bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic polymorphisms to predict progression-free survival in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone therapy: Results from the NCI 9012 trial.
Authors: Albany Costantine , Daignault-Newton Stephanie , Skaar Todd C , Ipe Joseph , Siddiqui Javed , Twardowski Przemyslaw , Stein Mark N. , Kunju Lakshmi Priya , Chinnaiyan Arul M. , Montgomery Robert B. , Antonarakis Emmanuel S. , Shevrin Daniel H. , Whang Young E. , Caram Megan Veresh , Smith David C. , Feng Felix Yi-Chung , Stadler Walter Michael , Hussain Maha 
Published: March 2017

145 Background: Abiraterone is a CYP17 inhibitor approved for treatment of men with mCRPC. The NCI 9012 trial evaluated abiraterone alone with or without the PARP inhibitor veliparib in mCRPC patients. We hypothesized that germline genetic variation in the androgen axis and other metabolic enzymes would predict response to veliparib + abiraterone vs. abiraterone alone. Methods: A randomized trial cohort of (148) men with advanced mCRPC treated with abiraterone with or without veliparib was genotyped for 120 DNA polymorphisms in genes involved in androgen metabolism using Lifetech Open array chips. Blood for pharmacogenomic SNP analysis were collected at pre-treatment from each subject into 10-mL EDTA tube. Polymorphisms were tested using Cox models without treatment for prognostic testing and with treatment arm for predictive testing. Results: Genotyping was completed in 143 of 148 men; all were treated with abiraterone; 72 without veliparib (Median PFS: 10.3m) and 71 with veliparib (Median PFS: 11.3m). Polymorphisms in separate genes (SLCO2B1, KIF3C CYP19A, ESR1) were significantly (P ≤ .025) associated with progression-free survival (PFS) during abiraterone (q-value < 0.69). Polymorphisms in (CYP11A1, HSD17B4, ABHD13;LIG4, CYP19A1, HSD17B4, TRMT11) were predictive for PFS in patients treated with combination of abiraterone/veliparib compared to abiraterone alone (p-value < 0.025; q-value < 0.28). Conclusions: This analysis examines the influence of inherited variations on the efficacy of abiraterone, establishing the importance of pharmacogenomics on individual’s response to this therapy. Genotyping patients at these loci could be predictive of improved PFS to valiparib in combination with abiraterone. Further analysis of the association of more than one polymorphisms compared to zero or one with PFS associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one is ongoing. Clinical trial information: NCT01576172.
Changes in prostate cancer detection rate of fusion versus systematic biopsy over time: A single center experience.
Authors: Calio Brian P. , Sidana Abhinav , Sugano Dordaneh , Jain Amit L , Maruf Mahir , Merino Maria J , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Pinto Peter A. 
Published: March 2017

15 Background: To determine the effect of learning curves and changes in fusion platform during 9 years of NCI’s experience with multiparametric MRI (mpMRI)/TRUS fusion biopsy. Methods: A review was performed of a prospectively maintained database of patients undergoing mpMRI followed by fusion biopsy (Fbx) and systematic biopsy (Sbx) from 2007−2016. The patients were stratified based on the timing of first biopsy in 3 groups. Cohort 1 included patients biopsied between 7/2007−12/2010, accounting for learning curve at our institution. Cohort 2 included patients biopsied from 1/2011 up to the debut of UroNav (Invivo) platform in 5/2013. Cohort 3 included patients biopsied after 5/2013. Clinically significant (CS) disease was defined as Gleason 7 (3+4) or higher. Cancer detection rates (CDR) between Sbx and Fbx during different time periods were compared using McNemar’s test. Age and PSA standardized CDRs were calculated for comparison between 3 cohorts. Results: 1528 patients were included in the study with 219, 549 and 761 patients included in 3 respective cohorts. Mean age, PSA and race distribution were similar across 3 cohorts. In cohort 1 there was no significant difference between CDR of CS disease by Fbx (24.7%) vs Sbx (21.5%), p = 0.377. Fbx was significantly better than Sbx in detection of CS disease in cohort 2 and cohort 3 (31.5% vs 25.3%, p = 0.001; 36.5% vs 30.2%, p < 0.001, respectively). There was significant decline in detection of low risk disease by Fbx compared to Sbx in the same period (cohort 2: 14.2% vs 20.9%, p < 0.001; cohort 3: 12.5% vs 19.5%, p < 0.001). Age and PSA standardized CDR of CS cancer by Fbx increased significantly between each successive cohort (cohort 1 and 2: 5.2%, 95% CI [2.1-8.5]), 2 and 3 (5.2%, 95% CI [1.8-8.6]). Conclusions: Our results show that after an early learning period using Fbx, CS prostate cancer was detected at significantly higher rates with Fbx than with Sbx, and low risk disease was detected at lower rates. Advances in software allowed for even greater detection of CS disease in the last cohort. This study shows that accuracy of Fbx is dependent on multiple factors; surgeon/radiologist experience and software improvements together produce improved accuracy.
Circulating tumor cells (CTCs) and plasma cell free DNA (cfDNA) androgen receptor amplification (ARamp)-based prognosis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Li Jian , Du Meijun , Hillman David W. , Tan Winston , Carlson Rachel , Wang Liguo , Wang Liewei , Liu Minetta C. , Zhang Huijuan , Zhang Peng , Wang Liang 
Published: March 2017

