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What Is This Summary About?: This is a plain language summary of a research article originally published in Clinical Genitourinary Cancer . The original article described the effect of rapidly rising prostate-specific antigen (PSA) levels on how long men with a type of advanced prostate cancer live and their healthcare costs. The prostate is a part of the male body that helps make semen. PSA is a protein produced by the prostate that can show how advanced prostate cancer has become. One measure of prostate cancer growth is assessing how quickly a patient's PSA level doubles. This is known as the PSA doubling time (PSADT). People with a shorter PSADT usually have faster-growing prostate cancer compared with people who have a longer PSADT of more than 12 months (long PSADT). Researchers wanted to know if PSADT can predict cancer spread (known as metastasis) or death for people with a type of advanced prostate cancer called non-metastatic castration-resistant prostate cancer (nmCRPC). Researchers also wanted to know if PSADT can predict healthcare costs. This could help doctors choose the right treatment for their patients with nmCRPC. This was a real-world study, not a clinical trial. This means that researchers looked at what happened when men received the treatments prescribed by their own doctor as part of their usual healthcare treatment. In this study, researchers used insurance claim information., What Were the Results?: Researchers looked at information for 2800 men with nmCRPC. Six out of every 10 men (60%) had a long PSADT of more than 12 months. Researchers found that it took longer for the cancer to spread to other parts of the body in men with a longer PSADT than men with PSADT of 12 months or less. Researchers also found that men with a longer PSADT lived longer than men with PSADT of 12 months or less. The long PSADT group had fewer healthcare visits overall than men with PSADT of 10 months or less. Over time, it cost less to treat men with a long PSADT than men with PSADT of 10 months or less. Generally, if PSADT was shorter, patients tended to do worse., What Do the Results of the Study Mean?: In this real-world study, researchers found that men with nmCRPC lived longer and had lower healthcare costs if they had a long PSADT of more than 12 months compared with men who had a shorter PSADT. Men with nmCRPC and a shorter PSADT may benefit from approved treatments that slow cancer spread and help them live longer. However, these treatments may have side effects and cost more than standard treatment. Doctors take all these things into account when choosing treatments for their patients. Most men in this study had a long PSADT of more than 12 months. Standard treatment may be the right choice for them because they are more likely to have better outcomes than men with a shorter PSADT.

Background: In the United States, Black men have a higher incidence of prostate cancer (PC)-related mortality than men of other races. Several real-world studies in advanced PC suggest, however, that Black men respond better to novel hormonal therapies than White men. Data on treatment responses to enzalutamide by race are limited. We assessed real-world prostate-specific antigen (PSA) response and clinical progression-free survival (cPFS) of Black vs. White men with chemotherapy-naïve PC treated with enzalutamide., Methods: This retrospective cohort study included patients with PC who initiated enzalutamide treatment from 2014 to 2018 in the IntrinsiQ Specialty Solutions™ database, a collection of electronic medical records from community urology practices. Index date was the date of the first prescription for enzalutamide, used as a proxy for metastatic castration-resistant PC (mCRPC). Patients who had undergone chemotherapy and/or abiraterone therapy were excluded. Kaplan-Meier and Cox models adjusted for baseline characteristics were used to estimate PSA response and cPFS by race., Results: The study included 214 Black and 1332 White men with chemotherapy-naïve PC presumed to have mCRPC based on the enzalutamide indication during the study period. Black men were younger and had higher baseline median PSA levels than White men. Enzalutamide therapy duration, follow-up time, and number of post-index PSA tests were similar between races. In multivariable analyses, the risk of patients achieving a ≥ 50% PSA decline was similar, whereas a numerically higher trend of ≥90% PSA decline was observed in Black men (HR 1.23; 95% CI 0.93-1.62 [P = 0.14]). In the multivariable analysis, Black men had significantly better cPFS (HR 0.82; 95% CI 0.68-0.98 [P = 0.03])., Conclusions: Black and White men with presumed chemotherapy-naïve mCRPC had similar PSA responses when treated with enzalutamide, but Black men had better cPFS than White men. Further research is warranted to validate these findings., (© 2022. The Author(s).)

Introduction: Limited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8-10 or prostate-specific antigen doubling time (PSADT) <9-12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy., Methods and Analysis: EMBARK is a randomised, phase 3 study of high-risk patients with nmCSPC, a PSADT of ≤9 months and a screening PSA of ≥2 ng/mL above the nadir after radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) with or without postoperative RT. Men (n=1050) are randomised 1:1:1 to enzalutamide 160 mg/day plus LHRHa or placebo plus LHRHa (double-blind arms) or enzalutamide monotherapy (open-label arm). Treatment is suspended at week 37 if PSA concentrations are <0.2 ng/mL and reinstated if levels rise to ≥2.0 ng/mL with RP or ≥5.0 ng/mL without RP. Patients with PSA ≥0.2 ng/mL at week 37 continue until treatment discontinuation criteria are met. The primary endpoint is MFS comparing enzalutamide plus LHRHa versus placebo plus LHRHa., Ethics and Dissemination: The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals., Trial Registration Number: NCT02319837., Competing Interests: Competing interests: SJF is a consultant to Astellas Pharma, Pfizer, Janssen, Bayer, Sanofi, Dendreon, Myovant, AstraZeneca and Merck. UDG is a consultant to Astellas Pharma, Bayer, BMS, Ipsen, Janssen, Novartis, Pfizer, Sanofi and Pharmamar; received institutional research funding from AstraZeneca, Roche and Sanofi and received travel funds from BMS, Ispen, Janssen, Pfizer and Roche during the conduct of the study. MG has stock or ownership interest in OncoGenex Technologies, Sustained Therapeutics and Sikta Pharmaceuticals; is a consultant to Astellas Pharma, AstraZeneca, Bayer, GDx, Janssen, Sanofi, Pfizer, Tersera and Roche; and holds patents for OGX-011, OGX-427, ST-CP and ST-POP. BR is an employee of and holds stock ownership in Pfizer. QS is an employee of Pfizer. JS is an employee of Astellas Pharma with stock ownership in AstraZeneca. GPH is an employee of Astellas Pharma. NDS is a consultant to or received research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, BMS, Dendreon, Exact Sciences, Ferring, Fergene, Janssen, MDx Health, Merck, Myovant, Nymox, Pfizer, Sanofi and Tolmar., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Prostate 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., Methods: A 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., Results: Over 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 < 0.001), while age, serum PSA, biopsy GG, and clinical T-stage were not (all p > 0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p < 0.001) and GC high-risk (vs low-risk, HR: 2.95, 95% CI: 1.79-4.87, p < 0.001) were significantly associated with metastasis. The addition of GC score to regression models based on NCCN risk group improved model AUC from 0.46 to 0.67, and CAPRA from 0.59 to 0.71., Conclusions: Among men with high-risk prostate cancer, conventional clinico-pathologic data had poor discrimination to risk stratify development of metastatic disease. GC score was a significant and independent predictor of metastasis and may help identify men best suited for treatment intensification/de-escalation.

