bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.
Authors: Margel David , Peer Avivit , Ber Yaara , Sela Sivan , Shavit Grievink Liat , Tabachnik Tzlil , Witberg Guy , Baniel Jack , Kedar Daniel , Duivenvoorden Wilhelmina CM , Rosenbaum Eli , Pinthus Jehonathan H 
Published: May 2019

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.
HSD3B1 and overall survival (OS) in men with low-volume (LV) metastatic prostate cancer (PCa) treated with androgen deprivation therapy (ADT) or chemohormonal therapy in the CHAARTED Randomized trial.
Authors: Hearn Jason W.D. , Sweeney Christopher , Almassi Nima , Reichard Chad A. , Reddy Chandana A. , Hobbs Brian , Jarrard David Frazier , Chen Yu-Hui , Dreicer Robert , Garcia Jorge A. , Carducci Michael Anthony , DiPaola Robert S. , Sharifi Nima 
Published: May 2019

5020 Background: The HSD3B1(1245A > C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. Multiple retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. We sought to validate these findings with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). Methods: Men with newly metastatic PCa were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). We determined germline HSD3B1 genotype in the subset of men with LV disease ( < 4 bone metastases, no visceral metastases). We analyzed freedom from castration-resistant prostate cancer (CRPC) and OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. Results: 197 patients with LV disease had blood samples available and were genotyped, including 97 in arm A and 100 in arm B. Docetaxel did not improve OS of LV men. Of the 197 men, 47% were homozygous wild-type (WT), 43% were heterozygous, and 10% were homozygous variant. When all 197 men were analyzed as one goup, the median time to CRPC was 39.7 mos. in homozygous WT men vs. 25.0 mos. in men with one or more copies of the variant allele (HR 1.27, 95% CI 0.89 to 1.82; p = 0.187). Although OS data are still maturing, at 52 months OS was 83% (95% CI 75% to 91%) in homozygous WT men vs. 64% (95% CI 55% to 74%) in men with one or more variant alleles. There was a suggestion that docetaxel delayed development of CRPC among men with at least 1 variant allele (20.3 vs. 40.7 mos.; HR 0.66, 95% CI 0.40 to 1.04; p = 0.08). Benefit for men with high-volume disease was not evident. Conclusions: Inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with lower OS in men treated with ADT with or without docetaxel for LV newly metastatic PCa. Additional study is warranted in patients with LV disease. Clinical trial information: NCT00309985.
Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients.
Authors: Lin Edwin , Hahn Andrew W , Sonpavde Guru , Lilly Michael B. , Nussenzveig Roberto , Ledet Elisa , Pal Sumanta K. , Grivas Petros , Rich Thereasa A. , Raymond Victoria M. , Sartor A. Oliver , Yandell Mark , Agarwal Neeraj 
Published: May 2019

5032 Background: All mPC patients eventually progress on current treatments and prognosis remains poor. In vitro models and small patient cohorts have shown that mPC progression is associated with increased MAPK/ERK signaling. However, in clinical mPC, the genomic alterations that cause aberrant MAPK/ERK signaling and their frequency are poorly defined. We hypothesize that profiling of genomic alterations in MAPK/ERK in a large cohort of heavily pretreated progressive mPC patients will provide a robust measure of importance, and reveal recurrent patterns of alteration. Given the large number of drugs that target MAPK/ERK, these may be incorporated into novel combinatorial treatments for mPC. Methods: 2,679 plasma samples from 2,309 men with mPC were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA) and profiles indels, amplifications, and fusions with high sensitivity and specificity. Genes were assigned to gene sets corresponding to biological pathways and molecular functional classes using the REACTOME database, followed by calculation of summary statistics. Interdependencies between genetic alterations at inter- and intra-gene set levels were discovered by a Bayesian network approach. Results: 56% of mPC samples harbored alterations in MAPK/ERK signaling genes. These included receptor tyrosine kinases (RTKs), MAP kinase cascade, and cell cycle control genes. Gene amplifications were the most frequent alterations in RTK, RAF, and cell cycle control genes, a novel finding. Bayesian network analysis revealed positive interdependencies between all MAPK/ERK genes. In RTK genes, co-amplifications were especially frequent between MET & EGFR and PDGFRA & KIT. Conclusions: In a large cohort of mPC patients, we show that MAPK/ERK gene alterations are present in over half of mPC patients. RTKs, BRAF, and CDK4/6 amplifications are among the most frequent events, display recurrent patterns of co-alteration, and are targetable by existing drugs. Future work to assess the biological and clinical significance of these recurrent patterns of alteration will pave the way for novel combinatorial treatments.
Interlesional response assessment with 18F-sodium fluoride (18F-NaF) PET/CT in men with chemotherapy-naive bone metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA).
Authors: Kyriakopoulos Christos , Heath Elisabeth I. , Ferrari Anna C. , Perlman Scott , Mayer Tina M. , Stein Mark N. , Modelska Katharina , Duggan William , Jeraj Robert , Liu Glenn 
Published: May 2019

