improve patient comfort during flexible cystoscopy should be adopted by clinicians.
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http://dx.doi.org/10.1097/JU.0000000000001139DOI Listing
November 2020

[F]DCFPyL PET-MRI/CT for unveiling a molecularly defined oligorecurrent prostate cancer state amenable for curative-intent ablative therapy: study protocol for a phase II trial.

BMJ Open 2020 04 22;10(4):e035959. Epub 2020 Apr 22.

Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

Introduction: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments.

Methods And Analysis: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions.

Ethics And Dissemination: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study.

Trial Registration Numbers: NCT03160794.
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http://dx.doi.org/10.1136/bmjopen-2019-035959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204865PMC
April 2020

A pilot window-of-opportunity study of preoperative fluvastatin in localized prostate cancer.

Prostate Cancer Prostatic Dis 2020 12 13;23(4):630-637. Epub 2020 Mar 13.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Background: Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Epidemiological and pre-clinical evidence support an association between statin use and delayed prostate cancer (PCa) progression. Here, we evaluated the effects of neoadjuvant fluvastatin treatment on markers of cell proliferation and apoptosis in men with localized PCa.

Methods: Thirty-three men were treated daily with 80 mg fluvastatin for 4-12 weeks in a single-arm window-of-opportunity study between diagnosis of localized PCa and radical prostatectomy (RP) (ClinicalTrials.gov: NCT01992042). Percent Ki67 and cleaved Caspase-3 (CC3)-positive cells in tumor tissues were evaluated in 23 patients by immunohistochemistry before and after treatment. Serum and intraprostatic fluvastatin concentrations were quantified by liquid chromatography-mass spectrometry.

Results: Baseline characteristics included a median prostate-specific antigen (PSA) level of 6.48 ng/mL (IQR: 4.21-10.33). The median duration of fluvastatin treatment was 49 days (range: 27-102). Median serum low-density lipoprotein levels decreased by 35% after treatment, indicating patient compliance. Median PSA decreased by 12%, but this was not statistically significant in our small cohort. The mean fluvastatin concentration measured in the serum was 0.2 μM (range: 0.0-1.1 μM), and in prostatic tissue was 8.5 nM (range: 0.0-77.0 nM). At these concentrations, fluvastatin induced PCa cell death in vitro in a dose- and time-dependent manner. In patients, fluvastatin treatment did not significantly alter intratumoral Ki67 positivity; however, a median 2.7-fold increase in CC3 positivity (95% CI: 1.9-5.0, p = 0.007) was observed in post-fluvastatin RP tissues compared with matched pre-treatment biopsy controls. In a subset analysis, this increase in CC3 was more pronounced in men on fluvastatin for >50 days.

Conclusions: Fluvastatin prior to RP achieves measurable drug concentrations in prostatic tissue and is associated with promising effects on tumor cell apoptosis. These data warrant further investigation into the anti-neoplastic effects of statins in prostate tissue.
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http://dx.doi.org/10.1038/s41391-020-0221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655503PMC
December 2020
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