Objective: To evaluate whether total serum PSA, free-PSA ratio and PSA density have similar diagnostic properties for detecting prostate cancer (PCa) and clinically-significant (cs) PCa in men with normal testosterone compared to men with low testosterone with a prior negative biopsy., Methods: We conducted a retrospective analysis of 3295 men undergoing a 2-year prostate biopsy following a negative prestudy biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events (REDUCE) study. Men were divided in 2 groups based on testosterone level < or ≥300 ng/dL. Diagnostic properties of total serum PSA, free-PSA ratio, and PSA density to predict PCa and csPCa, defined as Gleason score ≥7, were determined for several thresholds and plotted as receiver operator characteristic curves., Results: A total of 603 men (18.3%) had low testosterone. The prevalence of PCa and csPCa was 92 (15.3%) and 27 (4.5%), respectively, for low testosterone men compared to 458 (17.0%) and 138 (5.1%), correspondingly, for normal testosterone men. Total PSA, free-PSA ratio and PSA density showed similar sensitivity, specificity, and accuracy to predict PCa and csPCa among low testosterone men compared to normal testosterone men., Conclusion: Among subjects in a clinical trial with a prior negative biopsy, total PSA, free-PSA ratio and PSA density have comparable diagnostic characteristics for PCa screening in low and normal testosterone men., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To 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 Methods: We 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., Results: Overall, 922 men (22%) were of normal weight (BMI <25 kg/m 2 ), 1863 (45%) were overweight (BMI 25-29.9 kg/m 2 ), 968 (24%) were obese (BMI 30-34.9 kg/m 2 ), and 370 (9%) were moderately or severely obese (BMI ≥35 kg/m 2 ). After adjustment for multiple clinical characteristics, higher BMI was significantly associated with higher risk of BCR (P = 0.008). Among men with BCR, men in the four BMI categories had similar multivariable-adjusted PSADT values (increasing BMI categories: 20.9 vs 21.3 vs 21.0 vs 14.9 months; P = 0.48)., Conclusion: While we confirmed that higher BMI was associated with BCR, we found no link between BMI and PSADT at the time of recurrence. Our data suggest obese men do not have more aggressive recurrences. Future studies are needed to test whether obesity predicts response to salvage therapies., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Purpose: We assessed the predictive value of prostate specific antigen density to detect clinically significant prostate cancer, defined as prostate cancer grade group 2 or greater, in a series of men undergoing prostate biopsy with prostate specific antigen 4 to 10 ng/ml. We sought to define an optimum cutoff point for prostate specific antigen density and assess how race and body mass index affects prostate specific antigen density performance., Materials and Methods: We analyzed data on 2,162 men, of whom 56% were African American, with serum prostate specific antigen 4 to 10 ng/ml who underwent prostate biopsy. We compared the AUC between prostate specific antigen and prostate specific antigen density to predict clinically significant and any prostate cancer vs no cancer. We calculated the negative predictive value of prostate specific antigen density cutoff points ranging from 0.05 to 0.15 by every 0.01 step. We a priori defined the optimal cutoff point of prostate specific antigen density as a negative predictive value of 95% and tested whether the cutoff was sensitive to body mass index and race by comparing the negative predictive value across strata., Results: Median prostate specific antigen was 5.6 ng/ml (IQR 4.8-7) and median prostate specific antigen density was 0.15 ng/ml/cc (IQR 0.1-0.22). Prostate specific antigen density improved the performance of prostate specific antigen to detect significant cancer (AUC 0.58 to 0.68) and any cancer (AUC 0.55 to 0.69, each p <0.001). We identified a prostate specific antigen density cutoff point of less than 0.08 ng/ml/cc with a 96% negative predictive value for grade group 2 or greater. This was largely unchanged among different races and body mass indexes., Conclusions: Regardless of race or body mass index men with prostate specific antigen density less than 0.08 were unlikely to harbor grade group 2 or greater disease when prostate specific antigen was 4 to 10 ng/ml. If validated, prostate specific antigen density is a simple inexpensive and available tool that can be used to identify men who can likely forego prostate biopsies, thus reducing the over detection and morbidity of unnecessary biopsies., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA independent, study-mandated prostate biopsies., Methods: We conducted a post hoc analysis of data from 4974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. ≥7), were examined using multivariable logistic regression., Results: High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (OR per 10 mg/dL 1.05; 95% CI 1.00-1.09; p = 0.048), but cholesterol was unrelated to either overall or low-grade prostate cancer risk (p-values >0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values >0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (OR per 10 mg/dL 1.08; 95% CI 1.01-1.16; p = 0.033) and high-grade prostate cancer (OR per 10 mg/dL 1.14; 95% CI 1.01-1.28; p = 0.034)., Conclusions: In REDUCE, where all men received PSA independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link.

Background: The relationship between baseline prostate-specific antigen (PSA) and development of lower urinary tract symptoms (LUTS) in asymptomatic and mildly symptomatic men is unclear. We sought to determine if PSA predicts incident LUTS in these men., Methods: A post-hoc analysis of the 4-year REDUCE study was performed to assess for incident LUTS in 1534 men with mild to no LUTS at baseline. The primary aim was to determine whether PSA independently predicted incident LUTS after adjusting for the key clinical variables of age, prostate size, and baseline International prostate symptom score (IPSS). Incident LUTS was defined as the first report of medical treatment, surgery, or sustained clinically significant symptoms (two IPSS >14). Cox proportional hazards, cumulative incidence curves, and the log-rank test were used to test our hypothesis., Results: A total of 1534 men with baseline IPSS <8 were included in the study cohort. At baseline, there were 335 men with PSA 2.5-4 ng/mL, 589 with PSA 4.1-6 ng/mL, and 610 with PSA 6-10 ng/mL. During the 4-year study, 196 men progressed to incident LUTS (50.5% medical treatment, 9% surgery, and 40.5% new symptoms). As a continuous variable, higher PSA was associated with increased incident LUTS on univariable (HR 1.09, p = 0.019) and multivariable (HR 1.08, p = 0.040) analysis. Likewise, baseline PSA 6-10 ng/mL was associated with increased incident LUTS vs. PSA 2.5-4 ng/mL in adjusted models (HR 1.68, p = 0.016). This association was also observed in men with PSA 4.1-6 ng/mL vs. PSA 2.5-4 ng/mL (HR 1.60, p = 0.032)., Conclusions: Men with mild to no LUTS but increased baseline PSA are at increased risk of developing incident LUTS presumed due to benign prostatic hyperplasia.