152 Background: Plasma cfDNA ARcopy number variations (CNV) have been suggested to have prognostic significance in mCRPC stage. We compared plasma AR amplification ( ARamp) with CTC counts (the only FDA approved prognostic marker in mCRPC stage) in a prospective trial of patients (pts) progressing on androgen deprivation therapy. Methods: Plasma and CTC counts were obtained concurrently as part of a prospective clinical trial in mCRPC stage pts initiating abiraterone acetate (NCT# 01953640). Plasma cfDNA was purified using DNA Blood Mini Kit (Qiagen, Valencia, CA) and AR CNVs were detected using QuantStudio3D digital PCR system (Life Technologies, Carlsbad, CA, USA). CTC enumeration was performed using the FDA cleared CellSearch platform. The distributions of overall survival (OS) time based on ARamp status and CTC counts ( < 5 vs ≥ 5 cells) were estimated using the Kaplan-Meier method. Log-rank tests were used to test association of ARamp status and CTC counts with overall survival (OS). Univariate and multivariate logistic regression models and ROC evaluated association of OS at 24 months by ARamp status and CTCs ≥ 5. Results: Between 05/2013 and 09/2015, 92 pts were enrolled of which complete CTC, plasma and outcome data was available for 70 pts. Median age of the cohort (range) was 72 yrs (39-91); Median PSA–16.2 ng/ml (range: 0.9-2026.0); Median CTC count was 2.0 (range: 0-372); 58/70 pts had bone metastases; 38/70 had high volume and 32/70 had low volume metastatic disease at the time of sample collection. The median (range) follow up time at the time of this analysis was: 26.5 (7.9-37.0) months at which time 28/70 patients had died. ARamp was present in 19/70 pts while 51/70 did not have amplification. 24/70 had CTCs ≥ 5. A significant association of increased ARamp status with OS (p < 0.0001, log-rank test; AUC: 0.66) as well as with CTC counts ≥ 5 (p = 0.001, log-rank test; AUC: 0.67) was observed. Combining CTC status and plasma ARamp status the AUC was 0.75. Conclusions: Plasma cfDNA ARamp status and CTC counts have comparable and clinically meaningful prognostic marker value in mCRPC stage patients.
Circulating androgen receptor and serum chromogranin A in castration-resistant prostate cancers (CRPC) patients treated with abiraterone and enzalutamide.
Authors: Conteduca Vincenza , Salvi Samanta , Casadio Valentina , Lolli Cristian , Gurioli Giorgia , Schepisi Giuseppe , Martignano Filippo , Menna Cecilia , Burgio Salvatore Luca , Testoni Sara , Attard Gerhardt , De Giorgi Ugo 
Published: March 2017

