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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.

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

BackgroundRecent reports with a small number of patients showed an association of red blood cell distribution width (RDW) with prostate cancer (PCa) progression.ObjectiveTo investigate whether preoperative RDW can serve as a prognostic marker in patients with PCa undergoing radical prostatectomy (RP) in a large, equal access, and diverse patient cohort.Design setting and participantsData were retrospectively collected on 4756 men treated with RP at eight Veteran Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 1999 through 2017.Outcome measurements and statistical analysisBiochemical recurrence (BCR) was the primary outcome, while metastasis, all-cause mortality (ACM), and prostate cancer-specific mortality (PCSM) were secondary outcomes.Results and limitationsThe mean (standard deviation) age was 62 yr (6.1), and 1589 (33%) men were black. The median (interquartile range) follow-up was 82 mo (46-127). Preoperative RDW either as a continuous variable or when stratified by quartiles was not associated with BCR. Likewise, preoperative RDW was not associated with metastases or PCSM. However, higher RDW was significantly associated with higher ACM, both as a continuous variable (p < 0.001) and when stratified by quartiles in univariable and multivariable models (p < 0.001). RDW was found to be correlated with D'Amico risk classification of PCa. Study limitations include its retrospective nature and lack of data regarding advanced PCa.ConclusionsPreoperative RDW was not associated with PCa outcomes in men treated with RP but was associated with ACM. While RDW may be a biomarker of overall health, it is not a biomarker for PCa outcomes. These results emphasize the importance of diverse, larger sized studies in genitourinary cancer research.Patient summaryProstate cancer includes a wide spectrum of diseases with different genetic, pathological, and oncological behaviors. Red blood cell distribution width is helpful in predicting the overall survival for a localized prostate cancer patient, and hence, it can help inform personalized treatment decisions and operative care.

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

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

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

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

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 CDCP1low DU145 and PC3 prostate cancer cells, detachment-activation of FAK occurs through local production of PI(4,5)P2. PI(4,5)P2 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 CDCP1low prostate cancer cells to FAK inhibitors. In patients, CDCP1High versus CDCP1low 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, CDCP1low and CDCP1high detached prostate cancer cells activate distinct cytoplasmic kinase complexes and targetable transcription factors, which has important therapeutic implications.

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

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

BackgroundOne out of five patients with muscle-invasive bladder cancer undergo radical cystectomy-a guideline-recommended treatment. Previous studies have primarily evaluated patient characteristics associated with the use of radical cystectomy, ignoring potential nesting of data.ObjectiveTo determine the impact of patient, diagnosing urologist, and hospital characteristics on the variation in the use of radical cystectomy.Design setting and participantsThis is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Registry (SEER)-Medicare linked database.Outcome measurements and statistical analysisA total of 7097 muscle-invasive bladder cancer patients and 4601 diagnosing urologists affiliated to 822 hospitals from January 1, 2002 to December 31, 2012 were analyzed. Multilevel logistic regression analyses were used to determine variation and factors associated with the use of radical cystectomy.Results and limitationsOf the 7097 patients, only 27% underwent radical cystectomy. The intraclass correlation coefficient for variation in the use of radical cystectomy attributed to the hospital level was 4.3%. Higher radical cystectomy volume by diagnosing urologists (more than five vs zero to one surgery: odds ratio [OR], 1.27; 95% confidence interval [CI], 1.00-1.62) and hospitals (more than five vs zero to four surgeries: OR,1.48; 95% CI, 1.14-1.93) was associated with increased use of radical cystectomy. Patients diagnosed by female rather than male urologists were more likely to undergo radical cystectomy (OR, 1.32; 95% CI, 1.07-1.62).ConclusionsWe found that 4.3% variation in the use of radical cystectomy was attributed to the hospital level, leaving 95.7% variation in use unexplained. We identified significantly increased use among higher-volume and female diagnosing urologists. These findings support further investigation into measures beyond hospital volume, which largely impact the utilization of radical cystectomy.Patient summaryIn this large population-based study, we found that 4.3% of variation in the use of radical cystectomy was attributed to the hospital level, leaving 95.7% variation in use unexplained. Higher radical cystectomy volume of diagnosing urologists and female urologists were independently associated with increased use of radical cystectomy. These findings support further investigation into measures beyond hospital volume, which largely impact the utilization of radical cystectomy.

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

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