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Introduction: Black individuals have 2.1 times higher prostate cancer mortality rates than White individuals in the United States. Several dietary and lifestyle factors may influence the risk of lethal prostate cancer. This study evaluated to what extent differences in the prevalence of these modifiable risk factors by race could explain racial disparities in prostate cancer mortality. Methods: We compared the prevalence of seven potentially modifiable risk factors for lethal prostate cancer among Black and White individuals, using the National Health and Nutrition Examination Study at two time points (1988-1994; 2017-2018). Relative risks for lethal prostate cancer were estimated in the Health Professionals Follow-up Study. We calculated the population attributable fraction (PAF) for each factor by self-identified race, defined as the reduction in mortality that would be achieved if the population had been entirely unexposed, compared with the current exposure pattern. We also calculated the difference in the PAF between Black and White individuals, assuming causality of risk factors and no multiplicative effect measure modification by race. Results: Based on data from NHANES III (1988-1994), the largest prevalence differences between Black and White individuals were for vitamin D deficiency, current smoking, and coffee, respectively. Elimination of these risk factors among Black individuals could have led to a larger reduction in lethal prostate cancer in comparison to eliminating these same risk factors among White individuals. Given the prevalence of these risk factors in 2017-2018, current interventions on vitamin D deficiency, current smoking, and coffee could influence future PAF differences for lethal prostate cancer mortality among Black individuals compared to White individuals. Conclusions: Differences in the prevalence of some modifiable lifestyle and dietary factors are potentially responsible for a portion of the racial disparity in prostate cancer mortality. [ABSTRACT FROM AUTHOR]

Dynamic templating as a result of cathodic hydrogen gas production is suggested as a possible mechanism for the formation of tube-like corrosion products on an unlined cast iron pipe in a drinking water distribution system. Mounds of corrosion product, with protruding tubes and freestanding tubes, were observed within a single 30 cm section of piping. Internal morphologies for all shapes were texturally complex although mineralogically simple, composed of two iron oxide/oxyhydroxides minerals: α-FeOOH (goethite) and Fe4O4 (magnetite). Static templating by either microorganisms or minerals was rejected as a possible mechanism for tube formation in this study. [ABSTRACT FROM AUTHOR]

Throughout the history of the automotive industry, the average load on the electrical system has been increasing model year by model year. The main driver of this trend has been the increasing use of electric power due to the increasing level of equipment on the average vehicle. The electric power system of a modern vehicle has to supply enough electrical energy to drive numerous electrical and electronic systems and components. Usually, the electric power system of a vehicle consists of two major components, an alternator and a battery, with supplementary control systems sometimes used to aid system operation. For vehicle power supply analysis, a detailed understanding of the operational characteristics of the major components and how they interact as a part of the electric power system, including environmental and road conditions, is essential if the analysis is to aid system optimization.In this study, a simulation tool has been developed using SABERA® to enhance the process of vehicle electrical power system design, development, and optimization, which is becoming important as more electrical features are added to future vehicles. [ABSTRACT FROM AUTHOR]

Background: In ulcerative colitis (UC) the activation (i.e. nuclear translocation) of nuclear factor kappa B (NF-κB) is an important step in the regulation of cytokines secreted by lamina propria macrophages. Clinical trials suggest anti-inflammatory effects of locally administered butyrate in UC. The potential effects of butyrate on NF-κB activation in lamina propria macrophages of UC patients were investigated. Methods: Eleven patients with distal UC were treated for up to 8 weeks with butyrate at 100 mM (n = 6) or placebo (n = 5) enemas. At entry and after 4 and 8 weeks, clinical status was noted and intestinal inflammation was graded endoscopically and histologically. Double-staining with antibodies against NFκB (p65) and CD68 was employed to detect NF-κB and macrophages, respectively. Results: In untreated patients, nuclear translocation of NF-κB was detectable in virtually all macrophages. Butyrate treatment for 4 and 8 weeks resulted in a significant reduction in the number of macrophages being positive for nuclear translocated NF-κB. In addition, butyrate significantly reduced both the number of neutrophils in crypt and surface epithelia and of the lamina propria lymphocytes/plasma cells. These findings correlated with a significant decrease in the Disease Activity Index (DAI). Conclusions: The decrease in DAI and mucosal inflammation in butyrate-treated patients is associated with a reduction of NF-κB translocation in lamina propria macrophages. Since the inflammatory process in UC is mainly sustained by macrophage-derived cytokines, the known anti-inflammatory effects of butyrate may in part be mediated by an inhibition of NF-κB activation in these macrophages. [ABSTRACT FROM AUTHOR]

