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BACKGROUND: Nearly one-third of patients with prostate cancer (PCa) experience biochemical recurrence (BCR) after primary definitive treatment. BCR increases the risk of distant metastasis and mortality in patients with prognostically unfavorable features. These patients are best managed with a tailored treatment strategy incorporating risk stratification using clinicopathological factors, next-generation imaging, and genomic testing. OBJECTIVE: This narrative review examines the utility of risk stratification for the management of patients with BCR in the context of clinical trial data, referencing the latest recommendations by European and US medical societies. METHODS: PubMed was searched for relevant studies published through May 21 2023 on treatment of patients with BCR after radical prostatectomy (RP) or external beam radiotherapy (EBRT). RESULTS: European and US guidelines support the risk-stratified management of BCR. Post-RP, salvage EBRT (with or without androgen deprivation therapy [ADT]) is an accepted treatment option for patients with BCR. Post-EBRT, local salvage therapies (RP, cryotherapy, high-intensity focused ultrasound, stereotactic body radiotherapy, and low-dose-rate and high-dose-rate brachytherapy) have demonstrated comparable relapse-free survival rates but differing adverse event profiles, short and long term. Local salvage therapies should be used for local-only relapses while ADT should be considered for regional or distant relapses. In practice, patients often receive ADT, with varying guidance for intermittent ADT vs. continuous ADT, due to consideration of quality-of-life effects. CONCLUSIONS: Despite a lack of consensus for BCR treatment among guideline associations and medical societies, risk stratification of patients is essential for personalized treatment approaches, as it allows for an informed selection of therapeutic strategies and estimation of adverse events. In lower-risk disease, observation is recommended while in higher-risk disease, after failed repeat local therapy, ADT and/or clinical trial enrollment may be appropriate. Results from ongoing clinical studies of patients with BCR should provide consensus for management.

BACKGROUND: Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging (NGI) can identify local and metastatic recurrence with greater sensitivity than conventional imaging, potentially allowing for more effective interventions. This narrative review examines the current clinical evidence on the utility of NGI for patients with BCR. METHODS: A search of PubMed was conducted to identify relevant publications on NGI applied to BCR. Given other relevant recent reviews on the topic, this review focused on papers published between January 2018 to May 2023. RESULTS: NGI technologies, including positron emission tomography (PET) radiotracers and multiparametric magnetic resonance imaging, have demonstrated increased sensitivity and selectivity for diagnosing BCR at prostate-specific antigen (PSA) concentrations

Understanding patient interest among surgical options is challenging. We used Google Trends to analyze interest in benign prostatic hyperplasia (BPH) surgeries recommended for prostate volumes

BACKGROUND: The prognosis of diabetic men with advanced prostate cancer is poorly understood and understudied. Hence, we studied associations between diabetes and progression to metastases, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). METHODS: Data from men diagnosed with nmCRPC between 2000 and 2017 at 8 Veterans Affairs Health Care Centers were analyzed using Cox regression to determine HRs and 95% confidence intervals (CI) for associations between diabetes and outcomes. Men with diabetes were classified according to: (i) ICD-9/10 codes only, (ii) two HbA1c values > 6.4% (missing ICD-9/10 codes), and (iii) all diabetic men [(i) and (ii) combined]. RESULTS: Of 976 men (median age: 76 years), 304 (31%) had diabetes at nmCRPC diagnosis, of whom 51% had ICD-9/10 codes. During a median follow-up of 6.5 years, 613 men were diagnosed with metastases, and 482 PCSM and 741 ACM events occurred. In multivariable-adjusted models, ICD-9/10 code-identified diabetes was inversely associated with PCSM (HR, 0.67; 95% CI, 0.48-0.92) while diabetes identified by high HbA1c values (no ICD-9/10 codes) was associated with an increase in ACM (HR, 1.41; 95% CI, 1.16-1.72). Duration of diabetes, prior to CRPC diagnosis was inversely associated with PCSM among men identified by ICD-9/10 codes and/or HbA1c values (HR, 0.93; 95% CI, 0.88-0.98). CONCLUSIONS: In men with late-stage prostate cancer, ICD-9/10 code-identified diabetes is associated with better overall survival than undiagnosed diabetes identified by high HbA1c values only. IMPACT: Our data suggest that better diabetes detection and management may improve survival in late-stage prostate cancer.

PurposeLimited data exist to help surgeons decide between active surveillance (AS) versus treatment for men with favorable intermediate risk (FIR) prostate cancer. To estimate the theoretical excess risk of prostate cancer-specific mortality (PCSM) with AS versus radical prostatectomy (RP), we determined the risk of PCSM in FIR men undergoing RP and modeled the PCSM risk for AS using a range of increased PSCM scenarios ranging from 1.25x to 2x higher relative to RP.Materials and methodsWe retrospectively reviewed data from men undergoing RP from 1988 to 2017 at 8 Veterans Affairs hospitals within the SEARCH cohort. Men with FIR PC were identified using the NCCN risk criteria. Risk of PCSM at 5, 10, and 15 years after RP was estimated. Using these estimates, PCSM was then modeled for AS using a range of increased risk of PCSM relative to RP ranging from 1.25x to 2x higher.ResultsFor the 920 FIR men identified, 5-, 10-, and 15-year survival estimates for PCSM after RP were 99.9%, 99.0%, and 97.8%, respectively. If the risk of PCSM on AS were 1.25-2x greater than RP, there would be 0.54%-2.17% excess risk of PCSM at 15 years.ConclusionsThe risk of death for FIR after RP is very low. Assuming even modestly increased PCSM with AS versus RP, the excess risk of death for AS in FIR is low even up to 15 years. These data support the consideration of AS as a relatively safe alternative to RP in FIR men, though prospective randomized trials are needed to validate these findings.

BackgroundWe compared six commonly used logistic regression methods for accommodating missing risk factor data from multiple heterogeneous cohorts, in which some cohorts do not collect some risk factors at all, and developed an online risk prediction tool that accommodates missing risk factors from the end-user.MethodsTen North American and European cohorts from the Prostate Biopsy Collaborative Group (PBCG) were used for fitting a risk prediction tool for clinically significant prostate cancer, defined as Gleason grade group ≥ 2 on standard TRUS prostate biopsy. One large European PBCG cohort was withheld for external validation, where calibration-in-the-large (CIL), calibration curves, and area-underneath-the-receiver-operating characteristic curve (AUC) were evaluated. Ten-fold leave-one-cohort-internal validation further validated the optimal missing data approach.ResultsAmong 12,703 biopsies from 10 training cohorts, 3,597 (28%) had clinically significant prostate cancer, compared to 1,757 of 5,540 (32%) in the external validation cohort. In external validation, the available cases method that pooled individual patient data containing all risk factors input by an end-user had best CIL, under-predicting risks as percentages by 2.9% on average, and obtained an AUC of 75.7%. Imputation had the worst CIL (-13.3%). The available cases method was further validated as optimal in internal cross-validation and thus used for development of an online risk tool. For end-users of the risk tool, two risk factors were mandatory: serum prostate-specific antigen (PSA) and age, and ten were optional: digital rectal exam, prostate volume, prior negative biopsy, 5-alpha-reductase-inhibitor use, prior PSA screen, African ancestry, Hispanic ethnicity, first-degree prostate-, breast-, and second-degree prostate-cancer family history.ConclusionDevelopers of clinical risk prediction tools should optimize use of available data and sources even in the presence of high amounts of missing data and offer options for users with missing risk factors.