Objective: To analyze factors associated with metastases, prostate cancer-specific mortality, and all-cause mortality in pN1 patients., Materials and Methods: We analyzed 3,642 radical prostatectomy patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Pathologic Gleason grade, number of lymph nodes (LN) removed, and first postoperative prostate-specific antigen (PSA) (<0.2 ng/ml or ≥0.2 ng/ml) were among covariates assessed. Cox regression was used to analyze the association between characteristics and survival outcomes. Kaplan-Meier was used to estimate survival in pN1 patients stratified by first postoperative PSA., Results: Of 3,642 patients, 124 (3.4%) had pN1. There were 71 (60%) patients with 1 positive LN, 32 (27%) with 2 positive LNs, and 15 (13%) with ≥3. Among men with pN1, first postoperative PSA was<0.2ng/ml in 46 patients (51%) and ≥0.2ng/ml in 44 patients (49%). Univariable Cox regression determined pathological Gleason grade (P = 0.021), seminal vesicle invasion (P = 0.010), and first postoperative PSA ≥0.2 ng/ml (P = 0.005) were associated with metastases. First postoperative PSA ≥0.2ng/ml was associated with metastasis on multivariable analysis (P = 0.046). Log-rank analysis revealed a more favorable metastases-free survival in patients with a first postoperative PSA<0.2ng/ml (P = 0.001). Estimated 5-year metastases-free survival rate was 99% for patients with a first postoperative PSA<0.2ng/ml and 87% for ≥0.2ng/ml., Conclusions: pN1 patients with a first postoperative PSA ≥0.2ng/ml were more likely to develop metastases. First postoperative PSA may be useful in identifying pN1 patients who harbor distant disease and aid in secondary treatment decisions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Short prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis. Prostate specific antigen doubling time is traditionally calculated using prostate specific antigen values 0.2 ng/ml or greater. We determined whether early prostate specific antigen doubling time, calculated from the first detectable postoperative prostate specific antigen up to and including the first recurrence value, correlates with prostate cancer outcomes., Materials and Methods: Cox models were used to examine the association between early prostate specific antigen doubling time and castration resistant prostate cancer, metastases, and all cause and prostate cancer specific mortality in 674 men who underwent radical prostatectomy between 1988 and 2014 and had a biochemical recurrence. Early prostate specific antigen doubling time was examined as a log transformed continuous and a categorical variable., Results: After adjusting for multiple clinicopathological characteristics, log transformed early prostate specific antigen doubling time was not associated with any outcome. However, when early doubling time was categorized as 15 or greater, 9 to 14.9, 3 to 8.9 and less than 3 months, on multivariable analysis men with early doubling time less than 3 months were at increased risk for castration resistant prostate cancer (HR 6.20, p = 0.004), metastases (HR 5.26, p = 0.001), prostate cancer specific mortality (HR 5.06, p = 0.026) and all cause mortality (HR 1.63, p = 0.065) compared to those with an early doubling time of 15 months or greater. However, the association with all cause mortality was not significant. Those with an early prostate specific antigen doubling time of 3 to 8.9 months were at increased risk for castration resistant prostate cancer (HR 3.56, p = 0.015), all cause mortality (HR 1.67, p = 0.006) and prostate cancer specific mortality (HR 3.17, p = 0.044) but not metastases (p = 0.13)., Conclusions: Early prostate specific antigen doubling time less than 9 months, calculated using prostate specific antigen values before and up to biochemical recurrence, is associated with an increased risk of castration resistant prostate cancer, metastases, and prostate cancer specific and all cause mortality among men with biochemical recurrence after radical prostatectomy. Early prostate specific antigen doubling time allows for risk stratification at biochemical recurrence and before prostate specific antigen doubling time is calculable, enabling these men to be referred for early aggressive secondary treatment and/or clinical trials., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To 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 Methods: We 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)., Results: The 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: <3 months; 3-8.9 months; 9-14. months; and ≥15 months. As a categorical variable, PSADT was associated with metastases, ACM and PCSM (all P < 0.001). Specifically, PSADT <3 months was associated with an approximately ninefold increased risk of metastases (HR 8.63, 95% CI 5.07-14.7) and PCSM (HR 9.29, 95% CI 5.38-16.0), and a 4.7-fold increased risk of ACM (HR 4.71, 95% CI 2.98-7.43) on multivariable analysis compared with PSADT ≥15 months. The median times to metastasis for patients with PSADT <3, 3-8.9, 9-14.9 and ≥15 months were 9, 19, 40 and 50 months, respectively., Conclusion: Prostate-specific antigen doubling time was a strong predictor of metastases, ACM and PCSM in patients with M0 CRPC. As with patients at earlier disease stages, <3, 3-8.9, 9-14.9 and ≥15 months are reasonable PSADT thresholds for risk stratification in men with M0 CRPC. These thresholds can be used for selecting high-risk men for clinical trials., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Objective: To 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 Methods: This 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)., Results: Among 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 <.001 vs undetectable nadir and TTN of 3-6 months). Among men with a detectable PSA at 1-3 months, 53% had a lower PSA level during follow-up 3-6 months after RP, which was undetectable in 32% and lower but still detectable in 21%., Conclusion: In the post-RP setting, men with both a detectable nadir and a shorter TTN had an increased risk of BCR. Intriguingly, about half of the men with a detectable PSA in the first 3 months after RP had a lower PSA level during follow-up between 3 and 6 months after RP. If confirmed in future studies, this has important implications for patients considering adjuvant therapy based on postoperative PSA values in the first 3 months after RP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To examine if there is a subset of men with grade group 2 prostate cancer who could be potential candidates for active surveillance., Methods: We 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., Results: Grade 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)., Conclusions: Among 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., (© 2017 The Japanese Urological Association.)

