bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in prostate cancer.
Authors: Mazzu Ying Zhang , Gerke Travis A. , Chakraborty Goutam , Armenia Joshua , Atiq Mohammad Omar , Komura Kazumasa , Yoshikawa Yuki , Lee Gwo-Shu Mary , Mucci Lorelei A. , Kantoff Philip W. 
Published: February 2018

240 Background: DNA-repair defects are common in advanced prostate cancer (PC) and high-risk localized tumors. Besides deficiency of DNA repair, overexpression of DNA repair genes could also contribute to poorer outcomes for PC patients. The nucleotide metabolism enzyme ribonucleotide reductase (RNR) plays the key role in DNA synthesis and repair. RRM2, the rate-limiting RNR subunit, is frequently up-regulated in cancer, and its overexpression leads to chemoresistance. Although targeting RRM2 by siRNA and small molecules has been applied in clinical trials in multiple cancers, limited knowledge of RRM2 function in PC delays potential clinical application of RRM2 inhibition. Methods: We leveraged publically available PC clinical cohorts to examine RRM2 levels and clinical outcomes. siRNAs was applied to knockdown of RRM2 in multiple PC cell lines. Cell growth, cell cycle and apoptosis were analyzed to determine siRRM2 or RRM2 inhibitor (COH29)-induced phenotypes. RNA-seq and protein array were performed to identify downstream targets of RRM2. Immunohistochemistry staining was applied to determine prevalence of RRM2 protein expression in PC tissues microarrays (TMAs). Results: In PC cohorts, increased RRM2 expression was associated with a higher likelihood of metastasis, poorer disease-free survival, and increased risk of development of lethal disease (N = 1200, PHS/HPFS cohorts). In PC cells, Inhibition of RRM2 induced remarkable cell growth inhibition, cell cycle arrest (at S phase) and apoptosis. DNA damage was observed in siRRM2/COH29-treated PC cells with increased activation of DNA damage markers. GSEA analysis of the RNA-seq dataset revealed multiple biological processes were affected by inhibition of RRM2, such as cell cycle, apoptosis, and DNA damage response. Intriguingly, MYC oncogenic signaling is the major downstream targets of RRM2. Furthermore, inhibition of RRM2 can block multiple oncogenic signaling including mTOR/AKT, SFK, and STAT signaling by repressing the key phospho-kinases in PC cells. Among 121 cases on the PC TMAs, 20% showed strong RRM2 protein expression. Conclusions: RRM2 may serve as a prognostic biomarker and novel therapeutic target in PC.
Concurrent deletion of BRCA2 and RB1 and aggressive prostate cancer.
Authors: Chakraborty Goutam , Armenia Joshua , Mazzu Ying Zhang , Nanjangud Gouri , Chadalavada Kalyani , Atiq Mohammad Omar , Komura Kazumasa , Yoshikawa Yuki , Khan Nabeela , Du Shin-Yi , Lee Gwo-Shu Mary , Kantoff Philip W. 
Published: February 2018

241 Background: Pathogenic variants of BRCA2 have been observed in a substantial subset of men with metastatic castration resistance prostate cancer (mCRPC). Prostate cancer (PC) patients with germline mutations of BRCA2 experience more rapid progression of their localized PC to mCRPC. This stands in contrast to other cancers where BRCA2 alterations do not appear to be associated with a worse prognosis. We identified homozygous and hemizygous deletions of BRCA2 in a subset of primary PC, which had been previously unrecognized. BRCA2 deletion in PC more frequently co-exists with RB1 deletion rather than alone. BRCA2-RB1 co-deletion in primary PC (TCGA and Taylor cohort) is associated with a shorter disease free survival and increased genomic instability in patients, indicating that BRCA2-RB1 null tumors are likely very aggressive in nature. Methods: To determine the underlying molecular and genomic consequences of BRCA2- RB1 loss, we CRISPR/shRNA-out these genes from human PC cell lines and subjected them to various in vitro assays, RNA-seq and kinase arrays. We applied a 3-color FISH assay to identify the deletion of BRCA2 and RB1 in PC. Results: BRCA2-RB1 null LNCaP cells exhibit androgen independence as evidenced by relative resistance to enzalutamide, and increased growth in absence of androgen but show enhanced sensitivity towards PARPi or platinum. Moreover, the null cell induces an aggressive EMT like phenotype, which is associated with enhanced migration and invasion. RNA-seq and array results show significant activation of EMT related signaling pathways including an unexpected activation of WNK1 upon co-deletion of BRCA2-RB1. FISH assay revealed significant co-deletion of BRCA2-RB1 in ADT resistant aggressive PC tumor cells. More importantly these cells also show greater sensitivity towards PARPi or platinum. Conclusions: Our finding suggests that concurrent deletion of BRCA2-RB1 is most likely is a driver of therapy resistant aggressive PC rather than the consequence of exposure to therapy. We propose that screening for BRCA2-RB1 deletion early could be implemented to identify those at highest risk of aggressive PC and provide an opportunity for early intervention and alternative treatments.
Abiraterone acetate (AA) or docetaxel (D) in metastatic castration-sensitive prostate cancer (mCSPC): A systematic review and network meta-analysis of randomized clinical trials (RCTs).
Authors: Riaz Irbaz Bin , Almutairi Abdulaali , Ali Zeeshan , Alhifany Abdullah , Bhattacharjee Sandipan , Abraham Ivo , Kohli Manish 
Published: February 2018

