bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genomic profiling unravels molecular targets in patients with metastatic spinal cord compression from prostate cancer.
Authors: Duong Tony , Wang Jue 
Published: February 2022

147 Background: Spinal cord compression (SCC) from prostatic cancer is an oncologic emergency with significant negative impact on morbidity and survival. However, the molecular mechanisms involved in spinal metastases remains largely unclear. The aim of this study was to evaluate the histopathology, molecular profiles, and outcome in these patients. Methods: Twenty patients with magnetic resonance imaging-confirmed metastatic SCC from prostate cancer were identified at Dignity health Cancer Institute. Pathology slides were reviewed and the molecular analysis of 324 cancer-related genes was performed on tumor specimens using targeted next-generation sequencing. Characteristics including age, Gleason score, SCC anatomical site, time to diagnosis of SCC, gene alterations, number of lines of treatment and clinical outcome were analyzed. Results: At the time of diagnosis of SCC, the median age at diagnosis of SCC was 60.5 years old (range=50-76). The median PSA value was 626 ng/ml, 100% of patients have a Gleason score above 7, 30% of patients had visceral metastases. The thoracic spine affecting (15/20) patients is the most common site of SCC. Seventeen patients (75%) were initially treated with surgery combined with radiation therapy (RT), whereas 3 (15%) were managed with RT alone. At the time of this study, 11 patients remain alive (55%), median overall survival (OS) is 20 months, 18 months in treatment naive and 22 months in hormone refractory patients. Molecular analysis revealed gene mutations in all (100%) tumors, The most common gene alterations were PTEN (16%), followed by AR alterations AR (13%), TP53 (11%), TMPRSS2-ERG (8 %), BRCA1/2(4%), RB1(1%) and ATM (1%). Conclusions: Comprehensive genomic profiling revealed several molecular targets in patients with metastatic spinal cord compression from prostate cancer.[Table: see text]
Clinical and molecular features of low prostate-specific membrane antigen (PSMA) expression in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: de Kouchkovsky Ivan , Zhang Li , Huang Jiaoti , Trepka Kai , Chou Jonathan , Foye Adam , Shui David , Wong Chris , Friedl Verena , Weinstein Alana , Hope Thomas A , Quigley David A. , Stuart Josh , Beer Tomasz M. , Reiter Robert Evan , Gleave Martin E. , Evans Christopher P , Feng Felix Y , Small Eric Jay , Aggarwal Rahul Raj 
Published: February 2022

167 Background: Low PSMA uptake on positron-emission tomography is seen in up to 30% of mCRPC pts and represents a clinically distinct subgroup with adverse outcomes. We assessed transcriptional and clinical features associated with low PSMA ( FOLH1) gene expression in mCRPC. Methods: A retrospective analysis of mCRPC biopsy samples with RNA-seq data was undertaken. Normalized FOLH1 expression was compared across histologic subtypes and sites of disease. We assessed the association between FOLH1 expression, selected androgen receptor (AR) target genes, master regulators of neuroendocrine differentiation, and previously validated AR activity and treatment-associated small cell neuroendocrine carcinoma (t-SCNC) transcriptional signature scores using Pearson correlations. Associations between FOLH1 and both PSA50 response to subsequent AR-targeted therapy and overall survival (OS) were examined by logistic regression and Cox proportional hazard models, respectively. Results: Samples from 97 pts were identified, of which 18% harbored t-SCNC histology. 45% of pts had visceral metastases at the time of biopsy, and 41% received subsequent AR-targeted therapy. Median FOLH1 expression was lower in pts with visceral metastases vs no visceral metastases (14.7 vs 15.6, p = 0.02) but was not significantly different across t-SCNC vs adenocarcinoma biopsies (14.3 vs 15.4, p = 0.13). FOLH1 expression was positively correlated with AR transcriptional activity and AR target genes, and negatively correlated with master regulators of neuroendocrine differentiation and t-SCNC transcriptional signature scores (Table). Low FOLH1 expression did not predict PSA50 response to subsequent AR-targeted therapy (OR 0.97, p = 0.8), but was associated with shorter OS on univariate analysis (HR 1.09, 95% CI 1.02-1.16, p=0.01). A post-hoc analysis revealed a trend towards decreased median OS in pts with FOLH1 expression <12 (7.5 vs 17.1 months, log-rank p = 0.06). Conclusions: In this retrospective analysis of mCRPC pts, low FOLH1 expression was associated with transcriptional features of t-SCNC, decreased AR activity, and shorter OS. These findings are hypothesis-generating and prospective validation is needed.[Table: see text]
Evaluation of ctDNA alterations in mCRPC patients with germline pathogenic mutations.
Authors: Light Malcolm , Jaeger Ellen B. , Caputo Sydney , Fleming William , Manogue Charlotte , Huang Minqi , Sussman Isabelle P. , Lieberman Alex , Miller Patrick , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Ledet Elisa M. , Sartor A. Oliver 
Published: February 2022