Nuclear factor-kappa B (NF-kappaB) is a critical transcription factor for the inducible expression of multiple genes involved in inflammation. NF-kappaB is sequestered in the cytoplasm by inhibitory IkappaB proteins. Extracellular stimuli, notably interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) activate NF-kappaB nuclear translocation via IkappaB phosphorylation and degradation. Since previous reports suggest that the short chain fatty acid butyrate has antiinflammatory properties, the effects of butyrate on NF-kappaB nuclear translocation in human epithelial cells (HeLa229) were tested. In cells pretreated with butyrate, a time- and dose-dependent inhibition of IL-1beta-mediated NF-kappaB nuclear translocation was observed. However, IkappaB alpha phosphorylation and degradation occurred rapidly in both butyrate pretreated and nonpretreated cells, respectively. These data indicate that inhibition of IL-1beta-induced NF-kappaB activation by butyrate does not require an intact IkappaB alpha protein. [ABSTRACT FROM AUTHOR]

Purpose: Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms., Patients and Methods: BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety., Results: Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62-73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11)., Conclusions: In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially., (©2024 American Association for Cancer Research.)

Background: Studies have shown improved survival among individuals with cancer with higher levels of social support. Few studies have investigated social support and overall survival (OS) in individuals with advanced prostate cancer in an international cohort. We investigated the associations of marital status and living arrangements with OS among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer (IRONMAN)., Methods: IRONMAN is enrolling participants diagnosed with advanced prostate cancer (metastatic hormone-sensitive prostate cancer, mHSPC; castration-resistant prostate cancer, CRPC) from 16 countries. Participants in this analysis were recruited between July 2017 and January 2023. Adjusting for demographics and tumor characteristics, the associations were estimated using Cox regression and stratified by disease state (mHSPC, CRPC), age (<70, ≥70 years), and continent of enrollment (North America, Europe, Other)., Results: We included 2,119 participants with advanced prostate cancer, of whom 427 died during up to 5 years of follow-up (median 6 months). Two-thirds had mHSPC. Most were married/in a civil partnership (79%) and 6% were widowed. Very few married participants were living alone (1%), while most unmarried participants were living alone (70%). Married participants had better OS than unmarried participants [adjusted HR: 1.44; 95% confidence interval (CI): 1.02-2.02]. Widowed participants had the worst survival compared with married individuals (adjusted HR: 1.89; 95% CI: 1.22-2.94)., Conclusions: Among those with advanced prostate cancer, unmarried and widowed participants had worse OS compared with married participants., Impact: This research highlighted the importance of social support in OS within this vulnerable population., (©2024 American Association for Cancer Research.)

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44-4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales., Significance: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or  not standardized. Here, we present the curatedPCaData R package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights. curatedPCaData is an open and accessible community resource with code made available for reproducibility., (© 2023. The Author(s).)

Purpose: Multiple treatment options exist for patients with metastatic breast cancer (MBC). However, limited information is available on the impact of prior treatment duration and class on survival outcome for novel therapies, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ HER2-) MBC., Methods: This study used a nationwide, de-identified electronic health record-derived database to identify women with HR+ HER2- MBC who received at least one CDK 4/6i between 2011 and 2020. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for the association between prior duration and class of cancer treatment (both early-stage and metastatic) and prior CDK 4/6i survival as well as for those with multiple CDK 4/6i., Results: Of 5363 patients, the median survival from first CDK 4/6 inhibitor administration was 3.3 years. When compared to patients with no prior treatments, patients with < 1 year of prior treatment duration had a 30% increased hazard of death (HR, 1.30; 95% CI 1.15-1.46), those with 1 to < 3 years a 68% increased hazard of death (HR 1.68; 95% CI 1.49-1.88), and those with 3 or more years a 55% increased hazard of death (HR 1.55; 95% CI 1.36, 1.76). Patients who received prior therapy (endocrine or chemotherapy) before their CDK 4/6i had worse outcomes than those who received no prior therapy. Similar results were seen when comparing patients in the metastatic setting alone. Finally, patients who received a different CDK 4/6i after their first saw a lower hazard of death compared to patients who received subsequent endocrine or chemotherapy after their first CDK 4/6i., Conclusion: Prior treatment duration and class are associated with a decreased overall survival after CDK 4/6 inhibitor administration. This highlights the importance for clinicians to consider prior treatment and duration in treatment decision-making and for trialists to stratify by these factors when randomizing patients or reporting results of future studies., (© 2022. The Author(s).)

