bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world experience with docetaxel for castration-sensitive prostate cancer from a population-based analysis.
Authors: Lavoie Jean-Michel , Zou Kevin , Khalaf Daniel , Eigl Bernhard J. , Kollmannsberger Christian K. , Vergidis Joanna , Noonan Krista , Zulfiqar Muhammad , Finch Daygen L. , Chi Kim N. 
Published: February 2018

297 Background: Phase III clinical trials have demonstrated efficacy with an overall survival (OS) benefit for the addition of docetaxel (DOC) to androgen deprivation therapy (ADT) for the treatment of metastatic castration-sensitive prostate cancer (mCSPC). The clinical effectiveness of DOC with ADT in the general patient population remains undefined. Methods: A population-based retrospective review was conducted of patients (pts) with mCSPC who received DOC at the BC Cancer Agency from 04/2015 to 02/2017. Patient and disease characteristics were extracted. Safety and clinical-effectiveness were evaluated. Results: 183 records were identified; 156 pts received DOC in the mCSPC setting. Baseline characteristics included a median age of 67 years (range 44-86) and visceral metastases (mets) present in 18%; 80% had high volume disease with 74% having > 3, and 54% > 10 bone mets; 76% had de-novo metastatic disease. All 6 planned DOC cycles were delivered in 126 cases (81%); it was stopped early for: toxicity in 15 (10%), unrelated death in 1 (0.6%), pt preference in 5 (3%) or disease progression in 9 (6%) cases. Dose reductions and delays were required in 61 (39%) and 25 (16%) cases, respectively. Grade 3-5 adverse events were noted in 62 (40%) cases, with 28 (18%) cases of febrile neutropenia (FN); there were no treatment-related deaths. Pts with FN had more bone mets (p = 0.046), but there was no difference in time from start of ADT to initiation of docetaxel, age, baseline performance status, PSA, or visceral involvement. PSA ≤ 0.2 ng/L was achieved in 41 (28%) cases after 6 months of ADT and maintained in 13 (8%) cases after 12 months. 41% of pts had developed CRPC within 1-yr, with a median time to CRPC of 14.3 months. Treatment for CRPC was given in 54 cases, with most pts receiving either abiraterone or enzalutamide (87%) with a PSA decline ≥50% occurring in 47%. Conclusions: Effectiveness of DOC with ADT in a general population of pts with mCSPC was associated with poorer outcomes and high rates of toxicity compared to the phase III studies. Response rates to first-line treatment for mCRPC with abiraterone or enzalutamide appear similar to those previously reported.
TAS3681, a novel type of AR antagonist with AR downregulating activity, as a new targeted therapy for aberrant AR-driven prostate cancer.
Authors: Seki Masanao , Minamiguchi Kazuhisa , Kajiwara Daisuke , Mizutani Hiroya , Yoshida Shohei , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu 
Published: February 2018

298 Background: Recent reports suggest that AR aberrations are involved in the development of metastatic castration-resistant prostate cancer and in resistance to AR-targeted therapies. These aberrations include point mutations, copy number gain, and alternatively spliced AR forms. TAS3681 has demonstrated activity as a pure AR antagonist against several AR mutations and has shown an antitumor effect in an AR-v7 positive xenograft model. In order to further characterize the properties of TAS3681, we investigated its effects in cell-based AR overexpression/stabilization models and assessed the subcellular localization of FL-AR and AR-v7 in enzalutamide (Enz) -resistant cells. Methods: The Nano-bit assay was performed to analyze dimerization of FL-AR and AR-v7 proteins. Prostate cancer (PCa) cells expressing AR-v7 were treated with TAS3681, and nuclear and cytoplasmic fractions were prepared. Then the levels of FL-AR and AR-v7 protein in each fraction were determined by western blotting. AR-overexpressing PCa cells transfected with a wild-type AR expression vector were treated with TAS3681 in the presence of androgen. AR-stabilized PCa cells were transfected with a Speckle-type POZ protein (SPOP) mutant expression vector and then were treated with TAS3681. Results: AR antagonism by TAS3681 caused dose-dependent inhibition of FL-AR homodimerization (HD) and FL-AR/AR-v7 heterodimer formation in the presence of androgen. TAS3681 had no direct inhibitory effect on HD of AR-v7. However, AR downregulation by TAS3681 reduced nuclear AR-v7 protein in Enz-resistant cells under castration conditions. In AR-overexpressing PCa cells, TAS3681 reduced the AR protein and effectively suppressed both AR transactivation and cell proliferation. In contrast to Enz, TAS3681 also effectively reduced the AR protein in AR-stabilized PCa cells harboring SPOP mutation. Conclusions: TAS3681 suppresses aberrant AR activation, including AR overexpression and expression of constitutively active nuclear localized AR-v7, via downregulation of AR/AR-v7. These findings suggest that TAS3681 has the potential to overcome resistance to current AR-targeted therapies.
Evaluation of ability of low-molecular-weight protein tyrosine phosphatase expression to predict primary hormone therapy efficacy among men with metastatic hormone-naïve prostate cancer.
Authors: Hayashi Yutaro , Miyoshi Yasuhide , Yasui Masato , Ohtaka Mari , Kawahara Takashi , Yokomizo Yumiko , Hayashi Narihiko , Yao Masahiro , Uemura Hiroji 
Published: February 2018