Background: Prostate-specific antigen (PSA) hemodilution is the leading theory for lower PSA values in obese men. However, testosterone and dihydrotestosterone (DHT), which are necessary for PSA production, are reduced in obese men. We assessed the relationship of body mass index (BMI) and PSA, taking into consideration the effect of testosterone and DHT., Methods: Among 8,122 participants in Reduction by Dutasteride of Prostate Cancer Events (REDUCE), complete data were available for 7,275. BMI was categorized as normal (<25 kg/m 2 ), overweight (25-29.9 kg/m 2 ), obese (30-34.9 kg/m 2 ), or moderate + severely obese (≥35 kg/m 2 ). Associations between BMI, testosterone, and DHT and the outcome variable of PSA were examined using linear regression., Results: There were 1,964 (27.0%) normal weight, 3,826 (52.6%) overweight, 1,200 (16.5%) obese, and 285 (3.9%) moderately + severely obese patients. With increasing BMI, there was a progressive decrease in PSA (P = 0.02), increase in prostate volume (P < 0.001), and decrease in both testosterone (P < 0.001) and DHT (P < 0.001). Using linear regression, increasing BMI was associated with decreasing serum PSA values. Furthermore, BMI remained inversely associated with PSA after individually adjusting for testosterone and DHT, as well as when adjusting for testosterone and DHT in the same model. Decreased androgen levels accounted for only 19% of the lower PSA in men with higher BMI., Conclusions: Only a fraction of lower PSA in obese men could be attributed to testosterone and DHT levels. The remaining factors explaining lower PSA are unaccounted for, presumably secondary to hemodilution associated with increased plasma volume in obese men. Prostate 77:466-470, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: Racial 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 Methods: We 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., Results: We 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)., Conclusions: In 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., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine if men with adverse pathology but undetectable ultrasensitive (<0.01 ng/mL) PSA are at high-risk for biochemical recurrence (BCR), or if there is a subset of patients at low-risk for whom the benefit of adjuvant radiation therapy might be limited., Patients and Methods: We evaluated 411 patients treated with RP from 2001 to 2013 without adjuvant radiation who had an undetectable (<0.01 ng/mL) PSA level after RP but with adverse pathology [positive surgical margins (PSMs), extraprostatic extension (EPE), and/or seminal vesicle invasion (SVI)]. Multivariable Cox regression analyses tested the relationship between pathological characteristics and BCR to identify groups of men at highest risk of early BCR., Results: On multivariable analysis, only pathological Gleason 7 (4 + 3), Gleason ≥8, and SVI independently predicted BCR (P = 0.019, P < 0.001, and P = 0.001, respectively), although on two-way analysis men with Gleason 7 (4 + 3) did not have significantly higher rates of BCR compared with patients with Gleason ≤6 (log-rank, P = 0.074). Men with either Gleason ≥8 (with PSMs or EPE) or SVI (15% of the cohort) defined a high-risk group vs men without these characteristics (3-year BCR risk of 50.4% vs 11.9%, log-rank, P < 0.001)., Conclusions: Among men with adverse pathology but an undetectable (<0.01 ng/mL) PSA level after RP, the benefits of adjuvant radiation are probably limited except for men with Gleason 8-10 (with PSMs or EPE) or SVI who are at high-risk of early BCR., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Objective: To 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 Methods: Retrospective 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., Results: The 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., Conclusions: PSMs 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., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Background: Metastatic lesions in prostate cancer beyond the bone have prognostic importance and affect clinical therapeutic decisions. Few data exist regarding the prevalence of soft-tissue metastases at the initial diagnosis of metastatic castration-resistant prostate cancer (mCRPC)., Methods: This study analyzed 232 men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC) who developed metastases detected by a bone scan or computed tomography (CT). All bone scans and CT scans within the 30 days before or after the mCRPC diagnosis were reviewed. The rate of soft-tissue metastases among those undergoing CT was determined. Then, predictors of soft-tissue metastases and visceral and lymph node metastases were identified., Results: Compared with men undergoing CT (n = 118), men undergoing only bone scans (n = 114) were more likely to have received primary treatment (P = .048), were older (P = .013), and less recently developed metastases (P = .018). Among those undergoing CT, 52 (44%) had soft-tissue metastases, including 20 visceral metastases (17%) and 41 lymph node metastases (35%), whereas 30% had no bone involvement. In a univariable analysis, only prostate-specific antigen (PSA) predicted soft-tissue metastases (odds ratio [OR], 1.27; P = .047), and no statistically significant predictors of visceral metastases were found. A higher PSA level was associated with an increased risk of lymph node metastases (OR, 1.38; P = .014), whereas receiving primary treatment was associated with decreased risk (OR, 0.36; P = .015)., Conclusions: The data suggest that there is a relatively high rate of soft-tissue metastasis (44%) among CRPC patients undergoing CT at the initial diagnosis of metastases, including some men with no bone involvement. Therefore, forgoing CT during a metastatic evaluation may lead to an underdiagnosis of soft-tissue metastases and an underdiagnosis of metastases in general. Cancer 2015. © 2015 American Cancer Society. Cancer 2016;122:222-229. © 2015 American Cancer Society., (© 2015 American Cancer Society.)

To examine whether the predictive performance of prostate-specific antigen (PSA) and PSA-related markers for prostate cancer (PCa) is modified by body mass index (BMI). Patients with a PSA 2-10 ng/mL who underwent multicore prostate biopsies were recruited from three tertiary centers. Serum markers measured included total PSA (tPSA), free-to-total PSA (f/tPSA), p2PSA, percentage of p2PSA (%p2PSA), and prostate health index (PHI). The association between serum markers and PCa risk was assessed by logistic regression. Predictive performance for each marker was quantified using the area under the receiver operator curves (AUC). Among 516 men, 18.2% had PCa at biopsy. For all tested markers, their predictive value on PCa risk was lower in obese patients compared to normal weight patients. We found statistically significant interactions between BMI and tPSA (P = 0.0026) and p2PSA (P = 0.038). PHI achieved an AUC of 0.872 in normal weight patients and 0.745 in obese patients, which outperformed the other predictors regardless of BMI category. In conclusion, PHI achieved the best predictive performance for detecting PCa and was not influenced by BMI.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Previously, in prostate cancer-free men, we found that statin initiation resulted in a 4.1% decline in PSA. This decline in PSA was proportional to the decline in cholesterol, suggesting a link between cholesterol and PSA levels. Whether these associations vary by race has not been explored and therefore we examined the association between pre-statin serum cholesterol and PSA in black and white prostate cancer-free men., Methods: We conducted a retrospective, cross-sectional analysis of 1,163 men (709 white and 454 black) without prostate cancer who initiated a statin between 1994 and 2006. Linear regression was used to test the association between pre-statin serum cholesterol and PSA levels, adjusting for potential confounders and stratifying by race., Results: Black men were younger, had higher low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels (both P < 0.05) and a trend toward higher total cholesterol (P = 0.063). There was no difference in PSA or year of statin prescription by race (P = 0.900 and P = 0.217, respectively). On multivariable analysis, we found a positive correlation between serum PSA and total cholesterol (P = 0.005) and LDL (P = 0.003) in white men, but no association among black men. HDL was not significantly related to PSA levels in black or white men (both P > 0.5)., Conclusions: Among prostate cancer-free men about to begin a statin, pre-statin total cholesterol and LDL were correlated with PSA levels in white, but not black men. If confirmed in future studies, these findings suggest that serum cholesterol may be related to prostate biology, and that this effect may vary by race., (© 2015 Wiley Periodicals, Inc.)

Objective: To test the relationship of smoking and aggressive prostate cancer in men undergoing radical prostatectomy., Methods: A retrospective analysis of 2290 men who underwent radical prostatectomy from the Shared Equal Access Regional Cancer Hospital database from 2000 to 2013 was carried out. There were 1592 (70%) non-smokers and 698 (30%) smokers at radical prostatectomy. Logistic regression was used to examine whether smoking predicted Gleason score (≥4 + 3), margin status, extracapsular extension or seminal vesicle invasion. Linear regression was used to test the relationship between smoking and tumor volume., Results: Smokers were younger, more likely to be black, had lower body mass index, higher pathological Gleason score, more positive margins and extracapsular extension (all P < 0.05) versus non-smokers. On crude analysis, smoking was associated with positive margins (odds ratio 1.32; P = 0.003) and extracapsular extension (odds ratio 1.26; P = 0.036). After adjusting for multiple clinical factors, smoking remained associated with a 19-35% increased risk of every adverse feature studied, though only the association with extracapsular extension reached significance. On multivariable analysis, a trend for smokers to have larger tumor volumes (geometric mean 5.8 vs 5.3 g; P = 0.062) was found., Conclusions: In patients undergoing radical prostatectomy, there seems to be a trend for smokers to have worse pathological features compared with non-/former smokers. If confirmed in future studies, smoking should be considered a modifiable risk factor for aggressive prostate cancer., (© 2015 The Japanese Urological Association.)

