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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.

Additional file 1: Detailed description of the algorithms for the 6 risk modeling approaches. Differences between the cohorts in terms of distributions of the twelve risk factors and their associations with clinically significant prostate cancer.

Supplemental material, sj-docx-1-tam-10.1177_17588359221075458 for The DNA damage repair landscape in Black women with breast cancer by Aloran Mazumder, Athena Jimenez, Rachel E. Ellsworth, Stephen J. Freedland, Sophia George, Matthew N. Bainbridge and Svasti Haricharan in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-1-tam-10.1177_17588359221075458 for The DNA damage repair landscape in Black women with breast cancer by Aloran Mazumder, Athena Jimenez, Rachel E. Ellsworth, Stephen J. Freedland, Sophia George, Matthew N. Bainbridge and Svasti Haricharan in Therapeutic Advances in Medical Oncology

A major metastasis suppressing mechanism is the rapid apoptotic death of cancer cells upon detachment from extracellular matrix, a process called anoikis. Focal adhesion kinase (PTK2/FAK) is a key enzyme involved in evasion of anoikis. We show that loss of the Cub-domain containing protein-1 (CDCP1), paradoxically stimulates FAK activation in the detached state of prostate cancer cells. In CDCP1(low) DU145 and PC3 prostate cancer cells, detachment-activation of FAK occurs through local production of PI(4,5)P(2). PI(4,5)P(2) is generated by the PIP5K1c-201 splicing isoform of PIP5K1c, which contains a unique SRC phosphorylation site. In the detached state, reduced expression of CDCP1 and an alternative CDCP1-independent SRC activation mechanism triggers PIP5K1c-pY644 phosphorylation by SRC. This causes a switch of Talin binding from β1-integrin to PIP5K1c-pY644 and leads to activation of PIP5K1c-FAK. Reduced CDCP1 expression also inactivates CDK5, a negative regulator of PIP5K1c. Furthermore, immersion of prostate cancer cells in 10% human plasma or fetal bovine serum is required for activation of PIP5K1c-FAK. The PIP5K1c induced detachment-activation of FAK in preclinical models sensitizes CDCP1(low) prostate cancer cells to FAK inhibitors. In patients, CDCP1(High) versus CDCP1(low) circulating tumor cells differ in expression of AR-v7, ONECUT2 and HOXB13 oncogenes and TMPRSS2 and display intra-patient heterogeneity of FAK-pY397 expression. Taken together, CDCP1(low) and CDCP1(high) detached prostate cancer cells activate distinct cytoplasmic kinase complexes and targetable transcription factors, which has important therapeutic implications.

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 12months 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 12months 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.

To develop algorithms to identify metastatic castration-sensitive prostate cancer (mCSPC) patients and castration-resistant prostate cancer (mCRPC) patients, using health claims data and laboratory test results. A targeted literature review summarized mCSPC and mCRPC patient selection criteria previously used in real-world retrospective studies. Novel algorithms to identify mCSPC and mCRPC were developed based on diagnosis codes indicating hormone sensitivity/resistance, prostate-specific antigen (PSA) test results, and claims for castration and mCRPC-specific treatments. These algorithms were applied to claims data from Optum Clinformatics Extended DataMart (Date of Death) Databases (commercial insurance/Medicare Advantage [COM/MA]; 01 January 2014–31 July 2019) and Medicare Fee-for-Service (Medicare-FFS; 01 January 2014–31 December 2017). Previous real-world studies identified mCSPC primarily based on metastasis diagnosis codes, and mCRPC based on mCRPC-specific drugs. Using the current study’s algorithms, 7034 COM/MA and 19,981 Medicare-FFS patients were identified as having mCSPC, and 2578 COM/MA and 11,554 Medicare-FFS as having mCRPC. Most mCSPC patients were identified based on evidence of being hormone/castration-naive. Patients were identified as having mCRPC most commonly based on rising PSA (COM/MA), or at the metastasis diagnosis date if it occurred after castration (Medicare-FFS). Among patients with mCSPC, 14–17% had evidence of progression to castration resistance during a median 1-year follow-up period, mostly based on use of mCRPC-specific drugs. Comprehensive algorithms based on claims and laboratory data were developed to identify and distinguish patients with mCSPC and mCRPC. This will facilitate appropriate identification of mCSPC and mCRPC patients based on health claims data and better understanding of patient unmet needs in real-world settings.

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 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

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.

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).

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&nbsp

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

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

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.

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

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.

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.