BACKGROUND: The optimal upfront treatment modality for patients with nonmetastatic Gleason Score 9 and 10 prostate cancer (GS 9-10 PCa) is unknown. METHODS: We conducted a retrospective cohort study of patients in the Veterans Health Administration (VHA) with GS 9-10 PCa treated with radical prostatectomy (RP) or external beam radiation therapy with androgen deprivation therapy (EBRT+ADT) from 1/2000 to 12/2010. Outcomes included overall survival (OS), distant metastasis-free survival (DMFS), and salvage/adjuvant therapy-free survival (SAFS), as assessed by Kaplan-Meier analysis. RESULTS: We identified 1220 veterans with GS 9-10 PCa; 335 were treated with RP, and 885 were treated with EBRT+ADT. With a median follow-up of 9.9 years, propensity score-matched analyses demonstrated that RP had superior 10-year OS (70.8% [RP] vs. 61.2% [EBRT+ADT], p

BackgroundWorsening glycemic control indicates elevated risk of pancreatic ductal adenocarcinoma (PDAC). We developed prediction models for PDAC among those with worsening glycemic control after diabetes diagnosis.MethodsIn 2000-2016 records within the Veterans Affairs Health System (VA), we identified three cohorts with progression of diabetes: (i) insulin initiation (n = 449,685), (ii) initiation of combination oral hypoglycemic medication (n = 414,460), and (iii) hemoglobin A1c (HbA1c) ≥8% with ≥Δ1% within 15 months (n = 593,401). We computed 12-, 36-, and 60-month incidence of PDAC and developed prediction models separately for males and females, with consideration of >30 demographic, behavioral, clinical, and laboratory variables. Models were selected to optimize Akaike's Information Criterion, and performance for predicting 12-, 36-, and 60-month incident PDAC was evaluated by bootstrap.ResultsIncidence of PDAC was highest for insulin initiators and greater in males than in females. Optimism-corrected c-indices of the models for predicting 36-month incidence of PDAC in the male population were: (i) 0.72, (ii) 0.70, and (iii) 0.71, respectively. Models performed better for predicting 12-month incident PDAC [c-index (i) 0.78, (ii) 0.73, (iii) 0.76 for males], and worse for predicting 60-month incident PDAC [c-index (i) 0.69, (ii) 0.67, (iii) 0.68 for males]. Model performance was lower among females. For subjects whose model-predicted 36-month PDAC risks were ≥1%, the observed incidences were (i) 1.9%, (ii) 2.2%, and (iii) 1.8%.ConclusionsSex-specific models for PDAC can estimate risk of PDAC at the time of progression of diabetes.ImpactOur models can identify diabetes patients who would benefit from PDAC screening.

BackgroundThe link between diabetes and prostate cancer progression is poorly understood and complicated by obesity. We investigated associations between diabetes and prostate cancer-specific mortality (PCSM), castrate-resistant prostate cancer (CRPC), and metastases in obese and nonobese men undergoing radical prostatectomy (RP).MethodsWe included 4688 men from the Shared Equal Access Regional Cancer Hospital cohort of men undergoing RP from 1988 to 2017. Diabetes prior to RP, anthropometric, and clinical data were abstracted from 6 Veterans Affairs Medical Centers electronic medical records. Primary and secondary outcomes were PCSM and metastases and CRPC, respectively. Multivariable-adjusted hazard ratios (adj-HRs) and 95% confidence intervals (CIs) were estimated for diabetes and PCSM, CRPC, and metastases. Adjusted hazard ratios were also estimated in analyses stratified by obesity (body mass index: nonobese

Although obesity is one of the strongest risk factors for esophageal adenocarcinoma, the molecular mechanisms underlying this association remain unclear. We recently identified four esophageal adenocarcinoma-specific master regulator transcription factors (MRTF) ELF3, KLF5, GATA6, and EHF. In this study, gene-set enrichment analysis of both esophageal adenocarcinoma patient samples and cell line models unbiasedly underscores fatty acid synthesis as the central pathway downstream of three MRTFs (ELF3, KLF5, GATA6). Further characterizations unexpectedly identified a transcriptional feedback loop between MRTF and fatty acid synthesis, which mutually activated each other through the nuclear receptor, PPARG. MRTFs cooperatively promoted PPARG transcription by directly regulating its promoter and a distal esophageal adenocarcinoma-specific enhancer, leading to PPARG overexpression in esophageal adenocarcinoma. PPARG was also elevated in Barrett's esophagus, a recognized precursor to esophageal adenocarcinoma, implying that PPARG might play a role in the intestinal metaplasia of esophageal squamous epithelium. Upregulation of PPARG increased de novo synthesis of fatty acids, phospholipids, and sphingolipids as revealed by mass spectrometry-based lipidomics. Moreover, ChIP-seq, 4C-seq, and a high-fat diet murine model together characterized a novel, noncanonical, and cancer-specific function of PPARG in esophageal adenocarcinoma. PPARG directly regulated the ELF3 super-enhancer, subsequently activating the transcription of other MRTFs through an interconnected regulatory circuitry. Together, elucidation of this novel transcriptional feedback loop of MRTF/PPARG/fatty acid synthesis advances our understanding of the mechanistic foundation for epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma. More importantly, this work identifies a potential avenue for prevention and early intervention of esophageal adenocarcinoma by blocking this feedback loop. SIGNIFICANCE: These findings elucidate a transcriptional feedback loop linking epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma, indicating that blocking this feedback loop could be a potential therapeutic strategy in high-risk individuals.

PurposeCirculating inflammatory markers may predict prostate cancer (PC) outcomes. For example, a recent study showed that higher peripheral blood monocyte counts were associated with aggressive PC in Asian men undergoing radical prostatectomy (RP). Herein, we investigated whether peripheral monocyte count can predict long-term PC outcomes after RP in black and white men.MethodsWe retrospectively reviewed data on 2345 men undergoing RP from 2000 to 2017 at eight Veterans Affairs hospitals. Data on monocyte count within 6 and 12 months prior to surgery were collected. The study outcomes were biochemical recurrence (BCR), castration-resistant PC (CRPC), metastasis, all-cause mortality (ACM), and PC-specific morality (PCSM). Cox-proportional hazard models were used to assess the associations between pre-operative monocyte count and the above-mentioned outcomes accounting for confounders.ResultsOf 2345 RP patients, 972 (41%) were black and 1373 (59%) were white men. In multivariable analyses, we found no associations between monocyte count and BCR among all men (HR: 1.36, 95%CI 0.90-2.07) or when analyses were stratified by race (HR: 1.30, 95%CI 0.69-2.46, in black men; HR:1.33, 95%CI 0.76-02.33, in white men). Likewise, no overall or race-specific associations were found between monocyte count and CRPC, metastases, ACM, and PCSM, all p ≥ 0.15. Results were similar for monocyte count measured at 12 months prior to RP.ConclusionIn black and white PC patients undergoing RP, peripheral monocyte count was not associated with long-term PC outcomes. Contrary to what was found in Asian populations, monocyte count was not associated with PC outcomes in this study.