5036 Background: 18F-NaF PET/CT provides spatial and quantitative information on osteoblastic activity in men with bone mCRPC; thus, it can be used to assess interlesional response heterogeneity, a critical clinical issue. Here we assess the proportion of men treated with ENZA with responding lesions by 18F-NaF PET/CT at the time of prostate-specific antigen (PSA), standard radiographic, or clinical progression. Methods: Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of PSA progression (increase of ≥ 25% and ≥ 2.0 ng/mL above nadir), standard radiographic or clinical progression, or at 2 years without progression (PET3) using Quantitative Total Bone Imaging (QTBI). The primary endpoint was the proportion of men with ≥ 1 responding bone lesion (defined as a lesion with a total NaF standardized uptake value [SUV] less than baseline) on PET3. Evaluable men had scans at PET1 and PET3. Results: A total of 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled. The study met its primary objective; 22 of 22 (100%) evaluable men had ≥ 1 responding bone lesion on QTBI at PET3. Total disease burden changed from a mean baseline SUV of 5700 (range, 507-22,850) to 5590 (range, 213-17,090) at PET2 and 6020 (range, 118-16,650) at PET3. The proportion of progressive lesions increased from a mean 7.8% (range, 0-29) at PET2 to 9.4% (range, 0-32) at PET3. Conclusions: Although PSA response with ENZA is high, many men experience a mixed response to treatment. While overall functional disease burden improves during treatment, an eventual increase in global burden is seen at the time of progression as measured by 18F-NaF PET/CT. At the primary endpoint analysis the proportion of progressing lesions is low, supporting both the hypothesis that a substantial number of lesions continue to benefit from treatment and the concept of treating beyond progression and selectively targeting nonresponding lesions while keeping patients on ENZA. Clinical trial information: NCT02384382.
Randomized phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) versus GM-CSF adjuvant in patients with PSA-recurrent prostate cancer.
Authors: Liu Glenn , Fong Lawrence , Antonarakis Emmanuel S. , Eickhoff Jens C. , Wargowski Ellen G. , Johnson Laura E. , Jeraj Robert , McNeel Douglas G. 
Published: May 2019