316 Background: Protein tyrosine phosphorylation is an important event associated with the processes of cellular metabolism and is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Recent studies showed that low-molecular-weight protein tyrosine phosphatase (LMW-PTP) could be a biomarker for predicting overall survival among men with metastatic hormone-naïve prostate cancer (mHNPC). In this study, we evaluated the value of LMW-PTP expression for predicting primary hormone therapy efficacy among men with mHNPC. Methods: A total of 45 men with mHNPC diagnosed from 2003 to 2009 were enrolled in this retrospective study. All patients had received androgen ablation therapy as first-line treatment. Prostate cancer tissues obtained by needle biopsies before treatment were immunohistochemically stained for LMW-PTP. Correlations between the baseline clinical factors of age, PSA, Gleason scores, T stage, N stage, extent of disease on bone scan (EOD), LMW-PTP expression and primary hormone therapy efficacy (time to castration-resistant prostate cancer [CRPC]) were investigated by multivariate analysis using the Cox proportional hazard model. Continuous variables were classified as dichotomous. Results: Median age and PSA were 70.0 years and 87.8 ng/mL, respectively. Distribution number of Gleason score 8-10/6-7, T4/≤3, N1/0, and EOD 3-4/0-2 were 30 (66.7%)/15 (33.3%), 13 (28.9%)/32 (71.1%), 25 (55.6%)/20 (44.4%), and 7 (15.5%)/38 (84.5%). Median time to CRPC was 40.2 months. Patients with high LMW-PTP expression had significantly shorter time to CRPC than those with low expression (p = 0.005). Multivariate analysis showed that age (≥70 vs < 70, HR 2.5, 95%CI 0.96-6.32, p = 0.060) and LMW-PTP expression (high vs low; HR 3.3, 95%CI 1.2-8.6, p = 0.02) were significant prognostic biomarkers for predicting time to CRPC. Conclusions: LMW-PTP expression could be a potential biomarker for predicting primary hormone therapy efficacy among men with mHNPC.
Loss of RSPO3 as a potential mechanism of greater invasiveness in prostate cancer.
Authors: Mesci Aruz , Huang Xiaoyong , Shin David , Hoey Christianne , Ray Jessica , Liu Stanley K. 
Published: February 2018

333 Background: While prostate cancer can often manifest as an indolent disease, locally-advanced or metastatic disease can cause significant morbidity or mortality. Better understanding of molecular mechanisms leading to more aggressive presentations can lead to identification of prognostic or predictive biomarkers, as well as to possible therapeutic targets. Methods: We describe the generation of prostate cancer cell lines that have been selected through a course of hypofractionated radiotherapy. We show that R-spondin 3, a protein implicated previously as a marker of aggressive disease in colorectal and non-small cell lung cancer, is downregulated in these cell lines compared to parental cells. Then, we test the functional consequences of R-spondin 3 downregulation by siRNA-mediated interference using in vitro assays of radiation resistance, proliferation, and invasiveness . Experiments investigating any change in metastatic propensity following R-spondin 3 downregulation are forthcoming. We further investigate signaling pathways that may be implicated in the mechanism of R-spondin 3 action. Lastly, we use the Oncomine Platform to look for any changes in R-spondin 3 levels between normal prostate tissue and prostate adenocarcinoma. Results: Although siRNA-mediated loss of R-spondin 3 does not confer radiation resistance in vitro, it does result in increased invasiveness in Matrigel assays. Paradoxically, R-spondin 3 downregulation results in decreased proliferation. Interference with R-spondin 3 also results in decreased β-catenin, ERK, and Akt signaling, but increased JNK signaling. In support of our in vitro results, R-spondin 3 expression is lower in human prostate adenocarcinoma compared to normal prostate in several gene expression datasets. Conclusions: Our preliminary data suggest that R-spondin 3 loss may lead to increased disease aggression via altered cell signaling. R-spondin 3 downregulation may represent a potential biomarker to identify patients at greater risk of developing locally advanced or metastatic disease, or a potential mechanism to target in future therapeutic efforts.
Will second-line nonsteroidal antiandrogen drugs (NSAA) after the failure of bicalutamide affect the therapeutic efficacy of the sequential abiraterone treatment?
Authors: Zhao Jinge , Sun Guangxi , Zhang Xingming , Shen Pengfei , Chen Junru , Zeng Hao 
Published: February 2018