243 Background: AA and D have been shown in separate trials to increase overall survival in patients with mCSPC compared to Androgen Derivation Therapy (ADT). In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison of AA and D using network meta-analysis. Methods: We performed a search of MEDLINE, EMBASE, Cochrane Library, and Cochrane Central Register of Controlled Trials to identify relevant clinical trials. Collected data included hazard ratio and confidence interval (CI) for Overall Survival (OS) and number of adverse events in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparison of D and AA. Results: Five clinical trials were included in this analysis. Two trials (LATITUDE, STAMPEDE) compared AA to ADT and three trials (CHAARTED,STAMPEDE, GETUG-AFU 15 study) compared D to ADT. Results from both fixed effect and random effect network meta-analyses for the primary outcome (OS) revealed no statistical significance between AA and D (HR 0.81,95%CI 0.65-1.01; HR 0.81, 95%CI 0.40-1.82) respectively. Comparatively, abiraterone had statistically significant fewer events of anemia (OR 0.14,95%CI 0.08-0.23), neutropenia (OR 0.06,95%CI 0.03-0.12), peripheral edema (OR 0.21,95%CI 0.09-0.44), dyspnea (OR 0.22,95%CI 0.08-0.51), nausea (OR 0.09,95%CI 0.02-0.24), diarrhea (OR 0.06,95%CI 0.02-0.15), constipation (OR 0.25,95%CI 0.11-0.53), and fatigue (OR 0.12,95%CI 0.07-0.20). AA had statistically significant more events of hot flashes (OR 3.85, 95% CI2.33-6.25). For other adverse events, both drugs were statistically similar. Conclusions: There is no difference in OS using AA for longer periods in CSPC than a regimen of a limited number of cycles of D. There are significant differences in side effect profile of these drugs. Further analyses are needed to determine cost effectiveness of AA vs D under consideration of comparative efficacy and safety.
Radical prostatectomy in metastatic castration-resistant prostate cancer: Feasibility, safety, and quality of life outcomes.
Authors: Reichard Chad A. , Gregg Justin , Achim Mary F. , Aparicio Ana , Pisters Louis L. , Ward John Francis , Davis John W. , Chapin Brian Francis 
Published: February 2018

244 Background: Ongoing studies are evaluating the role of definitive treatment of the primary tumor in men with de novo metastatic prostate cancer. If proven beneficial, the optimal timing of the intervention will need to be considered. Little is known regarding the safety and quality of life outcomes of RP in metastatic castration resistant PCa (mCRPC). Methods: 14 pts undergoing RP on clinical trials and in the setting of mCRPC from 2008-2016 were analyzed. Intra-op and post-op complications were assigned Clavien-Dindo grade. Post-op expanded prostate cancer index composite (EPIC) urinary domains quality of life (QOL) outcomes were reviewed. Results: Patient characteristics were summarized (Table). 5 (36%) pts received platinum based chemo prior to RP. 4 pts had a decrease in PSA post RP (range: 0.2-57.3 ng/ml); 7 pts had an increase in PSA post RP (range: 0.1-24.5 ng/ml); and 3 pts’ PSA was unchanged. Positive surgical margin rate was 57%. 3 of 6 cN0 pts were pN1. 1 of 8 cN1 pts were pN0. 12/14 pts underwent extended lymphadenectomy with a median 3 (IQR 0-4) positive LNs out of 17 (IQR 11-25) LNs removed. Median op time was 239 min (IQR 186-304). Median EBL was 200cc (IQR 150-225). 8 pts had bilateral non-nerve sparing. Median pre-op and <3month post-op EPIC urinary function QOL scores were 84 (IQR 70-95) and 78 (IQR 62-810) respectively. 30-day mortality was 0% and 12/14 pts were alive at 1 year post RP. There were no intra-op complications. There was one Clavien Grade III complication (pelvic abscess), with remaining 5 complications either Grade I or II. Conclusions: In this select cohort of pts with mCRPC, RP was feasible with limited complications. Differences in pre-op and post-op urinary QOL scores were not clinically significant. Given the retrospective nature of the review and the heterogeneity of this heavily pre-treated population, clinical benefit cannot be ascribed to the intervention. Thus, we caution against RP in mCRPC outside of well-designed clinical trials other than for palliation. [Table: see text]
Multi-parametric MRI guided dose escalated radiotherapy for treatment of localized prostate cancer (PCa): Initial toxicity results of a prospective phase II trial.
Authors: Blumenfeld Philip , Chowdhary Mudit , Deane Leslie A. , Pfanzelter Nick , Shors Stephanie , Braun Ryan , White Greg M , Coogan Christopher , Hoeksema Jerome , Khare Narenda , Vourganti Srinivas , Turian Julius , Kuzel Timothy , Wang Dian 
Published: February 2018