BackgroundProstate cancer exhibits biological and clinical heterogeneity even within established clinico-pathologic risk groups. The Decipher genomic classifier (GC) is a validated method to further risk-stratify disease in patients with prostate cancer, but its performance solely within National Comprehensive Cancer Network (NCCN) high-risk disease has not been undertaken to date.MethodsA multi-institutional retrospective study of 405 men with high-risk prostate cancer who underwent primary treatment with radical prostatectomy (RP) or radiation therapy (RT) with androgen-deprivation therapy (ADT) at 11 centers from 1995 to 2005 was performed. Cox proportional hazards models were used to determine the hazard ratios (HR) for the development of metastatic disease based on clinico-pathologic variables, risk groups, and GC score. The area under the receiver operating characteristic curve (AUC) was determined for regression models without and with the GC score.ResultsOver a median follow-up of 82 months, 104 patients (26%) developed metastatic disease. On univariable analysis, increasing GC score was significantly associated with metastatic disease ([HR]: 1.34 per 0.1 unit increase, 95% confidence interval [CI]: 1.19-1.50, p  0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p

PurposeAfrican Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T.Patients and methodsOS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies.ResultsMedian follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P

BackgroundMetastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC.MethodsTo identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers.ResultsTranscriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC.ConclusionsWe conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

BackgroundThe National Death Index (NDI) is a centralized database containing information from death certificates that are frequently referenced by health and medical investigators to ascertain vital statistics. Yet, it commonly includes misclassified causes of death. Since the NDI is frequently relied upon in studies that evaluate outcomes following radical prostatectomy (RP) for prostate cancer (PC), we evaluated its validity by referencing mortality data from the Shared Equal Access Regional Cancer Hospital (SEARCH) database which is a prospectively managed database of 5009 Veterans who underwent a RP at eight Veterans Affairs medical centers between 1982 and 2016.MethodsWe compared vital status, cause of death and date of death from the SEARCH database with the NDI.ResultsA total of 1312 men in SEARCH were deceased, yet the NDI reported 17% (219) of those men as still alive. Among the 1093 men who had concordant vital status in both SEARCH and NDI, the date of death was an exact match within one day, a week, or 31 days in 94%, 97%, 99%, and 100%, respectively. Of those men coded as dying from prostate cancer in the SEARCH database (n = 105), 12% were coded as having died from non-PC causes in the NDI. Meanwhile, among patients coded by the NDI as having died of PC (n = 139), 34% were coded in SEARCH as having died of non-PC causes.ConclusionsThese findings demonstrate that the NDI provides accurate dates of death, but frequently misclassifies whether a death was due to prostate cancer. Studies that rely upon death certificates, as captured in the NDI, may be unreliable to report prostate cancer-specific mortality rates after prostatectomy.

BackgroundAlthough skeletal-related events (SREs) are linked with a reduced quality of life and worse outcomes, to the authors' knowledge the factors that predict SREs are minimally understood. The objective of the current study was to identify predictors of SREs and all-cause mortality among men with metastatic castration-resistant prostate cancer (mCRPC).MethodsData were collected on 837 men with bone mCRPC at 8 Veterans Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 2000 through 2017. Patients were followed to assess development of SREs (pathological fracture, radiotherapy to bone, spinal cord compression, or surgery to bone). Cox proportional hazards models were used to evaluate predictors of SREs and mortality.ResultsOf the 837 men with bone mCRPC, 287 developed a SRE and 740 men died (median follow-up, 26 months). Bone pain was found to be the strongest predictor of SREs (hazard ratio [HR], 2.96; 95% CI, 2.25-3.89). A shorter time from CRPC to the development of metastasis (HR, 0.92; 95% CI, 0.85-0.99), shorter progression to CRPC (HR, 0.94; 95% CI, 0.91-0.98), and visceral metastasis at the time of diagnosis of bone metastasis (HR, 1.91; 95% CI, 1.18-3.09) were associated with an increased risk of SREs. Ten or more bone metastases (HR, 2.17; 95% CI, 1.72-2.74), undergoing radical prostatectomy (HR, 0.73; 95% CI, 0.61-0.89), shorter progression to CRPC (HR, 0.97; 95% CI, 0.94-0.99), older age (HR, 1.03; 95% CI, 1.02-1.04), higher prostate-specific antigen level at the time of diagnosis of metastasis (HR, 1.21; 95% CI, 1.14-1.28), bone pain (HR, 1.44; 95% CI, 1.23-1.70), and visceral metastasis (HR, 1.72; 95% CI, 1.23-2.39) were associated with an increased mortality risk.ConclusionsAmong men with bone mCRPC, bone pain was found to be the strongest predictor of SREs and the number of bone metastases was a strong predictor of mortality. If validated, these factors potentially may be used for risk stratification and for SRE prevention strategies.

BackgroundNeoadjuvant chemotherapy is underutilized in bladder cancer patients who undergo radical cystectomy. However, the quality of regimens used in this setting remains largely unknown.ObjectiveTo determine utilization treatment patterns and survival outcomes according to regimens administered.Design, setting, and patientsWe used the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database to identify patients diagnosed with clinical stage TII-IV bladder cancer from January 1, 2001 to December 31, 2011.Outcome measurements and statistical analysisTemporal trends were assessed using the Cochran-Armitage test. Multivariable logistic regression models were used to identify predictors for neoadjuvant chemotherapy use. Cox proportional hazards models were used to compare overall survival according to regimens administered.Results and limitationsOf 2738 patients treated with radical cystectomy, 344 (12.6%) received neoadjuvant chemotherapy. The agents most commonly used were gemcitabine (72.3%), cisplatin (55.2%), and carboplatin (31.1%). The regimens most commonly used were gemcitabine-cisplatin (45.3%), gemcitabine-carboplatin (24.1%), and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC; 6.7%). Use of neoadjuvant chemotherapy more than tripled during the study period, from 5.7% in 2001 to 17.3% in 2011 (p

BackgroundAlthough diabetes is inversely related to prostate cancer (PC) risk, to the authors' knowledge the impact of glycemic control on PC progression is unknown. In the current study, the authors tested the association between hemoglobin A1c (HbA1c) and long-term PC outcomes among diabetic men undergoing radical prostatectomy (RP).MethodsThe authors retrospectively reviewed data regarding men undergoing RP from 2000 to 2017 at 8 Veterans Affairs hospitals. Diabetic patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes (250.x) or by an HbA1c value >6.5% at any time before RP. Cox models tested the association between HbA1c and biochemical disease recurrence (BCR), castration-resistant PC (CRPC), metastases, PC-specific mortality, and all-cause mortality. The model for BCR was adjusted for multiple variables. Due to limited events, models for long-term outcomes were adjusted for biopsy grade and prostate-specific antigen only.ResultsA total of 1409 men comprised the study population. Of these, 699 patients (50%) had an HbA1c value