Purpose: To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population., Patients and Methods: Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires., Results: Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service., Conclusion: To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naïve biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype-ICS High /Decipher High . Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICS High /Decipher High subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICS High /Decipher High subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76-10.6; p ≤  0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18-26.94; p ≤  0.0001) as compared with ICS Low /Decipher Low . The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. PATIENT SUMMARY: In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

New technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations. However, there are currently few approaches to analyze the spatial context of the TIME. Therefore, we have developed a framework for the spatial analysis of the TIME using Ripley's K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to epithelial ovarian cancer (EOC) using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 160 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 263 tissue cores; 93 subjects with 260 ROIs; 27 subjects with both TMA and ROI data). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes (CD3+), cytotoxic T-cells (CD8+CD3+), and regulatory T-cells (CD3+FoxP3+) with overall survival. Analysis was done on TMA and ROIs, treating the TMA data as validation of the findings from the ROIs. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and T-cell subsets in their tumors had the best overall survival. Additionally, patients with EOC tumors displaying high co-occurrence of cytotoxic T-cells and regulatory T-cells had the best overall survival. Grouping women with ovarian cancer based on both cell abundance and spatial contexture showed better discrimination for survival than grouping ovarian cancer cases only by cell abundance. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies., Competing Interests: The authors have declared that no competing interests exist.

Context: Prostate cancer (PCa) is a complex disease that disproportionately impacts Black men in the USA. The structural factors that drive heterogeneous outcomes for patients of differing backgrounds are probably the same ones that result in population-level disparities. The relative contribution of drivers along the PCa disease continuum is an active area of investigation and debate., Objective: To critically synthesize the available evidence on PCa disparities from a population-level perspective in comparison to data from "equal access and equal care settings" and to provide a consensus summary of the state of PCa disparities., Evidence Acquisition: A plenary panel on PCa disparities presented at the Prostate Cancer Foundation meeting on October 24, 2019 and ensuing discussions are reported here. We used a systematic literature review approach and the Preferred Reporting Items for Systematic Reviews and Meta-analyses to select the most relevant publications. A total of 3333 publications between 2011 and 2021 were retrieved, of which 52 were included in the review; an additional 13 articles on screening guidelines, seminal clinical trials, and statistical methodology were used in the evidence synthesis., Evidence Synthesis: Race disparities in PCa are a result of a complex interaction between socioeconomic factors impacting access to care and ancestral/genetic factors that may influence tumor biology. Black men in the USA continue to have a nearly 1.8 times higher population-level incidence rate than White men. Failure to account for the race-specific incidence burden would continue to lead to residual disparity even after achieving relatively similar outcomes after primary treatment, resulting in a higher long-term mortality burden. Selection bias remains possible in PCa studies, which often rely on highly specific cohorts of Black men with higher use of health care resources that may not represent the average Black patient in the USA. Novel methods including mediation analysis and genetic ancestry rather than self-identified race can optimize analytical models investigating racial disparities and may lead to a better understanding of PCa genomic diversity and behavior., Conclusions: Our findings emphasize the importance of racially diverse studies, including precision -omics, prevention, and targeted therapy initiatives, to elucidate mechanisms underlying racial differences in outcomes and response to therapy. We propose novel approaches for studying and addressing PCa disparities. Contemporary methods, particularly in the domain of mediation analysis, can promote scientific rigor in understanding these disparities., Patient Summary: Inaccurate data interpretation or lack of data altogether for Black men can impact policy and ultimately affect millions of individuals of African origin worldwide. Our review identifies a need to develop and prioritize a strategy for including Black and other men with prostate cancer in intervention studies and randomized clinical trials to halt the widening prostate cancer disparities., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer)., Methods: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian., Results: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years., Conclusions: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men., (© 2021 Wiley Periodicals LLC.)