25 Background: Multi-parametric MRI (mpMRI) of PCa uses advanced sequences to detect aggressive, high grade and bulky lesions. Given known advantages of hypofractionated radiotherapy (RT) to treat PCa (low a/b ratio), we conducted a phase II trial to escalate a high dose to mpMRI lesion(s) via Image-Guided (IG)-RT/Volumetric Arc Therapy (VMAT)/Stereotactic Body Radiotherapy (SBRT) technology. We present the acute toxicity results of this novel approach. Methods: 22 pts with mpMRI lesion(s) were prospectively treated to a course of IGRT/VMAT to the prostate & seminal vesicle +/- pelvic lymph nodes (PLN) to a dose of 45 Gy in 25 fractions followed by SBRT boost, 18 Gy in 3 fraction to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions (EQD2 = 85.2 Gy using a/b 3 or 93.4 Gy using a/b 1.5) to the mpMRI prostatic lesion(s). Placement of 3 polymer based fiducial markers visible in both CT and MRI for image co-registration and treatment guidance was performed. Genitourinary (GU) and gastrointestinal (GI) adverse events (AE) were scored using CTCAE v4. DSMC approved reporting of acute AE results prior to completion of trial accrual as an interim safety assessment prior to final trial accrual. Results: Median age was 66.5 years (range: 57-80). All patients had PI-RADS grade 3-5 mpMRI lesion(s); 41.0%, 45.4% and 13.6% having 1, 2 and 3 lesions respectively. Ten (45%) pts had Gleason Score (GS) 8-10 and 12 had GS 7 disease. Median PSA was 8.97 (range: 4.0-77.9). Eleven (50%), 10 (46%), and 1 (5%) pts had stage T1, T2, and T3 tumor, respectively. Nine pts received treatment to the PLN and 15 received androgen deprivation therapy. All patients completed the protocol treatment without reporting acute GI or GU AEs grade ≥3 during treatment or at follow up. Grade 2 GI (diarrhea) and GU toxicity (frequency) was seen in 2 (9%) and 9 (41%) pts, respectively, during treatment. Of the 16 pts (71%) with least 3 months follow-up all grade 2 GI and 55.5% GU toxicities had resolved. Conclusions: Early results of this prospective Phase II study suggest that high-dose RT for localized PCa via mpMRI-guided RT/VMAT and SBRT boost is tolerable with a favorable acute toxicity profile.
Whole blood AR-V7 and AR-V9 mRNA expression and treatment response in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Kwan Edmond Michael , To Sarah , Fettke Heidi , Mant Andrew Michael , Docanto Maria , Martelotto Luciano , Bukczynska Patricia , Ng Nicole , Graham Lisa-Jane , Parente Phillip , Pezaro Carmel Jo , Mahon Kate Lynette , Horvath Lisa , Todenhöfer Tilman , Azad Arun 
Published: February 2018