ImportanceBlack men are more likely to die of prostate cancer than white men. In men with similar stages of disease, the contribution of biological vs nonbiological differences to this observed disparity is unclear.ObjectiveTo quantify the association of black race with long-term survival outcomes after controlling for known prognostic variables and access to care among men with prostate cancer.Design, setting, and participantsThis multiple-cohort study included updated individual patient-level data of men with clinical T1-4N0-1M0 prostate cancer from the following 3 cohorts: Surveillance, Epidemiology, and End Results (SEER [n = 296 273]); 5 equal-access regional medical centers within the Veterans Affairs health system (VA [n = 3972]); and 4 pooled National Cancer Institute-sponsored Radiation Therapy Oncology Group phase 3 randomized clinical trials (RCTs [n = 5854]). Data were collected in the 3 cohorts from January 1, 1992, through December 31, 2013, and analyzed from April 27, 2017, through April 13, 2019.ExposuresIn the VA and RCT cohorts, all patients received surgery and radiotherapy, respectively, with curative intent. In SEER, radical treatment, hormone therapy, or conservative management were received.Main outcomes and measuresProstate cancer-specific mortality (PCSM). Secondary measures included other-cause mortality (OCM). To adjust for demographic-, cancer-, and treatment-related baseline differences, inverse probability weighting (IPW) was performed.ResultsAmong the 306 100 participants included in the analysis (mean [SD] age, 64.9 [8.9] years), black men constituted 52 840 patients (17.8%) in the SEER cohort, 1513 (38.1%) in the VA cohort, and 1129 (19.3%) in the RCT cohort. Black race was associated with an increased age-adjusted PCSM hazard (subdistribution hazard ratio [sHR], 1.30; 95% CI, 1.23-1.37; P

ObjectivesTo examine the association between body mass index (BMI) and aggressive biochemical recurrence (BCR) using the Shared Equal Access Regional Cancer Hospital (SEARCH) database.Material and methodsWe identified 4123 men with complete data treated by radical prostatectomy between 1988 and 2015. We tested the association between BMI and BCR using Cox models, and among men with BCR, prostate-specific antigen doubling time (PSADT) was compared across BMI categories using linear regression. Models were adjusted for age, race, prostate-specific antigen, biopsy Gleason score, clinical stage, year and surgical centre.ResultsOverall, 922 men (22%) were of normal weight (BMI

IntroductionWe previously found racial differences in biochemical recurrence (BCR) after radical prostatectomy (RP) persisted after adjusting for socioeconomic status (SES) while SES did not predict BCR. The impact on long-term prostate cancer (PC) outcomes is unclear. We hypothesized higher SES would associate with better long-term outcomes regardless of race.MethodsAmong 4,787 black and white men undergoing RP from 1988 to 2015 in the SEARCH Database, poverty (primary SES measure) was estimated by linking home ZIP-code to census data. Cox models were used to test the association between SES adjusting for demographic, clinicopathological features, and race with BCR, castration-resistant PC (CRPC), metastases, PC-specific mortality (PCSM), and all-cause mortality. Interactions between race and SES were tested.ResultsMedian follow-up was 98 months (Interquartile range: 54-150 months). There were no interactions between race and SES for BCR. Black men had 10%- to 11% increased BCR risk (P < 0.06) while SES was unrelated to BCR. There were interactions between SES and race for CRPC (P = 0.002), metastasis (P = 0.014), and PCSM (P = 0.004). Lower SES was associated with decreased CRPC (P = 0.012), metastases (P = 0.004), and PCSM (P = 0.049) in black, but not white men (all P ≥ 0.22). Higher SES was associated with decreased all-cause mortality in both races.ConclusionsIn an equal-access setting, lower SES associated with decreased CRPC, metastases, and PCSM in black but not white men. If confirmed, these findings suggest a complex relationship between race, SES, and PC with further research needed to understand why low SES in black men decreased the risk for poor PC outcomes after RP.

PURPOSE:We aimed to study the associations between androgen-deprivation therapy (ADT)-induced weight changes and prostate cancer (PC) progression and mortality in men who had undergone radical prostatectomy (RP). METHODS:Data from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort were used to study the associations between weight change approximately 1-year post-ADT initiation and metastases, castration-resistant prostate cancer (CRPC), all-cause mortality (ACM), and PC-specific mortality (PCSM) in 357 patients who had undergone RP between 1988 and 2014. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) using covariate-adjusted Cox regression models for associations between weight loss, and weight gains of 2.3 kg or more, and PC progression and mortality post-ADT. RESULTS:During a median (IQR) follow-up of 81 (46-119) months, 55 men were diagnosed with metastases, 61 with CRPC, 36 died of PC, and 122 died of any cause. In multivariable analysis, weight loss was associated with increases in risks of metastases (HR 3.13; 95% CI 1.40-6.97), PCSM (HR 4.73; 95% CI 1.59-14.0), and ACM (HR 2.16; 95% CI 1.25-3.74) compared with mild weight gains of ≤ 2.2. Results were slightly attenuated but remained statistically significant in analyses that accounted for competing risks of non-PC death. Estimates for the associations between weight gains of ≥ 2.3 kg and metastases (HR 1.58; 95% CI 0.73-3.42), CRPC (HR 1.33; 95% CI 0.66-2.66), and PCSM (HR 2.44; 95% CI 0.84-7.11) were elevated, but not statistically significant. CONCLUSIONS:Our results suggest that weight loss following ADT initiation in men who have undergone RP is a poor prognostic sign. If confirmed in future studies, testing ways to mitigate weight loss post-ADT may be warranted.

BackgroundIn this study among men who underwent radical prostatectomy (RP), African American men (AAM) were 28% more likely to develop recurrent disease compared with Caucasian men (CM). However, among those who had nonmetastatic, castration-resistant prostate cancer (CRPC), race did not predict metastases or overall survival. Whether race predicts metastases among men who receive androgen-deprivation therapy (ADT) after a biochemical recurrence (BCR) (ie, before CRPC but after BCR) is untested.MethodsThe authors identified 595 AAM and CM who received ADT for a BCR that developed after RP between 1988 and 2015 in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database. Univariable and multivariable Cox models were used to test the association between race and the time from ADT to metastases. Secondary outcomes included the time to CRPC, all-cause mortality, and prostate cancer-specific mortality.ResultsDuring a median follow-up of 66 months after ADT, 62 of 354 CM (18%) and 38 of 241 AAM (16%) developed metastases. AAM were younger at the time they received ADT (63 vs 67 years; P < .001), had received ADT in a more recent year (2008 vs 2006; P < .001), had higher prostate-specific antigen levels at RP (11.1 vs 9.2 ng/mL; P < .001), lower pathologic Gleason scores (P = .004), and less extracapsular extension (38% vs 48%; P = .022). On multivariable analysis, there was no association between race and metastases (hazard radio, 1.20; P = .45) or any of the other secondary outcomes (all P > .5).ConclusionsAmong veterans who received ADT post-BCR after RP, race was not a predictor of metastases or other adverse outcomes. The current findings suggest that research efforts to understand racial differences in prostate cancer biology should focus on early stages of the disease (ie, closer to the time of diagnosis).