Purpose: Higher body mass index is linked to lower prostate specific antigen. This has given rise to concerns that prostate specific antigen may be less reliable for predicting prostate cancer among obese men. We tested the accuracy of prebiopsy prostate specific antigen for predicting prostate cancer across body mass index categories., Materials and Methods: We used the REDUCE study, which tested dutasteride for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative pre-study biopsy. All men were required to have a biopsy at 2 and 4 years independent of prostate specific antigen. We assessed the performance of prebiopsy prostate specific antigen to predict overall and high grade prostate cancer (Gleason sum 7 or greater) in each body mass index group using AUC., Results: Of 6,103 men who had a 2-year biopsy 1,646 (27%) were normal weight, 3,209 (53%) were overweight and 1,248 (20%) were obese. Mean adjusted prostate specific antigen for normal weight, overweight and obese subjects on placebo was 7.73, 7.17 and 6.79 ng/ml (p-trend=0.192), and on dutasteride 3.16, 2.93 and 2.62 ng/ml (p=0.008). AUC analysis using raw prostate specific antigen data for predicting prostate cancer ranged from 0.60 to 0.64 in the placebo arm and 0.58 to 0.66 in the dutasteride arm with no difference across body mass index categories (p-interactions ≥0.212). Similar results were found for high grade prostate cancer with AUC ranging from 0.69 to 0.70 in the placebo arm and 0.65 to 0.75 in the dutasteride arm but no differences across body mass index categories (p-interactions ≥0.157)., Conclusions: Among men with a previous negative biopsy the accuracy of prebiopsy prostate specific antigen to predict overall and high grade prostate cancer was independent of body mass index., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the ability of preoperative prostate-specific antigen level, Gleason score and stage to predict prostate cancer outcomes beyond biochemical recurrence, specifically castration-resistant prostate cancer, metastases and prostate cancer-specific mortality in radical prostatectomy patients., Methods: We carried out a retrospective study of 2735 men in the Shared Equal Access Regional Cancer Hospital database treated by radical prostatectomy from 1988 to 2011 with data available on pathological stage, grade and preoperative prostate-specific antigen. We used Cox hazards analyses to examine the predictive accuracy (c-index) of the preoperative prostate-specific antigen (log-transformed), path Gleason score (≤ 7, 3 + 4, 4 + 3 and 8-10) and path stage grouping (pT2 negative margins; pT2 positive margins; pT3a negative margins; pT3a positive margins; pT3b; vs positive nodes) to predict biochemical recurrence, castration-resistant prostate cancer, metastases and prostate cancer-specific mortality., Results: Median follow up was 8.7 years, during which, 937 (34%) had biochemical recurrence, 108 (4%) castration-resistant prostate cancer, 127 (5%) metastases and 68 (2%) prostate cancer-specific mortality. For the outcomes of biochemical recurrence, castration-resistant prostate cancer, metastases and prostate cancer-specific mortality, the c-indices were, respectively: prostate-specific antigen 0.65, 0.66, 0.64 and 0.69; Gleason score 0.66, 0.83, 0.76 and 0.85; and pathological stage group 0.69, 0.76, 0.72 and 0.80., Conclusions: Gleason score can predict with very high accuracy prostate cancer-specific mortality in patients undergoing radical prostatectomy. Thus, Gleason score should be given more weight in nomograms to predict prostate cancer-specific mortality. Furthermore, men with a high Gleason score should be given special consideration for adjuvant treatment or referral to clinical trials because of a higher risk of prostate cancer-specific mortality., (© 2015 The Japanese Urological Association.)

Purpose: We investigated imaging practice patterns in men with nonmetastatic (M0) castration resistant prostate cancer., Materials and Methods: We analyzed data on 247 patients with documented M0 CRPC from the SEARCH database. Patients were selected regardless of primary treatment modality and all had a negative bone scan after a castration resistant prostate cancer diagnosis. Cox models were used to test associations of time to a second imaging test with several demographic and clinical factors., Results: During a median followup of 29.0 months (IQR 12.9-43.5) after a post-castration resistant prostate cancer bone scan was negative, 190 patients (77%) underwent a second imaging test. On univariable analysis patients with higher prostate specific antigen (HR 1.13, p = 0.016), shorter prostate specific antigen doubling time (HR 0.79, p < 0.001) and faster prostate specific antigen velocity (HR 1.01, p < 0.001) were more likely to undergo a second imaging test. Treatment center was also a significant predictor of a second imaging test (p = 0.010). No other factor was a significant predictor. Results were similar on multivariable analysis. It was estimated that approximately 20% of men with a prostate specific antigen doubling time of less than 3 months did not undergo an imaging test in the first year after a post-castration resistant prostate cancer negative bone scan. However, 50% of patients with prostate specific antigen doubling time 15 months or greater underwent a second imaging test in the first year., Conclusions: Clinicians use some known predictors of positive imaging tests to determine which patients with M0 castration resistant prostate cancer undergo a second imaging test . However, there may be under imaging in those at high risk and over imaging in those at low risk. Further studies are needed to identify risk factors for metastasis and form clear imaging guidelines in patients with M0 castration resistant prostate cancer., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate how statin use is associated with the probability of having an abnormal screening prostate-specific antigen (PSA) result according to common PSA thresholds for biopsy (>2.5, >4.0, and >6.5 ng/mL)., Methods: We conducted a cross-sectional study of 323,426 men aged ≥65 years who had a screening PSA test in 2003 at a Veterans Affairs facility. The primary predictor was the use of statin medications at the time of index screening PSA test. The main outcome was the screening PSA value. Poisson regressions were performed to calculate adjusted relative risks for having an abnormal screening PSA result according to statin usage., Results: Percentages of men with PSA results exceeding commonly used thresholds of >2.5, >4.0, and >6.5 ng/mL were 21.0%, 7.6%, and 1.6%, respectively. These percentages decreased with statin use, increasing statin dose, duration of statin use, and potency of the statin. For example, after adjusting for age, the percentage of men having a PSA level >4.0 ng/mL ranged from 8.2% in non-statin users to 6.2% in men prescribed with >40 mg of simvastatin dose. Adjusted relative risks of having a PSA level >4.0 ng/mL were 0.89 (95% confidence interval [CI], 0.86-0.93), 0.87 (95% CI, 0.84-0.91), and 0.83 (95% CI, 0.80-0.87), respectively for men on simvastatin dose of 5-20, >20-40, and >40 mg vs non-statin users., Conclusion: Statin use is associated with a reduction in the probability that an older man will have an abnormal screening PSA result, regardless of the PSA threshold. This reduction is more pronounced with higher statin dose, longer statin duration, and higher statin potency., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The University of California, San Francisco, Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score uses pathologic data from radical prostatectomy (RP) to predict prostate cancer recurrence and mortality. However, this clinical tool has never been validated externally., Objective: To validate CAPRA-S in a large, multi-institutional, external database., Design, Setting, and Participants: The Shared Equal Access Regional Cancer Hospital (SEARCH) database consists of 2892 men who underwent RP from 2001 to 2011. With a median follow-up of 58 mo, 2670 men (92%) had complete data to calculate a CAPRA-S score., Intervention: RP., Outcome Measurements and Statistical Analysis: The main outcome was biochemical recurrence. Performance of CAPRA-S in detecting recurrence was assessed and compared with a validated postoperative nomogram by concordance index (c-index), calibration plots, and decision curve analysis. Prediction of cancer-specific mortality was assessed by Kaplan-Meier analysis and the c-index., Results and Limitations: The mean age was 62 yr (standard deviation: 6.3), and 34.3% of men had recurrence. The 5-yr progression-free probability for those patients with a CAPRA-S score of 0-2, 3-5, and 6-10 (defining low, intermediate, and high risk) was 72%, 39%, and 17%, respectively. The CAPRA-S c-index was 0.73 in this validation set, compared with a c-index of 0.72 for the Stephenson nomogram. Although CAPRA-S was optimistic in predicting the likelihood of being free of recurrence at 5 yr, it outperformed the Stephenson nomogram on both calibration plots and decision curve analysis. The c-index for predicting cancer-specific mortality was 0.85, with the caveat that this number is based on only 61 events., Conclusions: In this external validation, the CAPRA-S score predicted recurrence and mortality after RP with a c-index >0.70. The score is an effective prognostic tool that may aid in determining the need for adjuvant therapy., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Serum prostate specific antigen (PSA) may be elevated in otherwise healthy men; systemic inflammation has been associated with cancer. The study of systemic inflammatory markers in men without clinical prostate disease, but with elevated PSA may characterize the subgroup of men at higher risk for subsequent prostate cancer., Methods: We investigated the associations between systemic inflammatory markers and serum PSA in 3,164 healthy men without prostatic disease, aged >40 years, from the 2001 to 2008 U.S. National Health and Nutrition Examination Survey (NHANES). Serum total PSA levels and concentrations of serum C-reactive protein (CRP) and plasma fibrinogen, neutrophil count, lymphocyte count, and platelet count were recorded. Neutrophil-lymphocyte ratio (NLR) ratio and platelet-lymphocyte (PLR) ratio were calculated. PSA elevation was defined as levels equal or greater than 4 ng/ml., Results: Elevated serum PSA (194 men, 6.1% of the total), was significantly associated with plasma fibrinogen (ORmultiv  = 1.88; 95% CI, 1.09-3.25), and NLR (ORmultiv  = 1.14; 95% CI, 1.03-1.26), after adjustment for age, smoking, body mass index, education, race, co-morbidities, and use of medications., Conclusions: Markers of systemic inflammation were associated with elevated PSA in men without known prostatic disease. Future studies are needed to examine these markers' relationship with prostate cancer occurrence and progression., (© 2014 Wiley Periodicals, Inc.)