177 Background: Germline alterations are found in approximately 12-17% of CRPC patients. Similarly, evaluating tumoral changes with circulating tumor DNA (ctDNA) has become an increasingly useful tool for understanding mechanisms underpinning disease progression. In this study, we evaluated both germline and somatic genetic changes in patients with mCRPC. Methods: Patients included had germline screening and ctDNA analyzed with the Guardant 360 assay. All patients were CRPC at the time of Guardant testing. Germline alterations were classified as pathogenic/likely-pathogenic or not pathogenic. Only ctDNA alterations with an alleleic fraction greater than 0.5% were included in analyses. Additional evaluation of CRPC status, treatment history, family history and other clinical covariates are ongoing. Chi-square and Fischer’s Exact tests were used for comparison of cohorts. Results: A total of 168 Caucasian CRPC patients had Guardant 360 testing at time of progression and germline testing between 2015-2021. 61% (n = 102/168) of patients have previously had treatment with abiraterone, 49% (n = 82/168) have had Enzalutamide and 40% (n = 68/168) have had treatment with taxanes. 12% (n = 20/168) of CRPC patients had a pathogenic/likely-pathogenic (P/LPv) germline alteration, 46% (n = 77/168) had a germline variant of unknown significance (VUS), 42% (n = 71/168) were germline negative. CRPC patients with pathogenic germline mutations were significantly more likely to have subsequent somatic alterations in BRCA2 (OR = 5.05, 95% C.I. (1.11, 23.01), p = 0.055), NF1 (OR = 7.89, 95% C.I. (2.15, 28.10), p = 0.004), and TP53 (OR = 3.52, 95% C.I. (1.28, 9.68), p = 0.015). In TP53, among germline positive patients, 45% (n = 9/20) had TP53 alterations compared to 30% (n = 45/148) of germline negative patients. Conclusions: Germline positive (P/LPv) CRPC patients were significantly more likely to have somatic alterations in BRCA2, NF1, and TP53. Understanding the totality of genetic changes, both germline and acquired somatic alterations is essential as the arsenal of targeted treatment for CRPC continues to expand. Additional studies including longitudinal assessment genetic changes and clinical correlates will be necessary to evaluate these findings in the context of treatment outcomes and disease progression.
Virtual genetics board for enhancing knowledge and practice of prostate cancer genetic testing: The ENGAGEMENT study.
Authors: Giri Veda N. , Gross Laura , Cheng Heather H. , Russo Jessica , Paller Channing Judith , Johnson Jennifer M , Weg Emily Steinberger , Loeb Stacy 
Published: February 2022