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

ObjectivesTo evaluate the impact of previous local treatment on survival in men with newly diagnosed metastatic castration-resistant prostate cancer.MethodsWe carried out a retrospective study of patients newly diagnosed with metastatic castration-resistant prostate cancer in the year 2000 or later from eight Veterans Affairs Medical Centers. Patients were categorized based on prior local therapy (none, prostatectomy ± radiation or radiation alone). Overall and cancer-specific survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression models were used to test the association between prior local treatment and survival.ResultsOf 729 patients, 284 (39%) underwent no local treatment, 176 (24%) underwent radical prostatectomy ± radiation and 269 (37%) underwent radiation alone. On multivariable analysis, men with prior prostatectomy had improved overall (hazard ratio 0.71, P = 0.005) and cancer-specific survival (hazard ratio 0.55, P

BackgroundProstate cancer prediction tools provide quantitative guidance for doctor-patient decision-making regarding biopsy. The widely used online Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) utilized data from the 1990s based on six-core biopsies and outdated grading systems.ObjectiveWe prospectively gathered data from men undergoing prostate biopsy in multiple diverse North American and European institutions participating in the Prostate Biopsy Collaborative Group (PBCG) in order to build a state-of-the-art risk prediction tool.Design, setting, and participantsWe obtained data from 15 611 men undergoing 16 369 prostate biopsies during 2006-2017 at eight North American institutions for model-building and three European institutions for validation.Outcome measurements and statistical analysisWe used multinomial logistic regression to estimate the risks of high-grade prostate cancer (Gleason score ≥7) on biopsy based on clinical characteristics, including age, prostate-specific antigen, digital rectal exam, African ancestry, first-degree family history, and prior negative biopsy. We compared the PBCG model to the PCPTRC using internal cross-validation and external validation on the European cohorts.Results and limitationsCross-validation on the North American cohorts (5992 biopsies) yielded the PBCG model area under the receiver operating characteristic curve (AUC) as 75.5% (95% confidence interval: 74.2-76.8), a small improvement over the AUC of 72.3% (70.9-73.7) for the PCPTRC (p

OBJECTIVE:To assess whether obesity is associated with progression to metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM), in patients with non-metastatic castration-resistant prostate cancer (non-mCRPC). At the population level, obesity is associated with prostate cancer mortality; however, some studies have found that higher body mass index (BMI) is associated with better long-term prostate cancer outcomes amongst men with mCRPC. PATIENTS AND METHODS:We identified 1 192 patients with non-mCRPC from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BMI was calculated from height and weight abstracted from the medical records at the time closest to but prior to CRPC diagnosis and categorised as underweight (

PurposeSystemic inflammation, as measured by C-reactive protein, has been linked with poor prostate cancer (PC) outcomes, predominantly in white men. Whether other immune measures like white blood cell counts are correlated with PC progression and whether results vary by race is unknown. We examined whether complete blood count (CBC) parameters were associated with PC outcomes and whether these associations varied by race.MethodsAnalyses include 1,826 radical prostatectomy patients from six VA hospitals followed through medical record review for biochemical recurrence (BCR). Secondary outcomes included castration-resistant PC (CRPC), metastasis, all-cause mortality (ACM), and PC-specific mortality (PCSM). Cox-proportional hazards were used to assess the associations between pre-operative neutrophils, lymphocytes, platelets, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) with each outcome. We used a Bonferroni-corrected p-value of 0.05/5 = 0.01 as the threshold for statistical significance.ResultsOf 1,826 men, 794 (43%) were black and 1,032 (57%) white. Neutrophil count (p

BackgroundHypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.MethodHypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).ResultsA 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P

BackgroundRisk of prostate cancer-specific mortality (PCSM) is highly variable for men with adverse pathologic features at radical prostatectomy (RP); a majority will die of other causes. Accurately stratifying PCSM risk can improve therapy decisions.ObjectiveValidate the 22 gene Decipher genomic classifier (GC) to predict PCSM in men with adverse pathologic features after RP.Design, setting, and participantsMen with adverse pathologic features: pT3, pN1, positive margins, or Gleason score >7 who underwent RP in 1987-2010 at Johns Hopkins, Cleveland Clinic, Mayo Clinic, and Durham Veteran's Affairs Hospital. We also analyzed subgroups at high risk (prostate-specific antigen >20 ng/ml, RP Gleason score 8-10, or stage >pT3b), or very high risk of PCSM (biochemical recurrence in 0.6) versus low-intermediate (≤ 0.6), the odds ratio for PCSM10 adjusted for CAPRA-S was 3.91 (95% confidence interval: 2.43-6.29), with AUC=0.77, an increase of 0.04 compared with CAPRA-S. Subgroup odds ratios were 3.96, 3.06, and 1.95 for high risk, BCR2, or MET, respectively (all p

IntroductionProstate cancer is a heterogeneous disease, and risk stratification systems have been proposed to guide treatment decisions. However, significant heterogeneity remains for those with unfavorable-risk disease.MethodsThis study included 3335 patients undergoing radical prostatectomy without adjuvant radiotherapy in the SEARCH database. High-risk patients were dichotomized into standard and very high-risk (VHR) groups based on primary Gleason pattern, percentage of positive biopsy cores (PPBC), number of NCCN high-risk factors, and stage T3b-T4 disease. Similarly, intermediate-risk prostate cancer was separated into favorable and unfavorable groups based on primary Gleason pattern, PPBC, and number of NCCN intermediate-risk factors.ResultsMedian follow-up was 78 months. Patients with VHR prostate cancer had significantly worse PSA relapse-free survival (PSA-RFS, P

PurposeWe evaluated the relative risk of biochemical recurrence, metastasis and death from prostate cancer contributed by biopsy Gleason pattern 5 among men at high risk with Gleason 8-10 disease in the SEARCH (Shared Equal Access Regional Cancer Hospital) cohort.Materials and methodsMen with biopsy Gleason sum 8-10 prostate cancer treated with radical prostatectomy were evaluated. The cohort was divided into men with Gleason 4 + 4 vs those with any pattern 5 (ie Gleason 3 + 5, 5 + 3, 4 + 5, 5 + 4 or 5 + 5). Predictors of biochemical recurrence, metastases, and prostate cancer specific and overall survival were analyzed using Kaplan-Meier, log rank test and Cox proportional hazards models.ResultsWe identified 634 men at high risk in the SEARCH database, of whom 394 (62%) had Gleason 4 + 4 and 240 (38%) had Gleason pattern 5 on biopsy. Baseline characteristics did not significantly differ between the groups. On multivariable analysis relative to Gleason 4 + 4 men at high risk with Gleason pattern 5 showed no difference in the risk of biochemical recurrence (HR 1.26, 95% CI 0.99-1.61, p = 0.065). However, they were at significantly greater risk for metastasis (HR 2.55, 95% CI 1.50-4.35, p = 0.001), prostate cancer specific mortality (HR 2.67, 95% CI 0.1.26-5.66, p = 0.010) and overall mortality (HR 1.60, 95% CI 1.09-2.34, p = 0.016).ConclusionsPreoperative subclassification of high risk prostate cancer by biopsy Gleason grade (4 + 4 vs any Gleason pattern 5) identified men at highest risk for progression. Any Gleason 5 on biopsy is associated with a greater risk of metastasis, and prostate cancer specific and overall mortality. Grouping all Gleason 8-10 tumors together as high risk lesions may fail to fully stratify men at highest risk for poor outcomes.