Purpose: Obese men have been reported to have lower serum PSA values relative to normal-weight men in population-based studies, screening cohorts, and in men with prostate cancer (CaP) treated with surgery. There are concerns that PSA may be less accurate in detecting prostate cancer in men with increased body mass index (BMI). We determine whether the diagnostic potential of PSA is negatively influenced by obesity by comparing its operating characteristics across BMI categories among men undergoing prostate biopsy., Methods: Demographic, clinical, and histopathological data on 917 men who underwent trans-rectal ultrasound-guided prostate needle biopsy from 2002 to 2010 at a University hospital in Italy were used in the study. Men were categorized for BMI as follows: <25 kg/m(2) (normal weight), 25-29.9 kg/m(2) (overweight), and ≥ 30 kg/m(2) (obese). Receiver operator characteristics (ROC) curves were used to assess PSA accuracy for predicting prostate cancer overall and then stratified according to digital rectal examination (DRE) findings using the area under the ROC curve (AUC)., Results: The obesity rate of the study cohort was 21 %. There was no statistically significant difference in the overall AUCs of PSA for predicting CaP among normal-weight (AUC = 0.56), overweight (AUC = 0.60), and obese men (AUC = 0.60; p = 0.68) in either DRE-positive or negative men., Conclusions: In a cohort of Italian men undergoing prostate biopsy, the performance accuracy of PSA as a predictor of CaP is not significantly altered by BMI. Obesity does not negatively impact the overall ability of PSA to discriminate between CaP and benign conditions.

Objective: To determine the distribution of screening prostate-specific antigen (PSA) values in older men, and how different PSA thresholds affect the proportion of white, black, and Latino men who would have an abnormal screening result across advancing age groups., Methods: We used linked national Veterans Affairs and Medicare data to determine the value of the first screening PSA test (ng/mL) of 327,284 men older than 65 years who underwent PSA screening in the Veterans Affairs health care system in 2003. We calculated the proportion of men with an abnormal PSA result based on age, race, and common PSA thresholds., Results: Among men older than 65 years, 8.4% had a PSA >4.0 ng/mL. The percentage of men with a PSA >4.0 ng/mL increased with age and was highest in black men (13.8%) vs white (8.0%) or Latino men (10.0%) (P <.001). Combining age and race, the probability of having a PSA >4.0 ng/mL ranged from 5.1% of Latino men aged 65-69 years to 27.4% of black men older than 85 years. Raising the PSA threshold from >4.0 ng/mL to >10.0 ng/mL reclassified the greatest percentage of black men older than 85 years (18.3% absolute change) and the lowest percentage of Latino men aged 65-69 years (4.8% absolute change) as being under the biopsy threshold (P <.001)., Conclusion: Age, race, and PSA threshold together affect the pretest probability of an abnormal screening PSA result. Based on screening PSA distributions, stopping screening among men whose PSA <3 ng/mL means more than 80% of white and Latino men older than 70 years would stop further screening, and increasing the biopsy threshold to >10 ng/mL has the greatest effect on reducing the number of older black men who will face biopsy decisions after screening., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: A prostate-specific antigen (PSA) level <0.2 ng/ml 8 mo after starting on androgen-deprivation therapy (ADT) is correlated with better outcomes. However, not all men reach a nadir PSA level within 8 mo. Whether the lowest PSA on ADT-specifically, <0.2 ng/ml-can be used for risk stratification is untested., Objective: We examined the predictive value of small but detectable PSA nadir values on prostate cancer (PCa)-specific outcomes in men treated with early ADT after radical prostatectomy (RP)., Design, Setting, and Participants: We performed a retrospective review of men treated with ADT after RP before metastases from the SEARCH database. We identified 402 men treated with ADT for elevated PSA following RP, of whom 294 men had complete data. Median follow-up after PSA nadir was 49 mo. All men had a PSA nadir <4 ng/ml; 223 men (76%) had an undetectable nadir., Intervention: ADT for an elevated PSA following RP with no radiographic evidence of metastatic disease., Outcome Measurements and Statistical Analysis: PSA nadir on ADT was defined as the lowest PSA value during ADT. Proportional hazards models and the C index were used to test the association and predictive accuracy, respectively, between PSA nadir and PCa-specific outcomes., Results and Limitations: Men with a PSA nadir between 0.01 and 0.2 ng/ml had a greater risk of progression to castration-resistant PCa (CRPC) (hazard ratio [HR]: 5.14; p<0.001), metastases (HR: 3.98; p=0.006), and PCa-specific mortality (PCSM) (HR: 5.33; p=0.003) than men with an undetectable nadir. When data were restricted to men followed with ultrasensitive PSA values (sensitivity of 0.01 ng/ml), the C index of PSA nadir alone for predicting CRPC, metastases, and PCSM was 0.88, 0.91, and 0.96, respectively., Conclusions: A PSA nadir on ADT, even at a very low level, strongly predicts progression to CRPC, metastases, and PCSM. Men with a detectable PSA nadir during ADT should be considered for clinical trials., (Published by Elsevier B.V.)