337 Background: Even in the era of novel targeted agents, second-line antiandrogens still have its effect on treating metastatic castration-resistant prostate cancer (mCRPC), especially for patients from undeveloped areas. Yet, it’s still uncertain if the prior use of second-line Non-steroidal antiandrogen Drugs (NSAA) would impact the efficacy of the sequential abiraterone (Abi) therapy. Methods: Eighty-seven patients from 2015 to 2017 were studied. All men were diagnosed with metastatic prostate cancer, and administrated with maximal androgen blockade (surgical or medical castration plus bicalutamide). After the median 32.0-Mo follow up, mCRPC was confirmed in the whole cohort. Abi was then administrated in these patients. Among them, 21 men previously received flutamide (FLU) as second-line NSAA hoping to postpone the initiation of the more expensive treatment. Therapeutic efficacy of Abi was analyzed and compared between those with and without prior second-line NSAA by Kaplan-Meier curves, Log-rank test and Cox regression models. Results: For patients with mCRPC, the prior exposure to FLU had no effect on the sequential treatment of Abi, in terms of either PSA progression-free survival (PSA-PFS, p = 0.967), radiographic progression-free survival (rPFS, P = 0.272), overall survival (OS, p = 0.606), or PSA response ( p = 0.370). However, when bringing ahead the observation point to the time of CRPC, those with second-line FLU showed better survival than those without, in either PSA-PFS (15.1 vs. 12.2-Mo, p = 0.120), rPFS (23.3 vs. 18.2-Mo, p = 0.029) or OS (not reach vs. 30.7-Mo, p = 0.306), though the difference of PSA-PFS and OS were not statistically significant. Conclusions: We firstly address the impact of the secondary NSAA on the efficacy of the sequential Abi treatment in mCRPC patients. Our study supported that, whether the patients received second-line NSAA prior to Abi should not be considered as an impact factor interfering physicians’ decision making of Abi treatment. Also, the switching treatment before Abi seemed to have a potential to extend the survival time of mCRPC patients by prolonging their PFS.
Cardiovascular comorbidities in German prostate cancer patients under androgen deprivation therapy: Results from a retrospective analysis of patient data in urological outpatient centers.
Authors: Eisenhardt Andreas , Vosgerau Sebastian , Gedamke Michael , Schneider Tim 
Published: February 2018

339 Background: Androgen deprivation therapy (ADT) with LHRH agonists leuprolide/goserelin compared to GnRH antagonists has been associated with higher risk for cardiovascular (CV) disease in patients with hormone-sensitive prostate carcinoma (hsPCa). Real life data from German PCa-patients with CV disease treated with ADT are lacking. Our study aimed to analyze occurrence of comorbidities with a focus on CV disease in hsPCa-patients treated with ADT. Methods: HsPCa-patients with initiation of ADT (1999–2014) and an ADT duration of a minimum of 12 months were included. Data were collected retrospectively from medical records and documented in a standardized electronic case report form by three German urological outpatient centers. Primary outcomes of interest were frequency of CV disease and hospitalization due to CV events. Descriptive statistics were performed. An ethics committee approval was obtained from Ärztekammer Nordrhein. Results: Data from 753 patients were evaluated. The mean and median age of patients was 75.4 years and 77 years. 556 patients were treated with a LHRH agonist, 59 with an antiandrogen, 132 with a LHRH agonist and an antiandrogen and 6 with a GnRH antagonist. CV disease was the most common comorbidity (241 patients), also when patients with hypertension as the sole CV comorbidity were disregarded (111 patients). 44 patients were hospitalized due to a CV event during or subsequently to an ADT. Of these, 27 patients initiated ADT with pre-existing CV disease. Overall, 21 patients were hospitalized due to myocardial infarction or stroke. Conclusions: Our results show CV disease as the most common comorbidity in German hsPCa-patients, yet our methods could be underestimating CV disease in this interdisciplinary field. Before initiating an ADT, the patient's CV risk profile should therefore be evaluated carefully. The literature suggests that different ADT types are associated with different CV risk, thus the choice of ADT should be considered to reduce the risk of additional CV events. Besides cost savings to health care systems, patients gain quality of life through prevented CV events.
Difference of genomic signatures and opportunities for targeted and immunotherapies in castrate resistant TMPRSS2:ERG fusion positive and TMPRSS2:ERG wild type refractory acinar (CRPC) and neuroendocrine prostate cancer (CRNEPC).
Authors: Bratslavsky Gennady , Fisher Hugh A.G. , Byler Timothy , Jacob Joseph M , Chung Jon , Elvin Julia Andrea , Vergilio Jo-Anne , Ramkissoon Shakti , Suh James , Severson Eric Allan , Daniel Sugganth , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. , Kotula Leszek , Ross Jeffrey S. 
Published: February 2018