252 Background: Androgen receptor splice variant (AR-V) expression has previously been regarded as a negative predictive biomarker for response to abiraterone and enzalutamide in mCRPC patients. However, recent data questions this association. We designed a whole blood assay to detect AR-V7 and AR-V9, the two most abundantly expressed AR-Vs, and correlated expression with clinical outcomes in patients commencing abiraterone or enzalutamide. Methods: We developed a quantitative real-time polymerase chain reaction assay to detect AR-V7 and AR-V9 from whole blood collected in PAXgene tubes. The assay was applied to samples prospectively collected from 37 mCRPC patients prior to commencing abiraterone or enzalutamide, and at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-V-negative if neither variant was detected. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (log-rank test). Assay sensitivity was determined by serially diluting RNA from VCaP prostate cancer cells (known to express AR-V7) to establish a lower limit of detection. Results: The median follow-up was 7.29 months (IQR 4.21-10.55); 9 of 37 patients (24%) were AR-V-positive. We observed similar response rates in AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p = 0.896). PSA-PFS did not differ significantly between groups (9.2 months vs. not reached, p = 0.355). Two patients converted from AR-V-negative to AR-V-positive (PSA-PFS 3.35 and 0.60 months respectively), and one patient remained AR-V-positive at baseline and end-of-treatment sampling. The lower limit of detection for AR-V7 was 0.1%, and AR-V7/V9 was not detected in any of the 13 normal male controls. Conclusions: We developed a sensitive and specific whole blood assay for AR-V7 and AR-V9 detection in patients with mCRPC. Neither PSA response rates nor PSA-PFS differed significantly between AR-V-positive and AR-V-negative patients. These data support recent literature questioning the role of AR-V expression as a negative predictive biomarker in mCRPC patients receiving abiraterone or enzalutamide.
Predict: Evaluation of baseline characteristics predictive of distant metastases in patients with castration-resistant prostate cancer—Updated data.
Authors: Freedland Stephen J. , Smith Matthew R. , Concepcion Raoul S. , Pieczonka Christopher Michael , Gartrell Benjamin Adam , Schiffman Zvi , Van Mouwerik Tim , Tyler Robert C. , Chang Nancy N. , Shore Neal D. 
Published: February 2018

253 Background: Metrics predicting a positive imaging test for men presumed M0 castration-resistant prostate cancer (CRPC) are not universally accepted/implemented. PREDICT (NCT01981109) evaluates characteristics predictive of a baseline (BL) imaging study positive for distant mets (M1) in men with presumed M0 CRPC, and follows those with confirmed M0 disease to M1 development. Methods: Men with no imaging in the previous 3 months (mos) were enrolled in the registry. Imaging modality to detect mets was at investigator’s discretion. Based on BL imaging, patients were classified as M0 or M1. Results: PREDICT enrolled 224 men, of whom 208 had BL scan/image data; 55 (25%) men presented with undetected M1. Visceral disease was noted in 11% of men presenting with M1 disease; 60% had bone only disease, 18% had nodal only disease and 11% had bone + nodal disease. Bone mets were found in 16% (25/160) of Tc99 scans vs 40% (19/48) of NaF PET (p = 0.0004). Of men with M0 at BL, 37/153 (24%) became M1 at a mean time from study entry of 11.9 mos. Mean follow-up was 28 mos. In these men, the only notable change in laboratory values from BL was PSA (mean: 16 vs 69 ng/mL; p = 0.020) and PSADT (7.7 vs 6.3 mos; p < 0.001). Baseline PSADT was 10.9 (M0) and 5.7 (M1) mos. BL mean laboratory values were significantly higher (p < 0.01) in the M1 vs M0 group for PSA (47 vs 10 ng/mL), alkaline phosphatase (111 vs 77 U/L), and prostatic acid phosphatase (8.2 vs 2.5 ng/mL). Conclusions: A high proportion (25%) of men presented with asymptomatic, occult mets, and 11% of the occult mets involved visceral disease. In men with documented M0 CRPC, approximately a quarter will develop mets in the next 12 mos. Early detection of occult mets will allow patients to initiate therapies shown to improve overall survival. Clinical trial information: NCT01981109.
ARV7/AR ratio and neutrophil-to-lymphocyte ratio (NLR) as predictors of docetaxel benefit in metastatic castration-resistant prostate cancer patients (mCRPC).
Authors: Pérez-Gago Maria Coral , Marín-Aguilera Mercedes , Reig Òscar , Pereira Maria Veronica , Milà Maria , Jimenez Natalia , Victoria Iván , Chic Nuria , Mellado Begona 
Published: February 2018