184 Background: With the increasing indications for germline testing for prostate cancer (PCA), there is a growing need for a spectrum of providers to develop working knowledge and understand considerations of germline testing and genetic counseling. A virtual genetics board was developed to provide case-based discussion of PCA germline testing, standard of care and clinical trial management, hereditary cancer management, and genetic counseling. Methods: A virtual genetics board was launched including experts in GU medical oncology, prostate cancer genetics, radiation oncology, urology, clinical trials, genetic counseling, and molecular oncology. Conferences are held monthly, with cases covering metastatic PCA, high-risk disease, early-stage PCA, or PCA screening. Participants complete a baseline survey of demographic information and cancer genetics knowledge. Post-conference survey includes retaking knowledge questions and feedback on cases and Zoom format. Results: At the time of this report, 57 participants have engaged in the virtual genetics board. Participants include genetic counselors (21%), nurse practitioners (21%), medical oncologists (14%), researchers/scientists (14%), nurses (9%), urologists (5%), radiation oncologists (4%), and other specialties. Practice settings include academic centers (49%), public hospitals (16%), private hospitals (11%), and other settings. The baseline survey was completed by 55 participants, and post-conference survey by 34 participants. Knowledge scores increased regarding cancer inheritance, rates of mutations in metastatic PCA, BRCA2-related cancers, risk of PCA for HOXB13 carriers, and risk for PCA in African American males. Feedback was positive, with over 90% favorable responses on usability of technology, usefulness of case discussions, and relevance to informational needs. Conclusions: Initial results support a virtual genetics board to increase PCA genetic evaluation knowledge. The ENGAGEMENT study is ongoing with monthly live case discussions that are also recorded for on-demand viewing; registration is available at www.prostategenetics.com/engagement.[Table: see text]
Trends in disease burden from prostate cancer amongst different regions of the world and extensively the European Union 15+ countries, from 1990 to 2019: Estimates from the Global Burden of Disease study.
Authors: Mouchati Christian , Abdallah Nour , Jani Chinmay , Mariano Melissa , Jani Ruchi Tusharkumar , Marshall Dominic C , Singh Harpreet , Shalhoub Joseph , Salciccioli Justin , McKay Rana R. 
Published: February 2022

187 Background: Prostate cancer was the third most commonly diagnosed cancer in 2020 and the fifth leading cause of cancer mortality worldwide. Global variations in the burden of prostate cancer have been observed in the past decades. This study aimed to assess the trends in incidence, mortality, and disability-adjusted life years from prostate cancer in the World Health Organization (WHO) regions and extensively in the European Union (EU) 15+ countries from 1990 to 2019. Methods: The Global Burden of Disease Study database was used to extract the mortality data of prostate cancer, based on the International Classification of Diseases versions 10 and 9. Data acquired for different WHO regions and each country of the EU15+ nations, per year from 1990 to 2019, included age-standardized incidence rates (ASIR), age-standardized death rates (ASDR), and disability-adjusted life years (DALYs). Mortality-to-incidence ratios (MIR) were then computed. Trends were assessed using Joinpoint regression. Results: Between 1990 and 2019, ASIRs increased worldwide (+13.16%), except in the American region, with the largest growth in the Eastern Mediterranean Region (EMR) (+72.43%). While ASDRs and DALYs increased in Africa, South-East Asia, and EMR, they decreased in the Americas, Europe, and Western Pacific Region (WPR). MIRs decreased universally (-25.52%), mainly in the WPR (-43.49%). In EU15+ countries, ASIRs increased in all countries, except for Canada (-11.27%) and the United States of America (USA) (-10.37%), with the largest rise in Finland (+75.11%). ASDRs decreased in all countries, with the widest drop in Luxembourg (-41.89%) and the lowest in Denmark (-13.96%). MIRs decreased in all countries, with the highest drop in Finland (-55.37%). Similarly, DALYs decreased in all countries, with the highest decrease in Luxembourg (-40.56%). In 2019, the highest ASIR was in the USA (118.24/100,000), whereas Denmark had the highest ASDR (31.35/100,000), MIR (0.38/100,000), and DALY (498.03/100,000). Conclusions: Over the 30 years, the incidence of prostate cancer has been rising worldwide, excluding Canada and the USA. However, the universal decrease of MIRs highlights improved outcomes and efficient screening and therapeutic strategies. All indices are represented per 100,000 population.[Table: see text]
Prevalence of Fanconi anemia gene mutations among men undergoing multigene germline testing for prostate cancer: Interim results from the EMPOWeR study.
Authors: Giri Veda N. , Gross Laura , Russo Jessica , Shimada Ayako , McNair Christopher , Kelly William Kevin , Gomella Leonard G. 
Published: February 2022