160 Background: Circulating aberrations (copy number/point mutation] of androgen receptor ( AR) as well as serum chromogranin A (CgA) have been associated to treatment response and clinical outcome in CRPC patients (pts) treated with abiraterone (abi)/enzalutamide(enza). Methods: We determined AR aberrations by digital PCR, Taqman and targeted-next generation sequencing on pre-treatment plasma from 169 CRPC pts treated with abi 1g/od (n = 96) and prednisone 5mg/bid or enza 160mg/od (n = 73) (Romanel, 2015; Salvi, 2015; Salvi, 2016). All pts were subdivided into 3 groups using receiver-operating characteristic (ROC) curves (Burgio, 2014; Conteduca, 2014) to evaluate properly the impact of CgA levels: serum CgA level was normal when < 120 ng/ml (group A,n = 76); within 3 times the upper normal value(UNV) when between 120 and 360(group B,n = 57), more than 3 times UNV when > 360(group C,n = 36). The primary endpoint was the correlation between AR aberrations and CgA level. The secondary endpoints were progression-free/overall survival (PFS/OS) and PSA response rate (RR) ( > 50% PSA decline after 12 weeks of therapy) stratified by AR status and CgA level. Results: We observed AR gain in 57(33.7%) of 169 pts, 29(30.2%) of 96 pts treated with abi and 28(38.3%) of 73 treated with enza. Circulating AR status was independent from baseline CgA levels in all pts (p = 0.36). In only AR-normal pts, we showed a significant survival difference among 3 CgA groups (P < 0.0001), particularly Group C vs. A+B [HR (hazard ratio) 5.1, 95%CI (confidence interval) 2.37-10.96 and HR 3.7 95%CI 1.79-7.69, respectively for PFS/OS]. We reported no difference of PFS/OS in AR-gained pts (P = 0.6 and P = 0.1, respectively with HR~0.6 in all CgA groups). In addition, group C vs. A+B had a significant PSA RR [P = 0.03 odds ratio (OR) 2.7 95%CI 1.02-7.30] in AR-normal pts. No PSA RR difference was observed in AR-gained pts (P = 1.0 OR 0.97 95%CI 0.18-5.26). Conclusions: In CRPC pts treated with abi/enza, baseline CgA levels may be an additional predictive/prognostic factor, especially in a particular set of CRPC pts with normal plasma AR status and worse treatment outcome. This association needs a prospective larger study.
Indomethacin to inhibit AKR1C3 intracrine androgen production and sensitizes prostate cancer (PCa) to enzalutamide.
Authors: Pan Chong-xian , Liu Chengfei , Lara Primo , Evans Christopher P. , Dall'Era Marc , Yap Stanley , Lou Wei , Gao Allen 
Published: March 2017

161 Background: Enzalutamide (Enza) improves the treatment of metastatic castration-resistant PCa (mCRPC). Acquired resistance is the most common cause of treatment failure. Our objective was to determine mechanisms of resistance to Enza and develop novel therapy to overcome resistance. Methods: Enza-resistant PCa cells were established through continuous culture of C4-2B cells with Enza. Global gene expression array and western blots were used to assess gene expression in cell lines and validated in clinical specimens using Oncomine and GEO databases. The therapeutic effects of indomethacin were determined in cell culture and in mice carrying CWR22Rv1 xenografts. A Phase I/II clinical trial with Enza plus indomethacin has been approved by IRB. Results: Steroid biosynthesis pathways, especially AKR1C3, were significantly elevated in Enza resistant cells and was associated with high production of androgens. AKR1C3 was also highly expressed in metastatic and recurrent CaP and in Enza-resistant xenograft tumors. Overexpression of AKR1C3 conferred resistance to Enza. Inhibition of AKR1C3 expression by its specific shRNAs or AKR1C3 enzymatic activity by indomethacin re-sensitized Enza-resistant CaP cells to Enza treatment both in vitro and in vivo. Combination of indomethacin and Enza resulted in significant inhibition of Enza-resistant tumor growth. Indomethacin treatment in one patient with mCRPC induced tumor shrinkage and PSA decrease. In a Phase I/II trial funded by the Department of Defense, patients with mCRPC, good performance status (ECOG 0-2) and vital organ function, and no history of Enza or indomethacin treatment will be recruited. The co-primary objective is to assess the toxicity and prostate-specific antigen (PSA) response ( ≥ 50% reduction). We will also assess the overall response as determined by the Prostate Cancer Working Group 2 criteria, progression-free survival and molecular correlative studies. Conclusions: AKR1C3 activation is a critical resistance mechanism associated with Enza resistance. Indomethacin targets AKR1C3 and intratumor androgen synthesis, and can be potentially used as a therapeutic agent for mCRPC. Clinical trial results will be presented. Clinical trial information: to be registered.
Randomized phase II trial of abiraterone +/- dasatinib for patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Quinn David I. , Pinski Jacek K. , Goldkorn Amir , Sadeghi Sarmad , Tsao-Wei Denice , Groshen Susan G. , Kuhn Peter , Gross Mitchell E. 
Published: March 2017

