bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer: A network meta-analysis.
Authors: Hird Amanda Elizabeth , Magee Diana E. , Bhindi Bimal , Ye Xiang Y. , Chandrasekar Thenappan , Goldberg Hanan , Klotz Laurence , Fleshner Neil , Satkunasivam Raj , Klaassen Zachary William Abraham , Wallis Christopher J.D. 
Published: February 2020

131 Background: Novel non-steroidal anti-androgens (NSAAs) including enzalutamide, apalutamide, and darolutamide with androgen deprivation therapy (ADT) have proven efficacy in men with high-risk non-metastatic castrate resistant prostate cancer (nmCRPC). However, in the absence of direct comparative trials, there is little evidence to guide therapeutic choice. Our objective was to perform a network meta-analysis to compare agents and perform a class-level meta-analysis of NSAAs with androgen deprivation therapy (ADT) versus ADT-alone. Methods: We performed a systematic review of phase III parallel-group RCTs in men ≥18 years of age with nmCRPC using EMBASE and MEDLINE, indexed as of March 8, 2019. Our primary outcome was metastasis free survival (MFS). Secondary outcomes included OS, PSA progression free survival (PFS), and rates of grade 3-4 adverse events (AEs). Three RCTs were identified. We performed a random effects meta-analysis of NSAA versus ADT-alone using the inverse variance technique for meta-analysis for efficacy outcomes and the Mantel-Haenszel method for meta-analysis of dichotomous data for AEs. We then performed a network meta-analysis to compare outcomes between NSAAs using fixed-effect models in a Bayesian framework. We estimated the relative ranking of the different treatments for each outcome. Results: Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (HR:0.32,95%CI:0.25-0.41, HR:0.08,95%CI:0.05-0.13, and HR:0.74,95%CI:0.61-0.90, respectively). Apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. There was a 61% chance that darolutamide was preferred with respect to AEs. Conclusions: NSAAs improve survival outcomes in patients with high-risk nmCRPC. Apalutamide and enzalutamide may offer improved oncological outcomes. Darolutamide may result in fewer adverse events. These differences, if confirmed, would be meaningful to patients and practitioners when selecting treatment.
Contribution of extragonadal steroids to the androgen receptor activity and to the castration-resistance development in recurrent prostate cancers after primary therapy.
Authors: Pouliot Frederic , Rouleau Mélanie , Neveu Bertrand , Toren Paul , Morin Fannie , Vélot Lauriane , Ding Keyue , Caron Patrick , Lacombe Louis , Levesque Eric , Klotz Laurence , Guillemette Chantal 
Published: February 2020

148 Background: Beyond testosterone, several steroids contribute to the activation of the androgen receptor (AR) pathway, but their relative contributions in castrated prostate cancer (PCa) patients remain unknown. Methods: Serum levels of nine steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (n=219) and from the PCA24 cohort (n=116). For each steroid, standard curves for dose-dependent prostate-specific antigen promoter activation were built in castration-sensitive (LAPC4) and resistant (VCaP) PCa models. Standard curves were used to determine the AR activation potency for each steroid measurement from patients. Results: In LAPC4 and VCaP cells, testosterone, dihydrotestosterone and androstenedione induced AR transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol, androsterone stimulated AR only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total AR transcriptional activity found in castrated patients. The total AR transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR=2.17; 95% CI: 1.12-4.23; p=0.02) in multivariate analysis using the castration-sensitive model (LAPC4). AR transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR=1.89; 95% CI: 1.04-3.44; p=0.036). Conclusions: Extragonadal steroids contribute significantly to the AR axis activation at testosterone castration levels in recurrent non-metastatic PCa and these sustain the development of castration resistance after primary local treatment.
Defining the monocyte subset transcriptional signature associated with progression during androgen-target therapy in prostate cancer patients.
Authors: Cavassani Karen Angelica , You Sungyong , Meza Rebecca , Santiskulvong Chintda , Goodridge Helen , Posadas Edwin M. 
Published: February 2020