188 Background: Germline testing for prostate cancer (PCA) is now central to treatment, screening, and hereditary cancer management. The Fanconi anemia (FA) pathway is a key DNA repair pathway involved in PCA biology and treatment. Prevalence of FA genes BRCA2, PALB2, and BRIP1 is well-described; however, multiple other FA genes are not routinely tested, with limited prevalence data. Here we report mutation prevalence of a spectrum of FA genes among men undergoing PCA multigene testing on the Evaluation and Management for Prostate Oncology, Wellness, and Risk (EMPOWeR) study. Methods: Eligibility includes any male with PCA or at-risk for PCA. Multigene testing includes 51 genes; FA pathway genes include BRCA2, PALB2, BRIP1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, and FANCM. Multiple additional cancer risk genes were tested. Fisher’s exact tests were conducted to compare the prevalence of FA gene mutations between participants in the EMPOWeR study vs population prevalence reported in the literature. Statistical significance level of all tests was set a priori to 0.05. Results: The current cohort includes 235 participants. Characteristics are White (83.3%), Black (13.7%), PCA diagnosis (83.4%), mean age of PCA diagnosis 61.7 + 7.69 years, Gleason score >=7 (66.2%), and T3 or higher (29.4%). Genetic results were available for 179 participants. Overall, 11.1% of participants (n=20) had a pathogenic/likely pathogenic mutation identified. Among mutation carriers, 45% (n=9) had mutations in FA genes, including FANCA (n=3), BRCA2 (n=2), FANCM (n=1), FANCD2 (n=1), PALB2 (n=1), and BRIP1 (n=1). Table shows clinical characteristics of participants with mutations in FANCA, FANCM, and FANCD2. Further mutation spectrum included: CHEK2 (n=3), NBN (n=2), MUTYH (n=2), BRCA (n=1), ATM (n=1), HOXB13 (n=1), APC (n=1). Compared to population prevalence, FA mutation prevalence was significantly higher overall (5.0% vs. 0.6%, p = 0.010) and among mutation carriers (45% vs. 0.6%, p<0.001). Conclusions: While prevalence of FA genes BRCA2, PALB2, and BRIP1 is well-described, our study supports testing a broader range of FA genes given the prevalence rates, potential implications for clinical trials, targeted therapy, inherited syndromes, and reproductive implications.[Table: see text]
Association between prostate-specific antigen screening and prostate cancer mortality in a racially diverse cohort of United States veterans.
Authors: Sherer Michael Vincent , Qiao Edmund Men , Kotha Nikhil V. , Qian Alexander , Rose Brent S. 
Published: February 2022

225 Background: African American (AA) men are known to develop more aggressive forms of prostate cancer at a younger age compared to their Non-Hispanic White (NHW) counterparts. However, few AA men were included in the major randomized trials assessing the efficacy of Prostate-Specific Antigen (PSA) screening. It is thus unknown whether PSA screening may be more beneficial in the AA population. Methods: We conducted a retrospective analysis of men diagnosed with prostate cancer in the United States (US) Veterans Affairs Health System (VA) using the VA Informatics and Computing Infrastructure. Inclusion criteria were AA or NHW men aged 55-69 diagnosed with intermediate or high-risk prostate cancer between 2004 and 2017. Patients were classified as never screened with PSA prior to diagnosis, screened at least once prior to diagnosis (some screening), or screened in 5 consecutive years prior to diagnosis (annual screening). A lead-time bias adjusted multivariate regression model was implemented to assess the effect of screening on prostate cancer specific mortality (PCSM), with covariates including age, comorbidities, BMI, smoking history, marital status and primary care utilization. Results: A total of 45,825 men met the inclusion criteria and were included in the analysis, including 14,294 (31.1%) AA men and 31,151 (68.9%) NHW men. When compared to no screening, any prior PSA screening was associated with improved PCSM for both AA (subdistribution hazard ratio (SHR) 0.64, p < 0.001) and NHW (SHR 0.62, p < 0.001) patients. Annual PSA screening (vs no or some screening) was associated with improved PCSM for AA men (SHR 0.68, p = 0.013) but not NHW men (SHR 0.90, p = 0.240). Other significant predictors of worse PCSM in both AA and NHW men included older age, earlier year of diagnosis, greater comorbidity burden, and cigarette smoking. Conclusions: In a diverse population of US veterans, at least one prior screening PSA was associated with improved PCSM in both AA and NHW patients. Annual PSA screening was associated with reduced PCSM in AA but not NHW men, suggesting that more intensive screening protocols may be beneficial for AA patients.
Comparison of prostate specific antigen testing in men aged 55 to 69 with and without a history of cancer.
Authors: Lazarovich Alon , Chandrasekar Thenappan , Shapiro Oleg , Jacob Joseph M , Basnet Alina , Bratslavsky Gennady , Goldberg Hanan 
Published: February 2022