OBJECTIVE. Supplemental screening breast MRI is recommended for women with an estimated lifetime risk of breast cancer of greater than 20-25%. The performance of risk prediction models varies for each individual and across groups of women. The present study investigates the concordance of three breast cancer risk prediction models among women presenting for screening mammography. SUBJECTS AND METHODS. In this prospective study, we calculated the estimated lifetime risk of breast cancer using the modified Gail, Tyrer-Cuzick version 7, and BRCAPRO models for each woman who presented for screening mammography. Per American Cancer Society guidelines, for each woman the risk was categorized as less than 20% or 20% or greater as well as less than 25% or 25% or greater with use of each model. Venn diagrams were constructed to evaluate concordance across models. The McNemar test was used to test differences in risk group allocations between models, with p ≤ .05 considered to denote statistical significance. RESULTS. Of 3503 screening mammography patients who underwent risk stratification, 3219 (91.9%) were eligible for risk estimation using all three models. Using at least one model, 440 (13.7%) women had a lifetime risk of 20% or greater, including 390 women (12.1%) according to the Tyrer-Cuzick version 7 model, 18 (0.6%) according to the BRCAPRO model, and 141 (4.4%) according to the modified Gail model. Six women (0.2%) had a risk of 20% or greater according to all three models. Women were significantly more likely to be classified as having a high lifetime breast cancer risk by the Tyrer-Cuzick version 7 model compared with the modified Gail model, with thresholds of 20% or greater (odds ratio, 6.4; 95% CI, 4.7-8.7) or 25% or greater (odds ratio, 7.4; 95% CI, 4.7-11.9) used for both models. CONCLUSION. To identify women with a high lifetime breast cancer risk, practices should use estimates of lifetime breast cancer risk derived from multiple risk prediction models.