157 Background: Myeloid-derived circulating monocytes are emerging as cells of interest in cancer biology. The role of circulating monocytes in human Prostate Cancer (PCa) is poorly understood. Here we asked what is the association of monocyte-specific subsets and their transcriptional signatures with PCa progression during (AR)-target therapy. Methods: Single-cell RNAseq analysis were performed in blood monocytes from 4 patients at two specific time points over their clinical, course: T1)responding to next generation androgen receptor signaling inhibitors (e.g. abiraterone or enzalutamide) as reflected by a decline in serum PSA and/or radiographic response, and T2)progressing through treatment as detected by increases in the serum PSA concentration and/or radiographic signs of progression .PBMC were subjected to Ficoll-purification, and FACS sorted to exclude dead cells and cells expressing B- and T- lineage markers. Samples were then pooled using a BD™ Single-Cell Multiplexing Kit. The samples for scRNA-seq analysis included monocytes defined as classical CD14++CD16−, intermediate CD14+CD16+, and non-classical CD14low/-CD16+++. Results: We have observed nine (9) transcriptionally-defined clusters.Clusters 0, 1, 4, 5, and 8 mapped closely to that of classical monocytes with high expression of CD14and low expression of FCG3RA (CD16). Clusters 2 and 3 mapped closely to that of NK cells with high expression of FCG3RA(CD16) and KLRB1(CD161), and clusters 6 and 7 corresponded to CD14low FCG3RAhigh SIGLEC10+ monocytes. Importantly, our preliminary data revealed a decrease in the percentage of cells in clusters 2 and 6 and an increase in the percentage of cells in cluster 4 in progressing patients (T2). At the transcriptional level, the three main clusters (classical, non-classical, NK-like) were distinguished by 32, 33, and 72 genes, respectively. Our preliminary findings show that progression was associated with several innate immune transcripts while cytotoxic genes were associated with response to Enzalutamide. Conclusions: These data suggest that monocytes transcriptional signature may be reshaped by PCa. Further study of monocytes in PCa progression are warranted.
Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study.
Authors: Fizazi Karim , Kramer Gero , Eymard Jean-Christophe , De Bono Johann S. , Sternberg Cora N. , TOMBAL Bertrand F. , Castellano Daniel , Wülfing Christian , Liontos Michail , Carles Joan , Iacovelli Roberto , Melichar Bohuslav , Sverrisdottir Asgerour , Theodore Christine , Feyerabend Susan , Helissey Carole , Picard Pascaline , Ozatilgan Ayse , Geffriaud-Ricouard Christine , De Wit Ronald 
Published: February 2020

16 Background: The CARD NCT02485691 study reported superior rPFS and OS with CBZ vs abiraterone or enzalutamide in patients with mCRPC who progressed on docetaxel and within 12 months on a previous alternative androgen-signaling-targeted inhibitor (ARTA). This analysis evaluated changes in pain and HRQL associated with CBZ and ARTA during the CARD study. Methods: Pain response was defined as a decrease > 30% from baseline in BPI-SF pain intensity score with no increased analgesic use. HRQL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had a baseline FACT-P score plus at least one subsequent FACT-P measurement. A clinically meaningful improvement or deterioration of total FACT-P score was defined as a difference of ± 10 points from baseline. Clinically meaningful changes in HRQL and pain response were confirmed at two consecutive evaluations ≥ 3 weeks apart during the on-treatment period. Survival curves were generated by Kaplan–Meier estimates. Results: Of the 255 patients randomized, 172 (67.5%) had moderate to severe pain at randomization. Pain response and HRQL were evaluable for 111 (86.0%) and 108 (83.7%) for CBZ and 109 (86.5%) and 114 (90.5%) for ARTA. Pain response was 45.9% vs 19.3% for CBZ vs ARTA (p < 0.0001). The probability of not having pain progression after 12 months was 66.2% vs 45.3% CBZ vs ARTA (HR 0.55; 95% CI 0.32–0.97; p = 0.0348). An improvement in total FACT-P score from baseline was reported by 27 (25.0%) patients vs 26 (22.8%) for CBZ vs ARTA. FACT-P score was maintained or improved for 81 (75.0%) patients with CBZ and 86 (75.4%) patients with ARTA. A deterioration in FACT-P from baseline was reported by 22.2% with CBZ vs 24.6% with ARTA. Median time to FACT-P deterioration was 14.8 months for CBZ vs 8.9 months for ARTA (HR 0.72; 95% CI 0.44–1.20; p = 0.2072). Conclusions: CBZ was associated with a greater pain response and delayed pain progression vs ARTA. CBZ and ARTA were associated with similar trends in HRQL but time to FACT-P deterioration was longer with CBZ vs ARTA. Clinical trial information: NCT02485691.
Prostate cancer CTC-RNA Assay: A new method for contemporary genomics and precision medicine via liquid biopsy.
Authors: Teng Pai-Chi , Jan Yu Jen , Chen Jie-Fu , Kim Minhyung , Yao Nu , Garraway Isla , Chu Gina Chia-Yi , Chen Pin-Jung , Wang Jasmine Jiemei , Lee Yi-Te , Zhu Yazhen , Chung Leland WK , Feng Felix Y , Freeman Michael , You Sungyong , Tseng Hsian-Rong , Posadas Edwin M. 
Published: February 2020