167 Background: Signaling via Src pathway is thought to be a mediator of resistance to androgen targeted therapy in mCRPC. We sought to determine whether adding the Src inhibitor dasatinib (Das) to abiraterone (Abi) would prolong progression free survival (PFS). Methods: Eligible patients had mCRPC which had progressed on androgen targeted therapies but no prior chemotherapy. Abi was prescribed at 1000 mg daily with prednisone 5 mg BID (both arms) and Das 100 mg daily added for Arm B. Primary endpoint was PFS at 24 weeks. Interim analysis planned after 48 subjects randomized but study terminated early due to lack of funding. PFS was evaluated using logrank testing and responses were compared using Fisher’s exact test. Circulating tumor cells (CTC) were evaluated with EPIC platform. Results: 26 men were randomized, 14 to Abi+Das and 12 to Abi. Median age was 67 (56-85), baseline PSA 19.8 (0.84-1387). Only 1 patient had received ketoconazole, none had received enzalutamide. With 30 months median follow-up, median PFS was 15.7 (95% CI:8.2, 31.1+) months for Abi+Das and 9 (95% CI: 4.4, 45.6+) months for Abi (p = 0.30). 86% were progression free at 24 weeks with Abi+Das compared to 75% on Abi. RECIST responses were seen in 5/14 (35%, 95% CI: 17%, 66%) with 2 CR on Abi+Das and 1/12 (8%, 95% CI (0%, 37%) on Abi (p = 0.16). With a specificity of 83%, the probability that the true rate of CR in intervention arm is higher or doubled (ex: 35% vs 17%) is 71%. Grade > 3 toxicities more common on Das arm included hypertension (43% vs 8% Abi), pleural effusion/dyspnea (14% vs 0 Abi), and gastrointestinal (25% vs 8%). CTC were detected at baseline in 8/17 evaluable patients (3/8 Abi, 5/9 Abi+Das), median 2.7 CTC/mL blood (range 0.5-59.7) At week 4, CTC increased in 1/8 (12.5%) on Abi vs 4/9 (44.4%) on Abi+Das but by week 12 CTC increases persisted in 2/8 (25%) on Abi and 1/9 (11%) on Abi+Das. Conclusions: Das did not significantly prolong PFS in combination with Abi although power was limited due to incomplete study cohort. Abi+Das was associated with robust objective responses including RECIST CR. Clinical trial information: NCT01685125.
A novel small molecule inhibitor of p300/CBP for the treatment of castration-resistant prostate cancer: Preclinical evaluation.
Authors: Brooks Nigel , Pegg Neil , Worthington Jenny , Young Barbara , Prosser Amy , Lane Jordan , Taddei David , Schiewer Matthew Joseph , Gordon Nicolas , Knudsen Karen E. 
Published: March 2017

168 Background: Targeted degradation of androgen receptor (AR) and androgen receptor variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferase proteins that act as transcriptional activators of AR. We have developed potent, selective and orally active small molecule inhibitors of the bromodomain of p300/CBP and investigated their role in regulating the expression and function of AR and ARV. Methods: Binding affinity to p300, CBP and BRD4 was measured in a surface plasmon resonance (SPR) assay and potency and functional activity was demonstrated in a panel of prostate cells lines representing hormone responsive (LNCaP), hormone independent (DU145, PC3) and castrate resistant disease (22Rv1, C4-2, VCaP, LNCaP-AR). Effects of p300/CBP inhibitors (and the BET inhibitor, JQ1), on AR, AR-V7 splice variant and c-Myc protein, as well as c-Myc, KLK3 and TMPRSS2 gene expression, were assessed in 22Rv1 cells in vitro. In vivoeffects on biomarkers were measured in a 22Rv1 xenograft model. Results: CCS1357, an in vitro probe compound, binds to p300 and CBP with high affinity (Kd=4nM) and selectivity (Kd=245nM; BRD4) and is a potent inhibitor of cell proliferation in castrate resistant cell lines (IC50=100nM in LnCaP-AR; 350nM in 22Rv1) with minimal effects in hormone independent lines. CCS1357 significantly down-regulated AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with JQ1 at equivalent proliferation IC50s. CCS1357 effects were reversed by the proteasome inhibitor, MG132. CCS1357 also caused a profound inhibition of c-Myc, KLK3 and TMPRSS2 genes measured by qPCR in 22Rv1 cells in vitro. A preclinical candidate (CCS1477) given as a single oral dose (30mg/kg) inhibited plasma PSA and tumour AR and AR-V7 in a 22Rv1 xenograft model. Conclusions: Small molecule inhibition of the bromodomain of p300/CBP, leads to down-regulation of AR, ARV and c-Myc as well as inhibition of key downstream PD biomarkers including PSA and TMPRSS2 and represents a promising new approach for the treatment of CRPC.
Impact of the primary information source used for decision making and implications for treatment regret in prostate cancer.
Authors: Shaverdian Narek , Kishan Amar Upadhyaya , Veruttipong Darlene , Jeffrey Demanes D. , Kupelian Patrick , McCloskey Susan Ann , Steinberg Michael L. , King Christopher R. 
Published: March 2017