Purpose: The use of genomics within cancer research and clinical oncology practice has become commonplace. Efforts such as The Cancer Genome Atlas have characterized the cancer genome and suggested a wealth of targets for implementing precision medicine strategies for patients with cancer. The data produced from research studies and clinical care have many potential secondary uses beyond their originally intended purpose. Effective storage, query, retrieval, and visualization of these data are essential to create an infrastructure to enable new discoveries in cancer research., Methods: Moffitt Cancer Center implemented a molecular data warehouse to complement the extensive enterprise clinical data warehouse (Health and Research Informatics). Seven different sequencing experiment types were included in the warehouse, with data from institutional research studies and clinical sequencing., Results: The implementation of the molecular warehouse involved the close collaboration of many teams with different expertise and a use case-focused approach. Cornerstones of project success included project planning, open communication, institutional buy-in, piloting the implementation, implementing custom solutions to address specific problems, data quality improvement, and data governance, unique aspects of which are featured here. We describe our experience in selecting, configuring, and loading molecular data into the molecular data warehouse. Specifically, we developed solutions for heterogeneous genomic sequencing cohorts (many different platforms) and integration with our existing clinical data warehouse., Conclusion: The implementation was ultimately successful despite challenges encountered, many of which can be generalized to other research cancer centers., Competing Interests: Steven A. EschrichEmployment: CvergenxLeadership: CvergenXStock and Other Ownership Interests: CvergenXPatents, Royalties, Other Intellectual Property: Patents on RSI, radiation sensitivity technology, January 15, 2019, Timothy Yeatman, Gregory C. Bloom, Steven A. Eschrich: Methods and Systems for Predicting Cancer Outcome, US Patent No. 10181009; August 1, 2017, Robert J. Gillies, Steven A. Eschrich, Robert A. Gatenby, Philippe Lambin, Andre L. A. J. Dekker, Sandy A. Napel, Sylvia Plevritis, Daniel L. Rubin, Systems: Methods and Devices for Analyzing Quantitative Information Obtained From Radiological Images, US Patent No. 9721340; February 4, 2014, Timothy J. Yeatman, Jeff Xiwu Zhou, Gregory C. Bloom, Steven A. Eschrich: Artificial Neural Network Proteomic Tumor Classification, US Patent No. 8642349Travel, Accommodations, Expenses: CvergenXUncompensated Relationships: Cvergenx Jamie K. TeerPatents, Royalties, Other Intellectual Property: Patent application: Large Data Set Negative Information Storage Model Erin SiegelResearch Funding: Bristol Myers Squibb/Sanofi Chandan ChallaStock and Other Ownership Interests: GE Healthcare, Apple, Microsoft, Google, Milestone Pharmaceuticals, Elite Pharmaceuticals, Mereo BioPharma, Liquidia Technologies Rodrigo CarvajalPatents, Royalties, Other Intellectual Property: Moffitt Cancer Center has submitted a patent on the Negative Storage Model (NSM) on behalf of Rodrigo Carvajal Scott CukrasStock and Other Ownership Interests: AbbVie, Genprex, Rigel Melissa AvedonStock and Other Ownership Interests: Pfizer Aik Choon TanResearch Funding: Bristol Myers Squibb Amilcar BlakeEmployment: KEDPLASMA Jennifer GreenmanEmployment: Cancer Treatment Centers of AmericaLeadership: Cancer Treatment Centers of AmericaUncompensated Relationships: MyCareGorithm Dana RollisonLeadership: NanoString TechnologiesStock and Other Ownership Interests: NanoString TechnologiesPatents, Royalties, Other Intellectual Property: I am a co-inventor on a provisional patent application filed in July of 2020. The patent pertains to the use of spectrophotometer-measured ultraviolet radiation exposure in combination with regulatory T cells measured in circulation to predict risk of subsequent skin cancerTravel, Accommodations, Expenses: Caserta Analytics Inc (not a health care company specifically, but they do business with health care companies), NanoString TechnologiesNo other potential conflicts of interest were reported.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10 -9 ) and 3145 (P < 1 × 10 -5 ) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care., Competing Interests: Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, AstraZeneca, CalitheraResearch Funding: Pfizer, Bayer, Tempus Jelani C. ZarifConsulting or Advisory Role: Riptide Bioscience Elisabeth HeathHonoraria: Bayer, Dendreon, Seattle Genetics, Sanofi, AstraZenecaConsulting or Advisory Role: Agensys, Bayer, Dendreon, Sanofi, AstraZenecaSpeakers' Bureau: SanofiResearch Funding: Tokai Pharmaceuticals, Seattle Genetics, Agensys, Dendreon, Genentech/Roche, Millennium, Celldex, Inovio Pharmaceuticals, Celgene, Zenith Epigenetics, Merck, AstraZeneca, Esanik, Zenith Epigenetics, Oncolys BioPharma, Curemeta, Bristol-Myers Squibb, eFFECTOR Therapeutics, Fortis, Astellas Pharma, Medivation, Ignyta, Synta, Caris Life Sciences, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Plexxikon, Corcept Therapeutics, Infinity Pharmaceuticals, Bayer, Modra Pharmaceuticals, Pellficure, Champions Oncology, AIQ Solutions, Novartis, Janssen Research & Development, Mirati Therapeutics, Peloton Therapeutics, Daiichi Sankyo Inc, Calibr, Eisai, Pharmacyclics, Five Prime TherapeuticsTravel, Accommodations, Expenses: Agensys, Bayer, SanofiOther Relationship: Caris Centers of Excellence Franklin W. HuangStock and Other Ownership Interests: GlaxoSmithKline Brandon MahalStock and Other Ownership Interests: Novavax, Moderna TherapeuticsHonoraria: Prostate Health Education Network Kellie PaichConsulting or Advisory Role: Bayer Stacey SimmonsEmployment: NovartisStock and Other Ownership Interests: Pfizer, BayerTravel, Accommodations, Expenses: Novartis, Bayer Clayton YatesStock and Other Ownership Interests: Riptide BioscienceConsulting or Advisory Role: Riptide Bioscience, QED TherapeuticsResearch Funding: Riptide BiosciencePatents, Royalties, Other Intellectual Property: I am a co-inventor on several patents assigned to Riptide Biosciences Philip W. KantoffLeadership: Context TherapeuticsStock and Other Ownership Interests: Placon, Druggablity Technologies, Context Therapeutics, SeerConsulting or Advisory Role: Bavarian Nordic, Janssen, Merck, OncoCellMDX, Genentech/Roche, Tarveda Therapeutics, Druggablity Technologies, Progenity, Context Therapeutics, GE Healthcare, SeerPatents, Royalties, Other Intellectual Property: Method for Predicting the Risk of Prostate Cancer Morbidity and Mortality, Predicting and Treating Prostate Cancer, Methods for Predicting Likelihood of Responding to Treatment, Chromosome Copy Number Gain as a Biomarker of Urothelial Carcinoma Lethality, Drug Combinations to Treat Cancer, Somatic ERCC2 Mutations Correlate with Cisplatin sensitivity in muscle-invasive Urothelial Carcinoma (Patent), Up-to-Date Royalties, Wolters Kluwer Royalties, Methods and Kits for Determining Sensitivity to Cancer Treatment, Composition and Methods for Screening and Diagnosis of Prostate CancerOpen Payments Link: https://openpaymentsdata.cms.gov/physician/55315/summary Daniel J. GeorgeLeadership: Capio BioSciencesHonoraria: Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology, Millennium Medical PublishingConsulting or Advisory Role: Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol-Myers Squibb, Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J. Hennessy Associates, Vizuri, Constellation Pharmaceuticals, Physician Education Resource LLCSpeakers' Bureau: Sanofi, Bayer, ExelixisResearch Funding: Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, Bristol-Myers Squibb, Acerta Pharma, Bayer, Dendreon, Innocrin Pharma, Calithera Biosciences, Sanofi/AventisTravel, Accommodations, Expenses: Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology, UroToday Lorelei A. MucciResearch Funding: Sanofi, Astellas Pharma, Bayer, JanssenNo other potential conflicts of interest were reported.