Importance: Despite ongoing controversies surrounding prostate-specific antigen (PSA) screening, many men 65 years or older undergo screening. However, few data exist that quantify the chain of events following screening in clinical practice to better inform decisions., Objective: To quantify 5-year downstream outcomes following a PSA screening result exceeding 4.0 ng/mL in older men., Design and Setting: Longitudinal cohort study in the national Veterans Affairs health care system., Participants: In total, 295,645 men 65 years or older who underwent PSA screening in the Veterans Affairs health care system in 2003 and were followed up for 5 years using national Veterans Affairs and Medicare data., Main Outcome Measures: Among men whose index screening PSA level exceeded 4.0 ng/mL, we determined the number who underwent prostate biopsy, were diagnosed as having prostate cancer, were treated for prostate cancer, and were treated for prostate cancer and were alive at 5 years according to baseline characteristics. Biopsy and treatment complications were also assessed., Results: In total, 25,208 men (8.5%) had an index PSA level exceeding 4.0 ng/mL. During the 5-year follow-up period, 8313 men (33.0%) underwent at least 1 prostate biopsy, and 5220 men (62.8%) who underwent prostate biopsy were diagnosed as having prostate cancer, of whom 4284 (82.1%) were treated for prostate cancer. Performance of prostate biopsy decreased with advancing age and worsening comorbidity (P < .001), whereas the percentage treated for biopsy-detected cancer exceeded 75% even among men 85 years or older, those with a Charlson-Deyo Comorbidity Index of 3 or higher, and those having low-risk cancer. Among men with biopsy-detected cancer, the risk of death from non-prostate cancer causes increased with advancing age and worsening comorbidity (P < .001). In total, 468 men (5.6%) had complications within 7 days after prostate biopsy. Complications of prostate cancer treatment included new urinary incontinence in 584 men (13.6%) and new erectile dysfunction 588 men (13.7%)., Conclusions and Relevance: Performance of prostate biopsy is uncommon in older men with abnormal screening PSA levels and decreases with advancing age and worsening comorbidity. However, once cancer is detected on biopsy, most men undergo immediate treatment regardless of advancing age, worsening comorbidity, or low-risk cancer. Understanding downstream outcomes in clinical practice should better inform individualized decisions among older men considering PSA screening.

Prostate cancer is the most common cancer among men. The prospective discrimination of aggressive and clinically insignificant tumors still poses a significant and, as yet, unsolved problem. PITX2 DNA methylation is a strong prognostic biomarker in prostate cancer. Recently, a diagnostic microarray for prostate cancer prognosis based on PITX2 methylation has been developed and validated. Because this microarray requires nonstandard laboratory equipment, its use in a diagnostic setting is limited. This study aimed to develop and validate an alternative quantitative real-time PCR assay for measuring PITX2 methylation that can easily be established in clinical laboratories, thereby facilitating the implementation of this biomarker in clinical practice. A methylation cut-off for patient stratification was established in a training cohort (n = 157) and validated in an independent test set (n = 523) of men treated with radical prostatectomy. In univariate Cox proportional hazards analysis, PITX2 hypermethylation was a significant predictor for biochemical recurrence (P < 0.001, hazard ratio = 2.614). Moreover, PITX2 hypermethylation added significant prognostic information (P = 0.003, hazard ratio = 1.814) to the Gleason score, pathological T stage, prostate-specific antigen, and surgical margins in a multivariate analysis. The clinical performance was particularly high in patients at intermediate risk (Gleason score of 7) and in samples containing high tumor cell content. This assay might aid in risk stratification and support the decision-making process when determining whether a patient might benefit from adjuvant treatment after radical prostatectomy., (Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors., Objective: To examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men., Design, Setting, and Participants: A retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration-based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo., Intervention: All patients underwent RP., Outcome Measurements and Statistical Analysis: We evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir., Results and Limitations: Mean BMI was 28.5 kg/m2. Higher BMI was associated with higher PSA nadir on both univariable (p=0.001) and multivariable analyses (p<0.001). Increased BMI was associated with increased BCR risk (hazard ratio [HR]: 1.06; p=0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p=0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir (p=0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available., Conclusions: Obese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression., (Published by Elsevier B.V.)

Background: The impact of race and socioeconomic status (SES) in prostate cancer (CaP) outcomes has been well-studied, but controversy remains. The associations of race/SES with intermediate CaP outcomes, including positive surgical margin (PSM) and biochemical recurrence (BCR), were explored in an equal-access setting., Methods: Data were retrospectively collected from 2502 men in the Shared Equal Access Regional Cancer Hospitals (SEARCH) database who underwent radical prostatectomy from 1989 to 2010. SES (income, education, employment, and poverty) was estimated from linkage of home ZIP code to census data. Logistic regression with adjustment for pre- and postoperative covariates estimated risk for associations between race/SES and pathologic outcomes. Cox proportional hazards models estimated risk for associations between race/SES and time to BCR., Results: Black men were more likely to have lower SES than white men (P < .001). On multivariate analysis, race was not associated with PSM, but higher SES was associated with less PSM and fewer Gleason sum ≥ 7 pathologic tumors when SES was assessed by education, employment, or poverty (P trend ≤ .051) and income, employment, or poverty (P trend ≤ 0.059), respectively. Crude Cox models showed black men had higher BCR risk (hazards ratio = 1.20, 95% confidence interval = 1.05-1.38, P = .009) that persisted after adjustment for covariates including SES (hazards ratio ≥ 1.18, P ≤ .040). Higher SES measured by income and poverty were associated with less BCR, but only for black men (P trend ≤ .048)., Conclusions: Even in an equal-access setting, higher SES predicted lower PSM risk, and race persisted in predicting BCR despite adjustment for SES. Low SES black patients may be at greatest risk for postprostatectomy BCR., (Copyright © 2012 American Cancer Society.)