5037 Background: Phase I/II studies of pTVG-HP showed safety and increases in prostatic acid phosphatase (PAP)-specific T cells. Based on these, we conducted a multi-center, randomized phase II trial using pTVG-HP with GM-CSF adjuvant vs GM-CSF alone in patients with PSA-recurrent, non-metastatic, non-castrate, prostate cancer (stage M0). Methods: 99 patients with M0 prostate cancer (negative CT and bone scan) with PSA doubling time (DT) of < 12m were randomly assigned to pTVG-HP + GM-CSF vs GM-CSF. Treatments were every 2 wk x 6, and then quarterly for up to 24m. Primary endpoint was 2-year MFS. Secondary endpoints included median MFS, changes in PSA DT, and immune response to PAP antigen. Additional analysis included quantitative changes in bone lesion activity by NaF PET/CT. Results: Few grade 3/4 events were observed and were not statistically different between arms. 2-year MFS between control and pTVG-HP was 42.3% and 41.8% (p = 0.97). Median MFS was not different (18.3m control versus 18.9m pTVG-HP, HR = 1.6, p = 0.13). Changes in PSA DT, and immunity to the PAP target, were not different between study arms. A pre-planned subset analysis showed median MFS was significantly longer in patients with rapid PSA DT ( < 3m) treated with pTVG-HP (6.1m versus 12.0m, n = 21, HR = 4.4, p = 0.03). In patients with baseline metastases detected on NaF PET/CT, total activity (SUVtotal) increased 17% with GM-CSF alone, but decreased 29% with pTVG-HP from baseline to month 6 (n = 27, p = 0.07). Conclusions: This trial did not demonstrate an overall increase in 2-year MFS following treatment with pTVG-HP, but suggested a modest effect in patients with rapidly progressive disease. NaF PET/CT imaging suggests that pTVG-HP has a detectable effect on decreasing metastatic activity in bone. A separate trial suggests that pTVG-HP is an immune activating agent that improves activity of PD-1 blockade. A trial using pTVG-HP in combination with nivolumab in patients with M0 prostate cancer is currently underway. Clinical trial information: NCT01341652.
Complex biologic heterogeneity of de novo hormone naïve metastatic prostate cancer (HNPCa): Comparison of early progressors and prolonged responders to initial systemic treatment.
Authors: Chapin Brian Francis , Wang Xuemei , Zhang Miao , Corn Paul Gettys , Zurita Amado J. , Elsheshtawi Mohamed A , Davis John W. , Pettaway Curtis Alvin , Adibi Mehrad , Gleave Martin , Cooperberg Matthew R. , Smaldone Marc C. , Mcguire Sean Eric , Tu Shi-Ming , Wang Jennifer , Subudhi Sumit Kumar , Efstathiou Eleni , Logothetis Christopher , Troncoso Patricia , Aparicio Ana 
Published: May 2019

5055 Background: Given the absence of biologically based biomarkers current therapy allocation strategies for men with mHNPCa are based on anatomic distribution and volume of metastases. We sought to determine the strength of the association between clinical predictors (including met volume) and outcomes in men with mHNPCa at extremes of response to initial systemic therapy (ST). Methods: Data from a population screened for a phase II trial of Best ST +/- local therapy in mHNPCa was analyzed (NCT01751438). Pts had to have sustained responses to ST (≥6 mos) in order to be randomized. Early Progressors (EP, castration resistant progression <6 mos from start of ST per PCWG2) were not randomized. Prolonged Responders (PR) were defined as those with progression free survivals (PFS) > median for the 109 randomized pts. Baseline demographics were compared between groups (Fisher’s exact test for categorical and Wilcoxon rank-sum test for continuous variables) and Kaplan Meier estimates of OS determined. Immunohistochemistry and genomic sequencing of untreated tumor biopsies are ongoing. Results: Of 208 screened pts, 27 (13%) were identified as EPs, with a median PFS of 5.9 mos (95%CI: 5.3-6.5). The median PFS for the randomized cohort was 16.8 mos (95%CI: 12.7-37.6). 55 (50%) pts were identified as PRs, with median PFS not reached (NR) at a median follow up of 31 mos (range: 7.5-75). Patients’ demographics are below (Table), grouped by EP and PR cohorts. Median OS was 24.8 mos vs NR in the Eps compared to PRs (p<0.001). Conclusions: The EP group was enriched for high risk features and had a worse outcome. However, 33% of men in the EP group had low volume disease and 22% in the PR group had high volume disease. This suggests that clinical volume is an inadequate predictor of biologic response and highlights the need for biologic sub-typing of de novo mHNPCa. [Table: see text]
Impact of germline DNA-repair gene BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naïve prostate cancer: A single center analysis.
Authors: Matveev Vsevolod Borisovich , Lyubchenko Liudmila , Kirichek Andrey 
Published: May 2019