17 Background: Patients with localized prostate cancer (PCa) assimilate information from varying sources to inform their treatment decision. We assessed the impact of the primary information source used to select a modern radiation treatment on patient perceptions of their treatment experience and on treatment regret. Methods: Patients with favorable-risk PCa treated with SBRT, IMRT or HDR brachytherapy and at least one year of follow-up were surveyed. The questionnaire explored the decision-making experience, expected treatment experience vs. the reality, and treatment regret via a validated tool. Multivariate logistic regression adjusted for demographics, disease characteristics, treatment modality, time since treatment and current bowel, urinary and sexual function. Results: 322 consecutive patients were surveyed with an 86% (n = 276) response rate. 48% (n = 132) selected their radiation oncologist as the primary information source, 23% (n = 62) selected their urologist, 16% (n = 44) selected the internet, 6% (n = 17) selected other patients and 8% (n = 21) selected other. Overall, 13% (n = 36) endorsed treatment regret. 39% of patients who selected the internet as their primary information source reported their actual treatment experience to be worse than expected vs. 13% of respondents who selected their urologist, 12% who selected other patients, 2% who selected their radiation oncologist and 9% who selected other ( p< 0.01). Similarly, 43% who selected the internet as their primary information source endorsed treatment regret vs. 10% who selected their urologist, 7% who selected their radiation oncologist, 6% who selected other patients and 6% who selected other ( p< 0.01). On multivariate logistic regression, only patients who selected the internet as their primary information source were more likely to endorse treatment regret (OR = 46.5, p< 0.01) and were more likely to choose a treatment they thought ‘had the least side effects’ (OR = 2.1, p= 0.016). Conclusions: Patients who used the internet as their primary source of information had a worse perception of their treatment experience and had more treatment regret, highlighting the need for physicians to proactively counsel patients.
Relationship between quality of life and overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients in ALSYMPCA.
Authors: Nilsson Sten , Sartor A. Oliver , Vogelzang Nicholas J. , Coleman Robert E. , O'Sullivan Joe M. , Shore Neal D. , Heinrich Daniel , Bottomley David , Hoskin Peter , Franzen Lars , Solberg Arne , Reuning-Scherer Jonathan D. , Zhan Lin , Parker Chris 
Published: March 2017

177 Background: Radium-223 improved overall survival (OS) with meaningful improvements vs placebo in health-related quality of life (HRQoL) in phase 3 ALSYMPCA (Parker NEJM 2013; Nilsson Ann Oncol 2016). We examined the relationship of OS to HRQoL scores at baseline or change from baseline. Methods: HRQoL in ALSYMPCA was assessed by FACT-P questionnaire at baseline, during treatment (wk 16, 24), and follow-up. Cox proportional hazards model for OS was fitted using HRQoL baseline scores and included previously identified covariates: treatment (radium-223 vs placebo); log10 baseline LDH, ALP, and PSA; age; baseline ECOG-PS; and albumin. A time-dependent model also included change from baseline HRQoL scores. Results: Analysis includedbetween 810-836 patients with baseline HRQoL scores for various FACT-P metrics. Significant associations were seen between OS and FACT-P total score at baseline or change from baseline. Every 10-point increase in FACT-P total score (ie, improvement) was associated with 7% decreased risk of death (Table). Results for FACT-P subscales were similar, except social well-being. Conclusions: This analysis of ALSYMPCA data shows that baseline HRQoL and changes in HRQoL are prognostic of OS in mCRPC. Clinical trial information: NCT00699751. [Table: see text]