© 2015 Elsevier Ltd. Objectives: To assess whether larger tumor volume in black men explains higher presurgical PSA levels versus white men with prostate cancer. Methods: We retrospectively analyzed 1904 men from the Shared Equal Access Regional Cancer Hospital database who underwent radical prostatectomy from 1990 to 2013. Geometric mean of tumor volume and preoperative PSA for each race were estimated from multivariable linear regression models. Results: There were 1104 (58%) white men and 800 (42%) black men. Black men were younger (60.2 vs. 62.9 years, p< 0.001) had a higher PSA (6.7 vs. 6.0 ng/mL, p< 0.001), more positive margins (47 vs. 38%, p< 0.001), and seminal vesicle invasion (13 vs. 9%, p=0.007). White patients had higher clinical stage (p< 0.001) and greater median tumor volume (6.0 vs. 5.3 gm, p=0.011). After multivariable adjustment (except for PSA), white men had smaller mean tumor volumes (5.2 vs. 5.8 gm, p=0.011). When further adjusted for PSA, there was no racial difference in mean tumor volume (p=0.34). After multivariable adjustment, black men had higher mean PSAs vs. white men (7.5 vs. 6.1 ng/mL, p< 0.001). Results were similar after further adjusting for tumor volume: black men had 16% higher mean PSAs versus white men (7.4 vs. 6.2 ng/mL, p< 0.001). Conclusions: In this study of men undergoing radical prostatectomy at multiple equal access medical centers, racial differences in tumor volume did not explain higher presurgical PSA levels in black versus white men. The exact reason for higher PSA values in black men remains unclear.

OBJECTIVES To determine if dutasteride-treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. To analyse whether the use of treatment-specific criteria for repeat biopsy maintains the usefulness of prostate-specific antigen (PSA) level for detecting high grade cancers. PATIENTS AND METHODS The REDUCE study was a randomized, double-blind, placebo-controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy-detectable prostate cancer in men with a previous negative biopsy. The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds. RESULTS Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8-10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8-10 cancers would have been missed in the placebo group. In both groups, the incidence of Gleason 7 and Gleason 8-10 cancers generally increased with greater rises in PSA. Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7-10 cancers in men treated with dutasteride vs placebo. Men with Gleason 7 and Gleason 8-10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds. CONCLUSION Using treatment-specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8-10) or higher than (Gleason 7-10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.

To evaluate the association between metabolic syndrome (MS) and prostate cancer diagnosis and grade in patients undergoing prostate biopsy.From 2009 onwards, a consecutive series of patients undergoing 12-core prostate biopsy for PSA value ≥4 ng/ml and/or positive digital rectal examination (DRE) were prospectively enrolled. Body mass index (BMI), waist circumferences, and blood pressure were measured before the biopsy. Blood samples were tested for: PSA, fasting glucose, triglycerides, and cholesterol HDL. MS presence was defined according to Adult Treatment Panel III criteria.One hundred ninety five patients were enrolled with a median age and PSA of 69 years and 5.6 ng/ml respectively. Median BMI was 27.6 kg/m(2) with 64 patients (33%) being classified as obese (BMI ≥ 30 kg/m(2) ). Eighty-six patients (44%) had MS. Eighty-three patients (43%) had cancer on biopsy; 37 (45%) with MS and 46 (55%) without (P = 0.48). PSA was independently associated with higher risk of cancer (OR 1.12/1 U PSA, P = 0.01). Out of 83 patients with prostate cancer, 42 (51%) had Gleason score 6 (12 (28.5%) presented a MS) and 41 (49%) a Gleason score ≥7 (25 (61%) presented a MS). The presence of MS was not associated with an increased risk prostate cancer (OR: 0.97, P = 0.94) but with an increased risk of Gleason ≥7 (OR: 3.82; P = 0.013).In our single center study, MS is associated with an increased risk of high grade Gleason score when prostate cancer is diagnosed on biopsy. However, these results should be confirmed in a larger multicenter study. .

BACKGROUND: Prostate 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. OBJECTIVE: We 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 PARTICIPANTS: We 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 ANALYSIS: We 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 LIMITATIONS: Cross-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 < 0.0001). However, calibration and clinical net benefit were far superior for the PBCG model. Using a risk threshold of 10%, clinical use of the PBCG model would lead to the equivalent of 25 fewer biopsies per 1000 patients without missing any high-grade cancers. Results were similar on external validation on 10 377 European biopsies. CONCLUSIONS: The PBCG model should be used in place of the PCPTRC for prediction of prostate biopsy outcome. PATIENT SUMMARY: A contemporary risk tool for outcomes on prostate biopsy based on the routine clinical risk factors is now available for informed decision-making.

Context: High-risk prostate cancer (PCa) is a potentially lethal disease. It is clinically important to identify patients with high-risk PCa early on because they stand to benefit the most from curative therapy. Because of recent advances in PCa management, a multimodal approach may be advantageous. Objective: Define high-risk PCa, and identify the best diagnostic and treatment patterns for patients with clinically localized and locally advanced disease. A critical analysis of published results following monomodal and/or multimodal therapy for high-risk PCa patients was also performed. Evidence acquisition: A review of the literature was performed using the Medline, Embase, Scopus, and Web of Science databases as well as the Cochrane Database of Systematic Reviews. Evidence synthesis: High-risk PCa accounts for

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