BackgroundUridine 5'-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.MethodsWe determined the expression of UGT2B15, UGT2B17, and UGT2B28 enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each protein's percent positive and H-score, a weighted score of staining intensity, and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were divided at the median and we tested the association between UGT2B17 group and risk of BCR.ResultsThe median follow-up for all patients was 118 months (IQR: 85-144). Of 190, 83 (44%) patients developed BCR. We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend for an association between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found that patients with UGT2B17 higher levels of expression had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041), although this association was attenuated in the multivariable model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088).ConclusionsOur findings suggest that UGT2B17 overexpression may be associated with a significant increased risk of BCR. These results are consistent with previous reports which showed UGT2B17 significantly expressed in advanced prostate cancer including prostate tumor metastases.

ObjectivesTo examine whether prostate-specific antigen doubling time (PSADT) correlates with metastases, all-cause mortality (ACM), and prostate cancer-specific mortality (PCSM) and to identify PSADT thresholds that can be used clinically for risk stratification in men with M0 castration-resistant prostate cancer (CRPC).Materials and methodsWe collected data on 441 men with M0 CRPC in 2000-2015 at five Veterans Affairs hospitals. Cox models were used to test the association between log-transformed PSADT and the development of metastasis, ACM and PCSM. To identify thresholds, we categorized PSADT into 3-month groups and then combined groups with similar hazard ratios (HRs).ResultsThe median (interquartile range) follow-up was 28.3 (14.7-49.1) months. As a continuous variable, PSADT was associated with metastases, ACM and PCSM (HR 1.40-1.68, all P < 0.001). We identified the following PSADT thresholds:

BackgroundA 5-tier prognostic grade group (GG) system was enacted to simplify the risk stratification of patients with prostate cancer in which Gleason scores of ≤6, 3 + 4, 4 + 3, 8, and 9 or 10 are considered GG 1 through 5, respectively. The authors investigated the utility of biopsy GG for predicting long-term oncologic outcomes after radical prostatectomy in an equal-access health system.MethodsMen who underwent prostatectomy at 1 of 6 Veterans Affairs hospitals in the Shared Equal Access Regional Cancer Hospital database between 2005 and 2015 were reviewed. The prognostic ability of biopsy GG was examined using Cox models. Interactions between GG and race also were tested.ResultsIn total, 2509 men were identified who had data available on biopsy Gleason scores, covariates, and follow-up. The cohort included men with GG 1 (909 patients; 36.2%), GG 2 (813 patients; 32.4%), GG 3 (398 patients; 15.9%), GG 4 (279 patients; 11.1%), and GG 5 (110 patients; 4.4%) prostate cancer. The cohort included 1002 African American men (41%). The median follow-up was 60 months (interquartile range, 33-90 months). Higher GG was associated with higher clinical stage, older age, more recent surgery, and surgical center (P < .001) as well as increased biochemical recurrence, secondary therapy, castration-resistant prostate cancer, metastases, and prostate cancer-specific mortality (all P < .001). There were no significant interactions with race in predicting measured outcomes.ConclusionsThe 5-tier GG system predicted multiple long-term endpoints after radical prostatectomy in an equal-access health system. The predictive value was consistent across races. Cancer 2017;123:4122-4129. © 2017 American Cancer Society.

BackgroundBlack race is associated with prostate cancer (PC) diagnosis and poor outcome. Previously, the authors reported that black men undergoing radical prostatectomy (RP) in equal-access hospitals had an increased risk of biochemical disease recurrence (BCR), but recurrences were equally aggressive as those occurring in white men. The authors examined the association between race and long-term outcomes after RP.MethodsData regarding 1665 black men (37%) and 2791 white men (63%) undergoing RP were analyzed. Using Cox models, the authors tested the association between race and BCR, BCR with a prostate-specific antigen (PSA) doubling time

ObjectiveTo evaluate the association between the prostate-specific antigen (PSA) nadir level and the time to nadir (TTN) with biochemical recurrence (BCR) risk after radical prostatectomy (RP) in the Shared Equal-Access Research Cancer Hospital (SEARCH) database.Materials and methodsThis is a retrospective analysis of 1939 men from the SEARCH database treated with RP between 1998 and 2015 with available ultrasensitive PSA nadir within 1-6 months after RP. Uni- and multivariable analyses of PSA nadir and TTN with time from nadir to BCR were performed with Cox models (adjusted for demographics, tumor features, and preoperative PSA).ResultsAmong men with an undetectable PSA nadir, the TTN was unrelated to BCR (1.0-2.9 vs 3-6 months: hazard ratio [HR] 0.86, P = .46). Regardless of TTN, men with detectable nadir had an increased risk of BCR (TTN of 3-6 months: HR 1.81, P = .024; TTN of 1.0-2.99 months: HR 3.75, P

ObjectivesTo examine if there is a subset of men with grade group 2 prostate cancer who could be potential candidates for active surveillance.MethodsWe used the Shared Equal Access Regional Cancer Hospital database to identify 776 men undergoing radical prostatectomy from 2006 to 2015 with >8 biopsy cores obtained and complete information. We compared men who fulfilled low-risk disease criteria (clinical stage T1c/T2a; grade group 1; prostate-specific antigen ≤10 ng/mL) with the exception of grade group 2 versus men who met all three low-risk criteria. Logistic regression was used to test the association between grade group and radical prostatectomy pathological features. Biochemical recurrence was examined using Cox models. To examine whether there was a subset of men with low-volume grade group 2 with comparable outcomes to low-risk men, we repeated all analyses limiting the percentage of positive cores in the grade group 2 group to ≤33%, and positive cores to ≤4, ≤3 or ≤2.ResultsGrade group 2 low-risk men had increased risk of pathological grade group 3 or higher (P < 0.001), extraprostatic extension (P < 0.001), seminal vesicle invasion (P < 0.001) and higher risk of biochemical recurrence (hazard ratio = 1.76, P = 0.006). Using increasingly strict definitions of low-volume disease, at ≤2 positive cores there was no difference in adverse pathology between groups (all P > 0.2), except higher pathological grade group (P = 0.006). Biochemical recurrence was similar in men in grade group 1 and grade group 2 (hazard ratio = 1.24; P = 0.529).ConclusionsAmong men with prostate-specific antigen ≤10 ng/mL and clinical stage T1c/T2a, those in grade group 2 with ≤2 total positive cores have similar rates of adverse pathology and biochemical recurrence as men with grade group 1.