170 Background: Transcriptome-based analysis has begun to reshape the approach to prostate cancer (PC). Two different gene expression signatures have shown that PC can be divided into 3 subclasses reflecting luminal-basal biology. These subtypes point toward biological drivers that may strongly influence how care should be personalized including optimization of androgen receptor targeted therapy. The majority of work done in this area has been based on tissue-based gene expression. With the advent of newer nanotechnology platforms for isolation of circulating tumor cells (CTCs), profiling of PC gene expression from blood is now possible. Methods: We recruited 34 patients with metastatic castration resistant PC at Cedars-Sinai Medical Center who had available blood specimens prior to initiation of androgen receptor signaling inhibitor (ARSI, e.g. abiraterone, enzalutamide and apalutamide) therapy.We utilized the NanoVelcro Assays which allow for capture and release of CTCs with intact mRNA. Gene sets from the PCS and PAM50 signatures were re-reviewed to optimize signal detection in the blood and enriched for genes upregulated in PC. The NanoString nCounter platform was used for RNA profiling. Results: The final assay was tested in banked blood samples and provided classifications of patients that associated with clinical responsiveness to therapy. Validation was conducted to examine the performance of the CTC-specific PCS/PAM50 panel in public databases (including Prostate Cancer Transcriptome Atlas and GenomeDx). Our pilot study showed that the median overall survival was significantly worse in PCS1 patients. Conclusions: This study shows initial proof of principle that genomic classification in blood is possible using contemporary tool for blood component isolation and RNA profiling. Additional technical and clinical validations are needed prior to widespread implementation, but these methods may make it possible to increase the utilization of genomic classifiers in clinical studies and in practice.
Circulating-free DNA (cfDNA) as biomarker of taxane resistance in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Francini Edoardo , Ou Fang-Shu , Rhoades Justin , Wolfe Eric G. , O'Connor Edward , Ha Gavin , Gregory Gydush , Kelleher Kaitlin , Bhatt Rupal Satish , Balk Steven P. , Sweeney Christopher , Adalsteinsson Viktor , Taplin Mary-Ellen , Choudhury Atish Dipankar 
Published: February 2020

174 Background: Docetaxel (D) and cabazitaxel (C) are standard chemotherapies for mCRPC. A reliable biomarker predictive of resistance to D or C is yet to be identified. We aimed to assess the association between genetic amplification of the multidrug resistance transporter ABCB1 (ABCB1 amp) and primary resistance (RES) to D or C for mCRPC, using cfDNA. Methods: A cohort (A) of 136 patients (pts) with at least 1 plasma sample drawn and stored within 1 year prior to starting D for mCRPC (2002-2014) and a cohort (B) of 42 pts with at least 1 plasma sample from within 1 year prior to starting C for mCRPC (2010-2016) were identified from the Dana-Farber Cancer Institute IRB approved database. Whole genome sequencing (WGS) at 0.1x coverage, termed ultra-low pass WGS (ULP-WGS), was performed on cfDNA extracted from the selected samples (1000μL/subject) and sequencing data were analyzed using a tool called ichorCNA to identify cases with sufficient tumor DNA content (>7%) for accurate detection of copy number alterations (CNAs) including ABCB1 amp. Primary objective was the association between ABCB1 amp and RES to D or C. RES was defined as lack of response (no PSA50 decline or radiologic response per RECIST criteria 1.1, within 4 months from treatment start). Odds ratio (OR) was used to compare odds of RES to D or C for pts with ABCB1 amp and P-values were calculated by Fisher’s exact test. Results: Of the selected 178 pts, 66 had tumor fraction >7%: 45 pts in cohort A and 21 in cohort B. No significant association was noted between ABCB1 amp and RES to D (P=0.7123; OR=1.600) or C (P=1.000; OR=1.0606). RES was observed in 26 pts (57.8%) of cohort A and 18 (85.7%) of cohort B. ABCB1 amp was found in 9 pts (20%; 95% CI, 9.6-34.6) in group A and 6 of them (66%) had RES to D. ABCB1 amp rate among D-resistant men was 23.1% (95% CI, 9.0-43.7). In group B, 2 pts (9.5%; 95% CI, 1.2-30.4) had ABCB1 amp and both of them had RES to C. ABCB1 rate among C-resistant pts was 11.1% (95% CI, 1.4-34.7). Conclusions: In this study, ABCB1 amp using cfDNA did not show statistically significant correlation with RES to D or C for pts with mCRPC. Future studies including ABCB1 amp in a suite of putative biomarkers and larger sample size may aid drawing definitive conclusions.
The association between PSA pattern changes and progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with abiraterone and prednisone (AA/P).
Authors: Sheng Iris Yeong- Fung , Fallah Jaleh , Gupta Ruby , Li Hong , Allman Kimberly D. , Martin Allison , Barata Pedro C. , Ornstein Moshe Chaim , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. 
Published: February 2020