230 Background: Prostate specific antigen (PSA) screening remains a controversial issue. However, most urological guidelines recommend PSA testing through a shared decision-making process with the patient. The rate of PSA screening in men with a history of cancer compared to men with no cancer history is not well known. We aimed to compare PSA testing in men aged 55-69 years with and without a history of cancer (excluding prostate cancer patients). Methods: Utilizing the National Health Interview Survey (NHIS) a retrospective cross-sectional study between the years 2015 and 2018 was carried out to analyze and compare PSA testing rates in men aged 55-69 years. Multivariable logistic regression model was implemented do demonstrate potential associations with PSA testing. Results: A total of 13,850 men aged 55-69 years included in the NHIS Survey were analyzed. 1519 (10.9%) men had a history of cancer (non-prostate). On multivariable analysis, men who were previously diagnosed with cancer had a higher rate of PSA testing compared to men with no history of cancer (OR: 1.88, 95% CI 1.39-2.54, p < 0.001). Other factors associated with an increased likelihood of undergoing PSA testing included: age, homosexual orientation, and married men. In contrast, current smokers, American Indians and Alaskan Natives and Asians were less likely to undergo PSA testing. Conclusions: Our data suggest that men aged 55-69 with a history of cancer are more likely to undergo PSA testing than men with no cancer history.[Table: see text]
The BARCODE1 study in primary care: Early results targeting men with increased genetic risk of developing prostate cancer—Examining the interim data from a community-based screening program using polygenic risk score to target screening.
Authors: McHugh Jana Kathlyn , ni Raghallaigh Holly , Bancroft Elizabeth , Kote-Jarai Zsofia , Benafif Sarah , Eeles Ros A. 
Published: February 2022

231 Background: A significant proportion of Prostate cancer (PrCa) risk is attributable to heritable risk factors of which only a minority are high risk Mendelian traits. A greater proportion of PrCa is due to the combined effect of multiple low risk variants. There have been approximately 170 single nucleotide polymorphisms (SNPs) identified that are associated with PrCa risk in Europeans. Although each of these confer a low to moderate risk of PrCa, the cumulative risk (polygenic risk score, PRS) of increasing numbers of these risk alleles may confer a substantial relative risk. In PrCa genetic profiling, using PRS, could be used to target population screening to those at highest risk. BARCODE1 is the first study to prospectively review the use of a genetic profile in PrCa screening in the general population in the UK. Methods: Our study invited healthy males aged 55-69 to participate through their Primary Care physicians. Collection kits were mailed to retrieve saliva samples. Genotyping was carried out after DNA extraction using a study specific assay and the PRS was calculated for each participant using the sum of weighted alleles for 130 risk loci. Prostate MRI and Biopsy were then offered to men in the top 10% of the genetic risk profile. Results: 40,292 men were invited by letter to participate. The uptake was 22%, of whom 91% of men were eligible for inclusion. Following DNA extraction, genotyping, and quality control checks, data were available for 5008 men. 573 participants had PRS in the top 10% and were invited for screening; 180 underwent a prostate MRI, and 100 went on to have a systematic +/- targeted prostate biopsy. There were 42 diagnoses of PrCa (42%). 52% of cancers detected were low-risk and are being managed with Active Surveillance (AS). Conclusions: The early data from BARCODE1 have shown the feasibility of this population-based study, with an overall uptake of 22% and a cancer incidence of 42% of men in the top decile of PRS. We have identified clinically significant PrCa in 48%. The BARCODE1 study results will be important in defining the role of PRS genetic profiling in targeted PrCa population screening. Clinical trial information: NCT03857477.