Purpose: Evidence is mixed on whether cholesterol plays a role in the pathogenesis of glioma. We explored the associations between circulating lipids and glioma risk in three prospective cohorts., Methods: Using prospective data from the UK Biobank, we examined the associations of total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), and triglycerides (TG) with glioma risk in multivariable (MV)-adjusted Cox proportional hazards models. Within the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS), we carried out a matched, nested case-control study to examine these same associations., Results: In the UK Biobank, 490 gliomas accrued over 2,358,964 person-years. TC was not significantly associated with glioma risk (MV HR = 1.20, 95% CI 0.89-1.61 for highest quartile vs. lowest, p-trend = 0.24). In 4-year lagged analyses (n = 229), higher TC was associated with significantly higher risk of glioma in men (MV HR = 2.26, 95% CI 1.32-3.89, p-trend = 0.002) but not women (MV HR = 1.28, 95% CI 0.61-2.68, p-trend = 0.72); similar findings emerged for HDL-C and, to a lesser extent, LDL-C. In the NHS/HPFS, no significant associations were found between cholesterol and glioma risk. No significant associations were identified for TG., Conclusion: In the UK Biobank, higher prediagnostic TC and HDL-C levels were associated with higher risk of glioma in 4-year lagged analyses, but not in non-lagged analyses, in men only. These findings merit further investigation, given that there are few risk factors and no reliable biomarkers of risk identified for glioma.

Background: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERG negative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied., Methods: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections., Results: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERG negative 81.4% vs. ERG positive 18.6%; p = .005) and EAM (ERG negative 60.4% vs. ERG positive 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERG negative (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERG negative were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC)., Conclusions: ERG negative tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location., (© 2020 Wiley Periodicals LLC.)

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7-59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18-3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82-3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54-2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. Although each of the participating cancer centers is structured differently, and leaders' titles vary, we know firsthand there are similarities in both the issues we face and the solutions we achieve. As a consortium, we have initiated a dedicated listserv, an open-initiatives program, and targeted biannual face-to-face meetings. These meetings are a place to review our priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues we, as informatics leaders, individually face at our respective institutions and cancer centers. Here we provide a brief history of the CI4CC organization and meeting highlights from the latest CI4CC meeting that took place in Napa, California from October 14-16, 2019. The focus of this meeting was "intersections between informatics, data science, and population science." We conclude with a discussion on "hot topics" on the horizon for cancer informatics.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 -4 ; 11p11.12, p = 7.0 × 10 -4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10 -6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 -4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 -4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies., (© 2019 UICC.)

Heterogeneity in tumors is recognized as a key contributor to drug resistance and spread of advanced disease, but deep characterization of genetic variation within tumors has only recently been quantifiable with the advancement of next generation sequencing and single cell technologies. These data have been essential in developing molecular models of how tumors develop, evolve, and respond to environmental changes, such as therapeutic intervention. A deeper understanding of tumor evolution has subsequently opened up new research efforts to develop mathematical models that account for evolutionary dynamics with the goal of predicting drug response and resistance in cancer. Here, we describe recent advances and limitations of how models of tumor evolution can impact treatment strategies for cancer patients.