348 Background: We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with refractory CRPC and CRNEPC. Methods: DNA was extracted from 40 µm of FFPE sections of 2,424CRPC and 143 CRNEPC. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median ages for all 4 groups was similar (Table). TMPRSS2+( TMP+) CRPC features significantly greater TP53 and PTEN GA and TMPRSS2-( TMP-) CRPC featured higher MYC and ATM GA. Differences in BRCA2 and RB1 GA were not significant in the CRPC group. RB1 GA were more frequent in CRNEPC than CRPC. TP53 GA were higher in TMP+ CRNEPC than in TMP+ CRPC whereas GA in PTEN and MYC were similar in comparative groups. GA in AR and ATM were more frequent in CRPC than CRNEPC. The median TMB was higher in CRNEPC than CRPC and higher in TMP- than TMP+ tumors. TMP- CRPC and TMP- CRNEPC had higher TMB levelsthan TMP+ tumors in both groups. MSI-High status was more frequent in the TMP- CRPC and TMP- CRNEPC groups. Conclusions: For CRPC but not CRNEPC, the frequency of TMP+CRPC cases appears lower in advanced vsearly stage disease (TCGA data). CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMP+ and TMP- CRPC and CRNEC. Thus, when CRPC and CRNEPC areevaluated as to their TMPRSS2:ERG fusion status, significant genomic differences emerge which may impact therapy selection.[Table: see text]
Effect of bypass kinase pathways on acquired CDK4/6 inhibitor resistance.
Authors: De Leeuw Renee , McNair Christopher , Schiewer Matthew Joseph , Neupane Neermala Poudel , Augello Michael , Li Zhen , Cheng Larry , Yoshida Akihiro , Diehl Alan , Hazard Starr , Courtney Sean , Hardiman Gary , Hussain Maha , Drake Justin , Kelly William Kevin , Knudsen Karen E. 
Published: February 2018

379 Background: Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors have shown clinical benefit in treatment of solid tumor types, including breast cancer. However, resistance is common, and the underpinning mechanisms of action are not well understood. Given the dependence of CDK4/6 inhibitors on retinoblastoma tumor suppressor (RB) function for activity, this class of agents may be particularly effective in tumor types for which RB loss is infrequent or occurs late in tumor progression. Methods: Here, models of acquired palbociclib resistance were generated in early stage, RB positive cancers, wherein it was shown acquired palbociclib resistance resulted in cross-resistance to other CDK4/6 inhibitors under clinical testing. Results: Cells showing acquired resistance exhibited aggressive in vitro and in vivo phenotypes without genetic loss of RB or RB pathway members, including enhanced proliferative capacity, migratory potential, and characteristics of epithelial to mesenchymal transition. Further analyses through integration of RNA sequencing and phospho-proteomics identified activation of the MAPK signaling pathway as a mediator of CDK4/6 inhibitor resistance, capable of bypassing CDK4/6 activity. However, this altered kinase dependence resulted in sensitization to MEK inhibitors, suggestive of new clinical opportunities in CDK4/6 resistant tumors. Conclusions: In sum, the studies herein not only identify activation of the MAPK pathway as capable of bypassing the CDK4/6 requirement and promoting aggressive tumor characteristics, but nominate MEK inhibitors as potential mechanisms to treat or prevent CDK4/6 inhibitor resistance.
Evaluating the impact of African American ancestry among men with localized prostate cancer treated with radical prostatectomy.
Authors: Canter Daniel , Reid Julia E. , Latsis Maria , Variano Margaret , Halat Shams , Gurtner Kristen E. , Brawer Michael K. , Stone Steven , Bardot Stephen 
Published: February 2018