Purpose To perform the first meta-analysis of the performance of the genomic classifier test, Decipher, in men with prostate cancer postprostatectomy. Methods MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports between 2011 and 2016 of men treated by prostatectomy that assessed the benefit of the Decipher test. Multivariable Cox proportional hazards models fit to individual patient data were performed; meta-analyses were conducted by pooling the study-specific hazard ratios (HRs) using random-effects modeling. Extent of heterogeneity between studies was determined with the I2 test. Results Five studies (975 total patients, and 855 patients with individual patient-level data) were eligible for analysis, with a median follow-up of 8 years. Of the total cohort, 60.9%, 22.6%, and 16.5% of patients were classified by Decipher as low, intermediate, and high risk, respectively. The 10-year cumulative incidence metastases rates were 5.5%, 15.0%, and 26.7% ( P < .001), respectively, for the three risk classifications. Pooling the study-specific Decipher HRs across the five studies resulted in an HR of 1.52 (95% CI, 1.39 to 1.67; I2 = 0%) per 0.1 unit. In multivariable analysis of individual patient data, adjusting for clinicopathologic variables, Decipher remained a statistically significant predictor of metastasis (HR, 1.30; 95% CI, 1.14 to 1.47; P < .001) per 0.1 unit. The C-index for 10-year distant metastasis of the clinical model alone was 0.76; this increased to 0.81 with inclusion of Decipher. Conclusion The genomic classifier test, Decipher, can independently improve prognostication of patients postprostatectomy, as well as within nearly all clinicopathologic, demographic, and treatment subgroups. Future study of how to best incorporate genomic testing in clinical decision-making and subsequent treatment recommendations is warranted.

BackgroundSkeletal-related events (SREs) are common complications of bone metastatic castration-resistant prostate cancer (mCRPC). To the authors' knowledge, there are limited data regarding which factors predict SREs. The authors identified risk factors for SREs in men with bone mCRPC using characteristics commonly available in the medical record.MethodsData from 454 patients with nonmetastatic CRPC were identified from 2 Veteran Affairs Medical Centers from 2000 through 2013. Among these men, 233 (51%) developed bone metastases during follow-up and represented the study cohort. First occurrence of an SRE was abstracted from the medical records. A stepwise multivariable Cox model was used to select the strongest predictors of time to SRE.ResultsThe median age of the patients at the time of diagnosis of bone mCRPC was 75 years (interquartile range, 68-81 years), and there were 153 nonblack patients (66%). During follow-up (median, 7.8 months [interquartile range, 2.9-18.3 months]), 88 patients (38%) had an SRE. On univariable analysis, more recent year of metastasis (hazard ratio [HR], 0.91), prostate-specific antigen doubling time of ≥9 months versus

ObjectiveTo identify the predictors of time from initial diagnosis of metastatic castration-resistance prostate cancer (mCRPC) to all-cause death within the Shared Equal Access Regional Cancer Hospital cohort.Patients and methodsWe performed a retrospective analysis of 205 mCRPC men. Overall survival was estimated and plotted using the Kaplan-Meier method. The uni- and multivariable overall survival predictors were evaluated with the Cox proportional hazards model. A nomogram was generated to predict overall survival at 1, 2, 3, and 5 years after mCRPC. Concordance index and calibration plot were obtained.ResultsA total of 170 men (83%) died over a median follow-up of 41 months. In univariable analysis, older age, more remote year of mCRPC, nonblack race, greater number of bone metastasis, higher prostate-specific antigen (PSA) levels, shorter PSA doubling time, and faster PSA velocity at mCRPC diagnosis were significantly associated with shorter overall survival (all P < .05). In multivariable analysis, older age, more remote year of mCRPC, greater number of bone metastasis, higher PSA levels, and shorter PSA doubling time at mCRPC diagnosis remained significantly associated with shorter overall survival (all P < .05). On the basis of these variables, a nomogram was generated yielding a concordance index of 0.67 and good calibration.ConclusionThe use of clinical parameter such as age, disease burden, and PSA levels and kinetics can be used to estimate overall survival in mCRPC patients.

PurposeRacial disparities in the incidence and risk profile of prostate cancer at diagnosis among African-American men are well reported. However, it remains unclear whether African-American race is independently associated with adverse outcomes in men with clinical low risk disease.Materials and methodsWe retrospectively analyzed the records of 895 men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database in whom clinical low risk prostate cancer was treated with radical prostatectomy. Associations of African-American and Caucasian race with pathological biochemical recurrence outcomes were examined using chi-square, logistic regression, log rank and Cox proportional hazards analyses.ResultsWe identified 355 African-American and 540 Caucasian men with low risk tumors in the SEARCH cohort who were followed a median of 6.3 years. Following adjustment for relevant covariates African-American race was not significantly associated with pathological upgrading (OR 1.33, p = 0.12), major upgrading (OR 0.58, p = 0.10), up-staging (OR 1.09, p = 0.73) or positive surgical margins (OR 1.04, p = 0.81). Five-year recurrence-free survival rates were 73.4% in African-American men and 78.4% in Caucasian men (log rank p = 0.18). In a Cox proportional hazards analysis model African-American race was not significantly associated with biochemical recurrence (HR 1.11, p = 0.52).ConclusionsIn a cohort of patients at clinical low risk who were treated with prostatectomy in an equal access health system with a high representation of African-American men we observed no significant differences in the rates of pathological upgrading, up-staging or biochemical recurrence. These data support continued use of active surveillance in African-American men. Upgrading and up-staging remain concerning possibilities for all men regardless of race.

ObjectivesTo test the external validity of a previously developed risk table, designed to predict the probability of a positive bone scan among men with non-metastatic (M0) castration-resistant prostate cancer (CRPC), in a separate cohort.Patients and methodsWe retrospectively analysed 429 bone scans of 281 patients with CRPC, with no known previous metastases, treated at three Veterans Affairs Medical Centers. We assessed the predictors of a positive scan using generalized estimating equations. Area under the curve (AUC), calibration plots and decision-curve analysis were used to assess the performance of our previous model to predict a positive scan in the current data.ResultsA total of 113 scans (26%) were positive. On multivariable analysis, the only significant predictors of a positive scan were log-transformed prostate-specific antigen (PSA): hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.71-2.66 (P < 0.001) and log-transformed PSA doubling time (PSADT): HR 0.53; 95% CI 0.41-0.68 (P < 0.001). Among men with a PSA level

ObjectiveTo investigate predictors of time to metastasis among men treated with androgen deprivation therapy for nonmetastatic prostate cancer who developed castration-resistant prostate cancer (CRPC) within the Shared Equal Access Regional Cancer Hospital cohort.MethodsThis is a retrospective analysis of 458 nonmetastatic CRPC men. Metastases were detected in routine bone scans or other imaging tests. Predictors of time to metastasis were analyzed using proportional hazards model with CRPC as time zero.ResultsA total of 256 (56%) men were diagnosed with metastatic disease over a median follow-up of 36 months. Metastasis-free survival was 79%, 65%, 52%, 47%, and 41% at 1, 2, 3, 4, and 5 years after CRPC, respectively. In multivariable analysis, Gleason score 8-10 (hazard ratio [HR] = 1.61; P = .026), receiving primary localized treatment (HR = 1.38; P = .028), higher prostate-specific antigen (PSA) levels at CRPC diagnosis (logPSA HR = 1.64; P