18 Background: Despite treatment with AA/P, many patients with mHSPC will develop castrate resistant disease (CRPC). Early recognition of progression is difficult. Changes in PSA patterns in patients with mHSPC treated with AA/P may help identify evolution to mCRPC. Methods: All patients with mHSPC who initiated ADT and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months (mo) from AA/P initiation. Time to PSA<0.03 and CRPC were estimated using Kaplan-Meier method. Progression was defined as a PSA rise at two consecutive time points. Results: Of the 143 patients who initiated AA/P, 134 men (median Gleason score 8, baseline PSA 15.0 ng/mL) with follow up were included. 52% had de novo mHSPC, 47.8% had prior therapy (21% surgery, 20% radiation, 7% both), and 16% had visceral disease. PSA levels dropped 98.2% in the first 3 mo (p<0.001), slowed from 3-9 mo (p<0.05) and plateaued after 9 mo. The % PSA reduction from time 0 to the other time points was small. The median time to PSA<0.03 was 11 mo. Of those who progressed to CRPC, the reduction within the first 3 mo was more significant than in those who did not (Table). Measurable PSA was higher in patients who progressed to CRPC at all-time points and plateaued by 6 mo. 12-mo CRPC-free after AA/P was 86.7% (95% CI: 79.2, 94.1). Patients with ≥ 98% 3-mo PSA reduction had better CRPC-free survival than patients with <98% reduction (12-mo CRPC-free: 94.4% vs 78.4%), p<0.001. Conclusions: The degree of PSA decline within 3 mo of AA/P may be used as treatment efficacy measurement. Tracking PSA pattern changes may alert clinicians for potential progression, consider frequent PSA and imaging, as well as initiate sequential therapy.[Table: see text]
CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.
Authors: Hupe Marie C. , Offermann Anne , Schreiber Cleopatra , Merseburger Axel Stuart , Perner Sven 
Published: February 2020

181 Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (<1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (>50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p<0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p<0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.
Comparison of Caucasian and African-American DNA repair alterations in men with metastatic prostate cancer.
Authors: Jaeger Ellen , Burgess Earle Frederick , Zhu Jason , Dellinger Beth , Elrefai Sara , Hatton Whitley , Moses Marcus W. , Lankford Anjali , Zaheri Alexa , Ledet Elisa Marie , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver 
Published: February 2020

199 Background: Data on germline DNA repair defects and VUS rates are sparse in African American (AA) men with metastatic prostate cancer (PCa). Methods: Germline testing data from two centers with a significant percentage of metastatic AA PCa patients were combined and compared to Caucasian American (CA) with metastatic PCa. Fourteen canonical DNA repair genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D) were assessed in all tested patients (pts) using a pathogenic/likely pathogenic (P/LP) classification. Variants of unknown significance (VUS) were assessed in an Invitae-derived dataset with consistent VUS reporting. Results: A total of 105 AA men with metastatic disease were evaluated and 7/105 of these men (6.67%) had P/LP alteration. Among the AA pt alterations, there were 4 pts with BRCA2, 2 pts with BRCA1, and 1 pt with PALB2. A total of 39/417 (9.3%) of CA metastatic patients had P/LP alterations in the canonical 14 genes. No differences were detected in the AA vs CA metastatic comparison (p=0.39). A total of 1/105 (0.95%) AA pts and 23/418 (5.5%) CA had non-BRCA P/LP mutations. The number of non-BRCA P/LP mutations were lower in the AA as compared to the CA men (p=0.045). When evaluating VUS calls in the metastatic AAs using Invitae multi-gene panels, 28/92 (30.43%) pts had a VUS in the canonical 14 genes as compared to 67/366 (18.31%) of the CA men. AAs were more likely than CA to have a VUS (p=0.010). These data indicate that metastatic AA pts and CA are not significantly distinct in the P/LP alterations in 14 canonical DNA repair genes but that there were lower percentages of P/LP in the AA non-BRCA gene subset. Further, when assessing these genes, it is clear that a VUS is more likely to be called in the AA men. Conclusions: Among men with metastatic PCa, AAs have similar rates of inherited P/LP alterations in 14 well accepted DNA repair genes as compared to CA men, however the non-BRCA gene P/LP alterations were less frequent among the AAs. Variants classified as a VUS were clearly higher in these AA pts as compared to the CA pts.