5056 Background: Germline mutations in DNA repair genes are common in patients with andvanced and metastatic prostate cancer (mPCa). Although BRCA mutation carriers have worse outcomes than noncarriers when conventionally treated for local or locally advanced PCa, recent studies reported conflicting results regarding their aggressiveness in patients with advanced disease. This study aimed to examine the impact of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with mPCa, receiving hormonal androgen deprivation therapy (ADT). Methods: A total of 76 patients with hormone-naive mPCa treated with first line ADT by luteinizing hormone-releasing hormone analogue (LHRHa) between 2014 and 2017 were recruited. Median follow-up was 34,8 mo. We focused on age, volume of metastatic spread, histologic grade, family history. All patients were genotyped for germline mutations in the BRCA1, BRCA2 and CHEK2 genes by polymerase chain reaction real-time and the Sanger sequencing. We used the standard definition of castration-resistance PCa (CRPC). Median time to CRPC were estimated using the Kaplan-Meier method, generated curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA1/2 and CHEK2 mutations. Results: Pathogenic and likely pathogenic germline mutations in the BRCA2 and CHEK2 gene were identified in 19 (25 %) patients. No cases of BRCA1 mutations were detected. Median time to CRPC was significantly shorter in BRCA2 and CHEK2 mutation carriers (7.9 mo, 95 % confidence interval (CI) 2.6 – 13.3), than in non-carriers (48.7 mo, 95 % CI 31.1 – 68.3, p < 0,001). There was no significant difference in median time to CRPC in BRCA2 (7.9 mo, 95 % CI 0.0 - 16.3) and CHEK2 mutation carriers (6.1 mo, 95 CI 5.0 - 7.2, p = 0,448) meanwhile both were shorter than in non-carriers (p = 0.002 and < 0,001). Multivariate analysis confirmed both BRCA2 (hazard ratio [HR]: 2.63; 95 CI 1.32-5.26, p = 0.006) and CHEK2 (HR 6.66, 95 CI 2.35-18.89, p < 0.001) mutations as an independent prognostic factor for time to CRPC, particularly in mPCa with low-volume metastatis spread (HR 3.09, 95 % CI 1.36–7.05, р = 0.007 and HR 14.1, 95 % CI 3.65-54.4, p < 0.001). Conclusions: BRCA2 and CHEK2 carriers had worse outcomes (shortened time to CRPC) than noncarriers when conventionally treated for metastatic PCa by standard first-line hormone treatment with LHRHa.
Clinical outcomes and genomic analysis in patients with very high-risk clinically localized prostate cancer treated by radical prostatectomy.
Authors: Velho Pedro Isaacsson , Lim David , Wang Hao , Kaur Harsimar B , Markowski Mark Christopher , Carducci Michael Anthony , Antonarakis Emmanuel S. , Pritchard Colin C. , Lotan Tamara L. , Eisenberger Mario A. 
Published: May 2019