Background: Higher intratumoral cholesterol synthesis is associated with a worse prognosis in prostate cancer. The vitamin D-regulated enzyme sterol-27-hydroxylase (CYP27A1) converts cholesterol to 27-hydroxycholesterol, potentially lowering intracellular cholesterol levels. We hypothesized that low CYP27A1 expression is associated with high cholesterol synthesis, low vitamin D signaling, and higher risk of lethal prostate cancer., Methods: In 404 patients from the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS), we assessed intratumoral CYP27A1 expression and proxies of cholesterol synthesis using transcriptome profiling, prediagnostic plasma 25-hydroxyvitamin D [25(OH)D; n = 132], and intratumoral vitamin D receptor protein expression (VDR; n = 300). Patients were followed for metastases and prostate cancer mortality (lethal cancer; median follow-up, 15.3 years)., Results: CYP27A1 expression was lower in tumors with higher Gleason grade and higher expression of cholesterol synthesis enzymes, including the second rate-limiting enzyme, SQLE . We did not detect consistent associations between CYP27A1 and 25(OH)D, VDR, or CYP24A1 mRNA expression. Lower CYP27A1 was associated with higher risk of lethal cancer in both cohorts, independent of SQLE [adjusted OR for lowest vs. highest quartile of CYP27A1 , 2.64; 95% confidence interval (CI), 1.24-5.62]. This association was attenuated when additionally adjusting for Gleason grade (OR, 1.76; 95% CI, 0.75-4.17)., Conclusions: Low CYP27A1 expression was associated with higher cholesterol synthesis and a higher risk of lethal disease., Impact: These observations further support the hypothesis that intratumoral cholesterol accumulation through higher synthesis and decreased catabolism is a feature of lethal prostate cancer., (©2019 American Association for Cancer Research.)

Background: Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS-) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS- PCa tumors., Methods: 10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS- (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA)., Results: Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS- and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes., Conclusions: ETS status influences the transcriptional repertoire of the AR, and ETS- PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.

Drug courts, therapeutic justice programs for individuals charged with drug offenses, have sub-optimal completion rates. The Courtroom Behavior Checklist (CRBCL), an assessment that quantifies readiness for drug court and drug court behaviors, was developed to predict female offenders who may be at-risk for non-compliance and termination. Data derived from 264 mainly urban women recruited from a Municipal Drug Court System in St. Louis, MO, were used to evaluate the association between substance use, victimization, HIV/AIDS risk behaviors, and observed drug court behaviors. Results showed that women who reported recent substance use or were categorized as at risk for HIV/AIDS were significantly more likely to have scores indicative of unfavorable drug court behaviors, while women who experienced victimization had scores indicative of favorable drug court behaviors. Other factors significantly associated with unfavorable drug court behaviors included greater lifetime arrests, lower education, and being less religious or spiritual. Our findings suggest that the CRBCL may have added utility in identifying women in drug court with recent substance use and risky sexual behaviors. However, further studies on other samples of offenders are needed to support these findings., (Copyright © 2018 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Background: 4%-9% of prostate cancers harbor homozygous deletions of the androgen-induced tumor suppressor gene, promyelocytic leukemia zinc finger ( PLZF, ZBTB16 ). PLZF loss induces an in vitro phenotype of castration resistance and enzalutamide resistance. The association of low expression of PLZF and clinical outcomes is unclear., Methods: We assessed PLZF mRNA expression in patients diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS; n = 254) and the Physicians' Health Study (PHS; n = 150), as well as in The Cancer Genome Atlas ( n = 333). We measured PTEN status (using copy numbers and IHC) and transcriptional activation of the MAPK pathway. Patients from HPFS and PHS were followed for metastases and prostate cancer-specific mortality (median, 15.3 years; 113 lethal events)., Results: PLZF mRNA expression was lower in tumors with PLZF deletions. There was a strong, positive association between intratumoral androgen receptor (AR) signaling and PLZF expression. PLZF expression was also lower in tumors with PTEN loss. Low PLZF expression was associated with higher MAPK signaling. Patients in the lowest quartile of PLZF expression compared with those in the highest quartile were more likely to develop lethal prostate cancer, independent of clinicopathologic features, Gleason score, and AR signaling (odds ratio, 3.17; 95% confidence interval, 1.32-7.60)., Conclusions: Low expression of the tumor suppressor gene PLZF is associated with a worse prognosis in primary prostate cancer., Impact: Suppression of PLZF as a consequence of androgen deprivation may be undesirable. PLZF should be tested as a predictive marker for resistance to androgen deprivation therapy., (©2019 American Association for Cancer Research.)