41 Background: Prostate cancer (PC) is the most common male malignancy. Prior data has suggested that African American (AA) men present with more aggressive disease relative to men of other ancestries. Here, we examined the effects of ancestry on clinical and molecular measures of disease aggressiveness as well as pathologic outcomes in men treated with radical prostatectomy (RP) for localized PC. Methods: Data was collected from patients undergoing RP at the Ochsner Clinic from 2006 to 2011. Formalin−fixed paraffin embedded biopsy tissue was analyzed for the RNA expression of 31 cell cycle progression (CCP) genes and 15 housekeeping genes to obtain a CCP score (a validated molecular measure of PC aggressiveness). Cancer of the Prostate Risk Assessment (CAPRA) scores were also determined based on clinicopathologic features at the time of diagnosis. Clinical (Gleason score, tumor stage, CAPRA score) and molecular (CCP score) measures of disease aggressiveness were compared based on ancestry (AA versus non−AA). Cox proportional hazards models were used to test association of ancestry to biochemical recurrence (BCR) and progression to metastatic disease. Fisher’s exact and Wilcoxon rank sum tests were used to compare ancestries. Results: A total of 384 patients were treated with RP, including 133 (34.8%) AA men. At the time of diagnosis, the median age was 62 years (interquartile range (IQR) 56, 66) and PSA was 5.4 ng/mL (IQR 4.2, 7.6). When compared by ancestry, there were no significant differences in biopsy Gleason score (p = 0.26), clinical stage (p = 0.27), CAPRA score (p = 0.58), or CCP score (p = 0.87). In addition, there was no significant difference in the risk of BCR between ancestries (p = 0.55). Only non−AA men progressed to metastatic disease within the ten years of follow−up. Conclusions: Contrary to prior reports, these data appears to indicate that men of AA ancestry do not necessarily present with or develop a more biologically aggressive form of PC. Although these data represents only one institution’s experience, it contains a highly robust AA population compared to prior reports. Further research is required to account for the discrepancy in the previously published literature.
Perceptions about cancer clinical trials among prostate cancer survivors.
Authors: Buzaglo Joanne S. , Miller Melissa F , McManus Shauna , Johnson Jamese , Zaleta Alexandra Katherine 
Published: February 2018

42 Background: Recruitment into cancer clinical trials (CCTs) remains challenging despite efforts to enhance patient understanding of and access to CCTs. We examined perceptions of CCTs among prostate cancer (PC) survivors. Methods: 86 PC survivors enrolled in Cancer Support Community’s Cancer Experience Registry online research platform, provided demographic and disease history, and rated their agreement (0 = strongly disagree; 4 = strongly agree) with 8 CCT statements. We examined bivariate associations between CCT counseling and individual factors via Spearman’s rank correlation and chi-square tests. Results: Participants were 95% White; mean (SD) age = 65 (7) years; time since diagnosis 4 (4) years. 24% had surgery, 34% underwent radiation, 20% both; 31% currently and 18% previously received hormone therapy. 32% were diagnosed 5+ years ago; 22% reported recurrence, 31% metastatic disease. 33% reported that their health care team spoke to them about participating in a CCT, with a non-significant trend for lower prevalence if all or part of care was received at a community hospital/cancer center (24%) vs. at an academic or comprehensive cancer center or private oncology practice (47%; χ2= 3.03, p = .082). 25% did not receive information about CCTs from the health care team prior to making a treatment decision. 21% reported there was a CCT available to them; 35% considered a CCT for treatment; 11% participated in a CCT. Regarding beliefs about CCTs (% agree or strongly agree): 64% felt uncomfortable with treatment random assignment; 52% feared receiving a placebo; 40% feared treatment side effects; 23% believed health insurance would not cover a CCT; 16% believed no clinical trials are available in their community; 16% felt mistrust and fear of being used as a “guinea pig” for research; 11% had concern about logistical barriers, e.g., transportation; 6% did not understand what CCTs are. Conclusions: Many prostate cancer survivors are uncomfortable with random assignment to treatment in a CCT and fear receiving a potentially ineffective placebo. Our findings underscore the need for comprehensive treatment decision counseling and patient education via health care providers and patient advocacy organizations.