5067 Background: Very high risk prostate cancer is associated with poor response to local and systemic treatments, however few cases have been molecularly profiled. We studied patients with primary Gleason pattern 5 disease (PG5; Gleason scores 5+5 or 5+4) after undergoing radical prostatectomy (RP). Methods: Consecutive PG5 cases were retrospectively studied. Clinical-pathologic features, tumor somatic sequencing (UW Oncoplex), germline sequencing and PTEN, TP53 and ERG status by immunohistochemistry were correlated with biochemical relapse (BCR), metastasis-free survival (MFS), time to castration-resistance (TCR) and overall survival (OS). Kaplan–Meier curves were used in time-to-event data. Univariate and multivariable (MVA) Cox proportional-hazards models (95% confidence intervals (CI Clinical-pathological variables were selected for the multivariate analysis using stepwise method and were used to adjust the effect of each mutation. Results: Of 60 patients with available tissue and follow-up, 90% had non-organ confined disease, 58% had seminal vesicle invasion (SVI), 27% had lymph node involvement, and 15% had ductal or intraductal histologic features. Overall, 43% developed metastasis with a TCR of 12 months. On multivariable analysis of clinical-pathologic variables, only ductal/intraductal histology (HR = 4.43; 95% CI: 1.76-11.15; p = 0.002) and SVI (HR = 5.14; 95% CI: 1.83-14.47 p = 0.002) were associated with metastasis. Of patients with somatic sequencing data, 22% (11/49) had homologous recombination (HR) and 12% (6/49) had mismatch repair (MMR) gene alterations. In addition, 33% (16/49) had TP53 mutation and 51% (29/57) had PTEN loss. Only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis and no genomic alterations remained significant in multivariable analyses. Conclusions: Patients with PG5 have poor outcomes and more than one third have mutations in DNA repair genes. The unusually high incidence of actionable HR and MMR alterations provides the rationale for the design of adjuvant clinical trials in this population. [Table: see text]
WNT activating pathway mutations confer resistance to first-line antiandrogen therapy in castration-resistant prostate cancer (CRPC).
Authors: Isaacsson Velho Pedro , Mirkheshti Nooshin , Qazi Fahad , Shaukat Farah , Fu Wei , Wang Hao , Carducci Michael Anthony , Markowski Mark Christopher , Denmeade Samuel R. , Marshall Catherine Handy , Lotan Tamara L. , Eisenberger Mario A. , Antonarakis Emmanuel S. 
Published: May 2019

5068 Background: Wnt signaling is a cellular pathway responsible for embryogenesis and neoplasm. When activated, in about 10-20% of mCRPC, the WNT signaling pathway may cause androgen-independent growth and consequently antiandrogen resistance. To further characterize the clinical features and biology of this subtype of mCRPC, we studied mutations in genes of this pathway, including APC, CTNNB1, RNF43, ZNRF3 and RSPO2, in patients who received treatment at Johns Hopkins Hospital (JHH). Methods: Patients with CRPC who received first-line antiandrogen (abiraterone or enzalutamide) therapy for CRPC at JHH were retrospectively studied. Pathological staging, extension of primary disease, tumor somatic genomic data by Next Generation Sequencing (NGS) were correlated with clinical outcomes such as time to PSA progression, PSA response and overall survival (OS). Cox regression was used to test associations between variables and clinical outcomes and Kaplan-Meier method was used for time-to-event data. Results: Of 137 pts who received first-line antiandrogen therapy for CRPC, 10.9% (15 pts) had NGS with at least one activating WNT pathway alteration, including mutations in APC (6 pts), CTNNB1 (8 pts) and RNF43 (3 pts). Patients with WNT mutations had fewer T3/T4 tumors (30.8% vs. 51.4%, p = 0.24), but were balanced in other aspects. The median time to PSA progression in WNT activated patients was 6.5 months vs. 9.6 months in WNT negative patients (HR 2.3, 95% CI 1.3 - 4.1, p = 0.003). The presence of WNT mutations (HR 2.3, 95% CI 1.2 - 4.3, p = 0.007) and previous chemotherapy (HR 1.8, 95% CI 1.2 – 2.7, p = 0.003) were independently associated with shorter time to PSA progression. PSA50 response was numerically worse in WNT activated patients (53% vs 75%, p = 0.12). The OS in patients with WNT mutations was 23.6 months vs 27.7 months in patients without WNT mutations (HR 2.2, 95% CI 1.1 - 4.5, p = 0.01). Conclusions: Patients with WNT pathway mutations may have worse outcomes to first-line abi/enza compared to patients without these aberrations. Time to PSA progression and OS were inferior in WNT activated population. Our data reinforce the necessity to develop effective WNT pathway inhibitors to test in clinical trials for WNT activated patients.