Background: The impact of treatment delays on prostate cancer-specific outcomes remains ill-defined. This study investigates the effect of time to treatment on biochemical disease control after prostatectomy., Methods: This retrospective study includes 1,807 patients who received a prostatectomy as a primary treatment at two large tertiary referral centers from 1987 to 2015. Multivariate cox model with restricted cubic spline was used to identify optimal time to receive treatment and estimate the risk of biochemical recurrence., Results: Median follow-up time of the study was 46 (interquartile range, 18-86) months. Time to treatment was subcategorized based on multivariate cubic spline cox model. In multivariate spline model, adjusted for all the pertinent pretreatment variables, inflection point in the risk of biochemical recurrence was observed around 3 months, which further increased after 6 months. Based on spline model, time to treatment was then divided into 0 to 3 months (61.5%), >3 to 6 months (31.1%), and 6 months (7.4%). In the adjusted cox model, initial delays up to 6 months did not adversely affect the outcome; however, time to treatment >6 months had significantly higher risk of biochemical recurrence (HR, 1.84; 95% confidence interval, 1.30-2.60; P < 0.01)., Conclusions: The initial delays up to 6 months in prostate cancer primary treatment may be sustainable without adversely affecting the outcome. However, significant delays beyond 6 months can unfavorably affect biochemical disease control., Impact: Time to treatment can aid clinicians in the decision-making of prostate cancer treatment recommendation and educate patients against unintentional treatment delays., (©2018 American Association for Cancer Research.)

Background: Prostate-specific antigen (PSA) measurement in midlife predicts long-term prostate cancer (PCa) mortality among white men., Objective: To determine whether baseline PSA level during midlife predicts risk of aggressive PCa in black men., Design, Setting, and Participants: Nested case-control study among black men in the Southern Community Cohort Study recruited between 2002 and 2009. A prospective cohort in the southeastern USA with recruitment from community health centers. A total of 197 incident PCa patients aged 40-64 yr at study entry and 569 controls matched on age, date of blood draw, and site of enrollment. Total PSA was measured in blood collected and stored at enrollment., Outcome Measurements and Statistical Analysis: Total and aggressive PCa (91 aggressive: Gleason ≥7, American Joint Committee on Cancer stage III/IV, or PCa-specific death). Exact conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) for PCa by category of baseline PSA., Results and Limitations: Median PSA among controls was 0.72, 0.80, 0.94, and 1.03ng/ml for age groups 40-49, 50-54, 55-59, and 60-64 yr, respectively; 90th percentile levels were 1.68, 1.85, 2.73, and 3.33ng/ml. Furthermore, 95% of total and 97% of aggressive cases had baseline PSA above the age-specific median. Median follow-up was 9 yr. The OR for total PCa comparing PSA >90th percentile versus ≤median was 83.6 (95% CI, 21.2-539) for 40-54 yr and 71.7 (95% CI, 23.3-288) for 55-64 yr. For aggressive cancer, ORs were 174 (95% CI, 32.3-infinity) for 40-54 yr and 51.8 (95% CI, 11.0-519) for 55-64 yr. A composite endpoint of aggressive PCa based on stage, grade, and mortality was used and is a limitation., Conclusions: PSA levels in midlife strongly predicted total and aggressive PCa among black men. PSA levels among controls were similar to those among white controls in prior studies., Patient Summary: Prostate-specific antigen (PSA) level during midlife strongly predicted future development of aggressive prostate cancer among black men. Targeted screening based on a midlife PSA might identify men at high risk while minimizing screening in those men at low risk., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological and prognostic role in lethal prostate cancer., Methods: In vitro assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal prostate cancer (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and Memorial Sloan Kettering Cancer Center. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration-resistant prostate cancer (mCRPC) were assessed in a Cornell University cohort., Results: In vitro tristetraprolin expression was inversely associated with NF-κB-controlled genes, proliferation, and enzalutamide sensitivity. Men with localized prostate cancer and lower quartile of tumor tristetraprolin expression had a significant, nearly two-fold higher risk of lethal prostate cancer after adjusting for known clinical and histologic prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized prostate cancer., Conclusions: Lower levels of tristetraprolin in human prostate cancer prostatectomy tissue are associated with more aggressive prostate cancer and may serve as an actionable prognostic and predictive biomarker., Impact: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized prostate cancer., (©2018 American Association for Cancer Research.)