ObjectiveTo determine whether there are subsets of men with pathological high grade prostate cancer (Gleason score 8-10) with particularly high or low 2-year biochemical recurrence (BCR) risk after radical prostatectomy (RP) when stratified into groups based on combinations of pathological features, such as surgical margin status, extracapsular extension (ECE) and seminal vesicle invasion (SVI).Materials and methodsWe identified 459 men treated with RP with pathological Gleason score 8-10 prostate cancer in the SEARCH database. The men were stratified into five groups based on pathological characteristics: group 1, men with negative surgical margins (NSMs) and no ECE; group 2, men with positive surgical margin (PSMs) and no ECE; group 3, men with NSMs and ECE; group 4, men with PSMs and ECE; and group 5, men with SVI. Cox proportional hazards models and the log-rank test were used to compare BCR among the groups.ResultsAt 2 years after RP, pathological group was significantly correlated with BCR (log-rank, P < 0.001) with patients in group 5 (+SVI) having the highest BCR risk (66%) and those in group 1 (NSMs and no ECE) having the lowest risk (14%). When we compared groups 2, 3, and 4, with each other, there was no significant difference in BCR among the groups (~50% 2-year BCR risk; log-rank P = 0.28). Results were similar when adjusting for prostate-specific antigen, age, pathological Gleason sum and clinical stage, or after excluding men who received adjuvant therapy.ConclusionsIn patients with high grade (Gleason score 8-10) prostate cancer after RP, the presence of either PSMs, ECE or SVI was associated with an increased risk of early BCR, with a 2-year BCR risk of ≥50%. Conversely, men with organ-confined margin-negative disease had a very low risk of early BCR despite Gleason score 8-10 disease.

ObjectivesTo determine if men with adverse pathology but undetectable ultrasensitive (

BackgroundBlack men are disproportionately affected by both cardiovascular disease and prostate cancer. Epidemiologic evidence linking dyslipidemia, an established cardiovascular risk factor, and prostate cancer progression is mixed. As existing studies were conducted in predominantly non-black populations, research on black men is lacking.MethodsWe identified 628 black and 1,020 non-black men who underwent radical prostatectomy and never used statins before surgery in the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Median follow-up was 2.9 years. The impact of preoperative hypercholesterolemia on risk of biochemical recurrence was examined using multivariable, race-stratified proportional hazards. In secondary analysis, we examined associations with low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, overall and among men with dyslipidemia.ResultsHigh cholesterol was associated with increased risk of recurrence in black [HR(per10 mg/dL) 1.06; 95% confidence interval (CI), 1.02-1.11] but not non-black men (HR(per10 mg/dL) 0.99; 95% CI, 0.95-1.03; P(interaction) = 0.011). Elevated triglycerides were associated with increased risk in both black and non-black men (HR(per10 mg/dL) 1.02; 95% CI, 1.00-1.03 and 1.02; 95% CI, 1.00-1.02, respectively; P(interaction) = 0.458). There were no significant associations between LDL or HDL and recurrence risk in either race. Associations with cholesterol, LDL, and triglycerides were similar among men with dyslipidemia, but low HDL was associated with increased risk of recurrence in black, but not non-black men with dyslipidemia (P(interaction) = 0.047).ConclusionElevated cholesterol was a risk factor for recurrence in black but not non-black men, whereas high triglycerides were associated with increased risk regardless of race.ImpactSignificantly contrasting associations by race may provide insight into prostate cancer racial disparities.

ObjectiveTo evaluate performance of pelvic lymph node dissection during radical prostatectomy within an equal access care setting over a period of time, and stratified by prostate cancer risk group and surgical technique.MethodsWe identified men in the Shared Equal Access Regional Cancer Hospital database who had open or robotic-assisted radical prostatectomy from 2006 to 2013. Univariable logistic regression was used to test the association between age, race, body mass index, total biopsy cores, number of positive biopsy cores, risk group, year, center, surgical volume and surgical technique on pelvic lymph node dissection use. Multivariable logistic analysis was used to examine surgical technique and pelvic lymph node dissection performance. Spearman's correlation examined temporal changes in pelvic lymph node dissection utilization stratified by risk group and surgical technique.ResultsA total of 1425 men met inclusion criteria; 67% of them underwent pelvic lymph node dissection. On multivariable analysis, robotic-assisted radical prostatectomy was associated with an 92% decreased use of pelvic lymph node dissection in low-risk, 84% decreased in intermediate-risk and 91% decreased in high-risk men (all P < 0.001). In robotic-assisted radical prostatectomy, there was a trend for increased pelvic lymph node dissection utilization over time in high-risk men (Spearman; P = 0.077) reaching ~85% in 2012-2013, which was accompanied by increased use in low-risk men (P = 0.016). For open radical prostatectomy, fewer pelvic lymph node dissections were carried out in low-risk men over time, decreasing to ~35% (P = 0.047) in 2012-2013, whereas rates remained high for high-risk men throughout (~95%; P = 0.621).ConclusionRegardless of risk group, pelvic lymph node dissection is carried out significantly less during robotic-assisted radical prostatectomy. For robotic-assisted radical prostatectomy, pelvic lymph node dissection utilization increased over time for high-risk men, but rates also increased for low-risk men. Further attention to the discrepancy between provided and guideline recommended pelvic lymph node dissection performance is required to improve prostate cancer care.

ObjectiveTo assess the impact of positive surgical margins (PSMs) on long-term outcomes after radical prostatectomy (RP), including metastasis, castrate-resistant prostate cancer (CRPC), and prostate cancer-specific mortality (PCSM).Patients and methodsRetrospective study of 4,051 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort treated by RP from 1988 to 2013. Proportional hazard models were used to estimate hazard ratios (HRs) of PSMs in predicting biochemical recurrence (BCR), CRPC, metastases, and PCSM. To determine if PSMs were more predictive in certain patients, analyses were stratified by pathological Gleason score, stage, and preoperative prostate-specific antigen (PSA) level.ResultsThe median (interquartile range) follow-up was 6.6 (3.2-10.6) years and 1 127 patients had >10 years of follow-up. During this time, 302 (32%) men had BCR, 112 (3%) developed CRPC, 144 (4%) developed metastases, and 83 (2%) died from prostate cancer. There were 1,600 (40%) men with PSMs. In unadjusted models, PSMs were significantly associated with all adverse outcomes: BCR, CRPC, metastases and PCSM (all P ≤ 0.001). After adjusting for demographic and pathological characteristics, PSMs were associated with increased risk of only BCR (HR 1.98, P < 0.001), and not CRPC, metastases, or PCSM (HR ≤1.29, P > 0.18). Similar results were seen when stratified by pathological Gleason score, stage, or PSA level, and when patients who underwent adjuvant radiotherapy were excluded.ConclusionsPSMs after RP are not an independent risk factor for CRPC, metastasis, or PCSM overall or within any subset. In the absence of other high-risk features, PSMs alone may not be an indication for adjuvant radiotherapy.

BackgroundBenign human prostate tubule-initiating cells (TIC) and aggressive prostate cancer display common traits, including tolerance of low androgen levels, resistance to apoptosis, and microenvironment interactions that drive epithelial budding and outgrowth. TIC can be distinguished from epithelial and stromal cells that comprise prostate tissue via cell sorting based upon Epcam, CD44, and CD49f antigenic profiles. Fetal prostate epithelial cells (FC) possess a similar antigenic profile to adult TIC and are capable of inducing tubule formation. To identify the TIC niche in human prostate tissue, differential keratin (KRT) expression was evaluated.ResultsGene expression data generated from Affymetrix Gene Chip human U133 Plus 2.0 array of sorted adult and fetal epithelial cells revealed KRT13 to be significantly enriched in FC and TIC compared to basal cells (BC) and luminal cells (LC) (p