254 Background: The constitutively active androgen receptor (AR) variant 7 (ARV7) has been associated to AR inhibitors resistance, but its role in taxane-benefit has not been stablished. Moreover, the neutrophil-to-lymphocyte ratio (NLR) has been associated with poor outcome in prostate cancer.The PBMC population may contain circulating tumor cells (CTCs) but is mainly constituted by lymphocytes and monocytes, that also express the AR. Here we studied the expression of ARV7 and AR in peripheral blood mononuclear cells (PBMC) and its correlation with NLR and clinical outcome in mCRPC treated with docetaxel. Methods: ARV7 and AR mRNAs were tested by quantitative reverse-transcription PCR. Baseline neutrophil and lymphocyte values and PBMC samples were prospectively collected before treatment initiation. Patients were stratified according to NLR ratio (low NLR: ≤3; high NLR:>3) and to ARV7/ARFL ratio expression (Maxstat Cutoff 1.99). Correlation between NLR and PSA progression-free (PSA-PFS) and overall survival (OS), were measured from the start of docetaxel treatment and calculated by log rank test. Results: Fifty patients were included:25 (50%) had low NLR. Thirty-eight patients (76%) expressed high ARV7/ARFL. No significant correlation between NLR with ARV7, AR and ARV7/AR was observed. High ARV7/ARF ratio correlated to a better PSA-PFS (median PSA-PFS 7.47; HR 0.38, 95%CI 0.17-0.85; P=0.0179) , but not OS. High NLR was associated to a lower OS [Median OS was 9.2 months versus 30.17 months in those with low NLR (HR 2.19, 95% CI 1.17-4.09, p= 0.01)]. When both parameters were combined, high NLR and low ARV7/ARFL ratio were associated to a worse PSA-PFS in comparison with low NLR and high ARV7/ARFL ratiogroup(median PSA-PFS: 4.9 vs. 7.5; p=0.008 and HR 5.08, 95% CI 1.33-19.41, p= 0.08) and OS (median OS: 7.4 vs. 30.5; p=0.001 and HR 22.79, 95% CI 4.29-121.17, p= 0.00). Conclusions: The combination of low ARV7/ARFL high NLR and ratio evaluated in PBMC prior to docetaxel treatment has a predictive impact on response and survival in mCRPC patients.
cfDNA analysis of mCRPC patients expressing mutations in Wnt signaling.
Authors: Shahbandi Ashkan , Ledet Elisa , Christensen Bryce Raymon , Moses Marcus Marie , Steinwald Peter , Chapman Lynne , Cotogno Patrick , Layton Jodi Lyn , Lewis Brian E. , Schiff Joshua , Sartor A. Oliver 
Published: February 2018

256 Background: Alterations in Wnt signaling have been shown to play a role in the development of castrate resistant prostate cancer. Cell free DNA (cfDNA) isolated from patient plasma can provide a non-invasive way to further assess this role. The goal of this study was to identify patients with cfDNA alterations in major canonical Wnt signaling components (APC and/or beta-catenin), and relate the emergence of these mutations during treatment to alterations in other common mutations. Methods: 134 clinically progressive metastatic CRPC patients from Tulane Cancer Center underwent cfDNA analysis through Guardant360 test (Guardant Health, Redwood City, CA). This analysis consisted of exonic coverage of 70 genes as well as amplifications in 18 genes, with mutations categorized as either pathologic, non-pathologic or as variants of unknown significance (VUS). Clinical annotation of prior treatment history was recorded. Results: 21.6% (29/134) of the mCRPC patients evaluated had a canonical Wnt signaling (APC and/or CTNNB) alteration. Of these patients, 62.1% (18/29) had mutations identified as pathologic. 77.8% (14/18) of patients identified with a pathologic Wnt mutation were treated with abiraterone and/or enzalutamide prior to Guardant360 testing. To determine potential associations between Wnt signaling alterations and other detected changes in cfDNA, the relationship between Wnt mutations (APC and/or CTNNB1) with pathologic TP53 mutations, AR mutations, BRAF amplifications, and MYC amplifications was assessed using a patient’s latest Guardant360 test. A significant positive association was found between Wnt mutations (n = 18) and MYC amplifications (n = 22), (p = 0.0373). 33.3% (6/18) of patients with a pathologic Wnt mutation were found to have amplification in MYC. Other notable associations included Wnt mutations and AR mutations (n = 74), which approached statistical significance (p = 0.112). Conclusions: While the understanding of the role of Wnt signaling in the treatment of mCRPC is still evolving, co-segregation of Wnt-signaling alterations with other oncogenic alterations, particularly MYC, which has been identified as a target of canonical Wnt signaling, may provide insights with regards to future management of mCRPC.