Objectives: To analyze the association between prostate-specific antigen doubling time with prostate cancer risk and grade among men with prostate-specific antigen levels ≥4.0 ng/mL undergoing repeat prostate biopsy., Methods: A total of 286 patients with prostate-specific antigen ≥4 ng/mL and available prostate-specific antigen doubling time data, who underwent repeat prostate biopsy from 1996-2009, were included in this analysis. Prostate-specific antigen doubling time was divided into three groups: >9 years, 3-9 years and <3 years. Multivariate analyses of prostate-specific antigen doubling time with cancer risk and grade (≤3 + 4 vs ≥4 + 3) were carried out using logistic regression adjusting for prebiopsy prostate-specific antigen, race, age, digital rectal examination, year of biopsy and number of prior negative biopsies., Results: The median prostate-specific antigen doubling time before biopsy was 4.5 years (interquartile range = 2.5-10). Shorter prostate-specific antigen doubling time was associated with higher prostate-specific antigen (P < 0.001), but it was unrelated to age, digital rectal examination or race. Shorter prostate-specific antigen doubling time as a continuous variable was associated with greater prostate cancer risk in both uni- (hazard ratio = 0.99, 95% confidence interval = 0.98-0.99, P = 0.001) and multivariate analysis (hazard ratio = 0.99, 95% confidence interval = 0.98-0.99, P = 0.004). The prevalence of cancer among prostate-specific antigen doubling time groups (>9, 3-9, <3 years) was 17%, 37% and 40%, respectively. Shorter prostate-specific antigen doubling time groups were associated with higher cancer risk (P = 0.001). Stratified by grade, short prostate-specific antigen doubling time as a continuous variable significantly predicted both low- (P = 0.010) and high-grade disease (P = 0.049). The inclusion of prostate-specific antigen doubling time groups in a multivariate model to predict biopsy positivity increased its accuracy from 0.69 to 0.74., Conclusion: Prostate-specific antigen doubling time seems to provide further cancer risk assessment in men undergoing repeat biopsy for prostate-specific antigen ≥4.0 ng/mL. If validated in future studies, the present findings support the use of prostate-specific antigen doubling time in the risk stratification of this patient population., (© 2012 The Japanese Urological Association.)

Background: Although guidelines recommend against prostate-specific antigen (PSA) screening in elderly men with limited life expectancy, screening is common., Objective: We sought to identify medical center characteristics associated with screening in this population., Design/participants: We conducted a prospective study of 622,262 screen-eligible men aged 70+ seen at 104 VA medical centers in 2003., Main Measures: Primary outcome was the percentage of men at each center who received PSA screening in 2003, based on VA data and Medicare claims. Men were stratified into life expectancy groups ranging from favorable (age 70-79 with Charlson score = 0) to limited (age 85+ with Charlson score ≥1 or age 70+ with Charlson score ≥4). Medical center characteristics were obtained from the 1999-2000 VA Survey of Primary Care Practices and publicly available VA data sources., Key Results: Among 123,223 (20%) men with limited life expectancy, 45% received PSA screening in 2003. Across 104 VAs, the PSA screening rate among men with limited life expectancy ranged from 25-79% (median 43%). Higher screening was associated with the following center characteristics: no academic affiliation (50% vs. 43%, adjusted RR = 1.14, 95% CI 1.04-1.25), a ratio of midlevel providers to physicians ≥3:4 (55% vs. 45%, adjusted RR = 1.20, 95% CI 1.09-1.32) and location in the South (49% vs. 39% in the West, adjusted RR = 1.25, 95% CI 1.12-1.40). Use of incentives and high scores on performance measures were not independently associated with screening. Within centers, the percentages of men screened with limited and favorable life expectancies were highly correlated (r = 0.90)., Conclusions: Substantial practice variation exists for PSA screening in older men with limited life expectancy across VAs. The high center-specific correlation of screening among men with limited and favorable life expectancies indicates that PSA screening is poorly targeted according to life expectancy.

Purpose: Patients question whether multiple biopsy sessions cause worse prostate cancer outcomes. Therefore, we investigated whether there is an association between the number of prior biopsy sessions and biochemical recurrence after radical prostatectomy., Materials and Methods: Men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who underwent radical prostatectomy between 1988 and 2010 after a known number of prior biopsies were included in the analysis. Number of biopsy sessions (range 1 to 8) was examined as a continuous and categorical (1, 2 and 3 to 8) variable. Biochemical recurrence was defined as a prostate specific antigen greater than 0.2 ng/ml, 2 values at 0.2 ng/ml or secondary treatment for an increased prostate specific antigen. The association between number of prior biopsy sessions and biochemical recurrence was analyzed using the Cox proportional hazards model. Kaplan-Meier estimates of freedom from biochemical recurrence were compared among the groups., Results: Of the 2,739 men in the SEARCH database who met the inclusion criteria 2,251 (82%) had only 1 biopsy, 365(13%) had 2 biopsies and 123 (5%) had 3 or more biopsies. More biopsy sessions were associated with higher prostate specific antigen (p<0.001), greater prostate weight (p<0.001), lower biopsy Gleason sum (p=0.01) and more organ confined (pT2) disease (p=0.017). The Cox proportional hazards model demonstrated no association between number of biopsy sessions as a continuous or categorical variable and biochemical recurrence. Kaplan-Meier estimates of freedom from biochemical recurrence were similar across biopsy groups (log rank p=0.211)., Conclusions: Multiple biopsy sessions are not associated with an increased risk of biochemical recurrence in men undergoing radical prostatectomy. Multiple biopsy sessions appear to select for a low risk cohort., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether salvage radiation therapy (SRT) may promote prostate cancer (PCa) transformation to more aggressive phenotypes. To accomplish that, we identified men who underwent SRT after radical prostatectomy for PCa and failed SRT. PSA doubling time (PSADT) was used as a surrogate endpoint for cancer aggressiveness. We compared PSADT calculated before start of SRT and after SRT failure., Methods: Of 287 men in the SEARCH database since 1988 who underwent SRT, we detected 78 with SRT failure defined as PSA ≥ 0.2 ng/mL above the post-SRT nadir. Of these, 39 had PSADT available before and after SRT, which was compared using Wilcoxon's paired test with men serving as their own controls. We tested predictors of PSADT change using multivariable logistic regression., Results: There were no differences in PSADT before and after SRT (10.2 vs 12.6 months; P = .46). However, in some individual cases, large changes were observed. Only seminal vesicle invasion showed a trend towards an association with a shorter post-SRT PSADT relative to the pre-SRT PSADT (P = .13)., Conclusion: Overall, the PSADT after and before SRT were statistically identical, suggesting that after SRT failure, PCa does not emerge with more aggressive biological features. Further studies are needed to identify predictors and the clinical relevance of individual PSADT changes noted in our study., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the discrimination, calibration, and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European randomized study of screening for prostate cancer (ERSPC), 1 United Kingdom, 1 Austrian, and 3 US biopsy cohorts., Methods: PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history, history of prior biopsy, and imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves., Results: AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well calibrated in the SABOR, Tyrol, and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts., Conclusions: External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.

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., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)