bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient characteristics at time of prostate cancer diagnosis in different races at an academic center serving a diverse population.
Authors: Suresh Tejas , Gao Qi , Kim Mimi , Goel Sanjay , Gartrell Benjamin Adam
Published: February 2017

158

Background: In the United States, prostate cancer (PCa) incidence and death rate differ among racial groups. Non-Hispanic Blacks (NHB) have a higher incidence and death rate than non-Hispanic Whites (NHW), whereas incidence and death rate are slightly lower in Hispanics (H) than in NHW. We sought to compare the socioeconomic, demographic and baseline prognostic factors at PCa diagnosis among different races at a large, urban academic center serving a diverse population. Methods: Following institutional review board approval, the Montefiore Medical Center Cancer Registry was used to generate a comprehensive list of patients diagnosed with PCa 2004 to 2013. Clinical Looking Glass (a searchable database of patient information) and individual patient chart review were used to obtain data including age at diagnosis, socioeconomic score (SES), Gleason score, stage at diagnosis and PSA at diagnosis. Patients were classified by self-identified race as H, NHB or NHW. For categorical variables the chi-square test was used, whereas the ANOVA or the Kruskal-Wallis tests were employed for continuous variables. Results: During the specified period 2352 patients were diagnosed with PCa among which 778 were self-classified as H, 1046 as NHB, 486 as NHW and 42 as other (O). The mean age at diagnosis differed between these groups (H 63.2, NHB 63.4, NHW 67, O 63.0, p < 0.0001). The proportion of men below the mean SES also differed between races (H 92.8%, NHB 91.3%, NHW 56.6%, O 75%, p < 0.0001). Median PSA (ng/ml) at diagnosis was similar (H 8.0, NHB 8.4 NHW 7.2, O 6.4, p = 0.0768) whereas Gleason score differed between racial groups (Gleason ≤ 6: H 42.8%, NHB 39.1%, NHW 52.2%, O 50%; Gleason 8-10: H 15.8%, NHB 17.6%, NHW 14.3%, O 16.7%, p = 0.0005). The proportion of men with metastatic disease at diagnosis also differed significantly in these groups (H 7.5%, NHB 9.0%, NHW 4.3%, O 9.5%, p = 0.0139). Conclusions: At our center, in patients with newly diagnosed PCa, there are significant differences among racial groups. These include age at diagnosis, SES, Gleason score and proportion with metastatic disease. Such differences at diagnosis suggest that minority patients are at risk for inferior PCa outcomes.
Combined impact of diet and lifestyle after diagnosis on risk of prostate cancer death.
Authors: Kenfield Stacey A.
Published: February 2017

159

Background: Several lifestyle factors have been independently associated with prostate cancer progression and mortality, but little is known about their combined effect.Our objective wasto develop scores based on post-diagnostic diet and lifestyle behaviors for the prevention of prostate cancer death. Methods: We developed four scores (food-only: range 0-5; food & drinks: range 0-8; lifestyle-only: range 0-3; food, drinks & lifestyle: range 0-11) among 3,583 men in the Health Professionals Follow-Up Study diagnosed with non-metastatic prostate cancer in 1986-2008 with follow-up through 2012. Potential factors and their cut-points were based on the literature. One point was given for each factor: not currently smoking or quit ≥ 10 years ago, BMI < 30 kg/m2, ≥ 3 h/wk vigorous activity or ≥ 7 h/wk brisk walking, ≥ 1 serv/d cruciferous vegetables, ≥ 3 serv/wk nuts or oil-based dressings, ≥ 4 cups/d coffee, ≥ 7 serv/wk wine, < 2 serv/wk processed meat, 0 serv/wk poultry with skin or poultry sandwiches, and < 140 ug/d of supplemental selenium. We used multivariable Cox proportional hazards regression. Results: We observed 240 prostate cancer deaths during a median of 11 years follow-up. A 1-unit increase in each score was associated with a similar reduction in risk of prostate cancer death: food-only (HR = 0.71; 95%CI = 0.60,0.85); food & drinks (HR = 0.71; 95%CI = 0.61,0.82); lifestyle-only (HR = 0.72; 95%CI = 0.56,0.92); and total diet & lifestyle (HR = 0.71; 95%CI = 0.63,0.81). Men with 3 vs 0-1 points for the lifestyle-only score had a 51% decreased risk of prostate cancer death (95%CI = 0.28,0.83); men with ≥ 5 vs 0-2 points on the food & drinks score had a 73% decreased risk of prostate cancer death (95%CI = 0.14,0.51); and men with 4-7 and 8-11 vs 0-3 points for the total diet & lifestyle score had a 48% (95%CI = 0.32,0.84) and 75% (95%CI = 0.09,0.69) decreased risk of prostate cancer death. Conclusions: Adhering toa lifestyle characterized by frequent vigorous activity; not smoking; a healthy weight; a diet rich in cruciferous vegetables, healthy fats from vegetable sources, coffee, and wine and low in processed meat and poultry with skin; and avoiding excess supplemental selenium after prostate cancer diagnosis may lower risk of prostate cancer death.
Celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: Survival results from STAMPEDE (NCT00268476).
Authors: James Nicholas D. , Sydes Matthew Robert , Clarke Noel W. , Mason Malcolm David , Dearnaley David P. , Spears Melissa Ruth , Ritchie Alastair W S , Russell J. Martin , Parker Chris C. , Rentsch Cyrill A. , Wallace Jan , Barber Jim , Lydon Anna , Parmar Mahesh K B
Published: February 2017

162

Background: STAMPEDE is a randomised controlled trial using a multi-arm multi-stage design. It recruits men (pts) with high-risk locally advanced or metastatic prostate cancer (PCa) starting long-term hormone therapy (HT) for the first time. The trial initially assessed adding one or two of three treatment approaches to standard-of-care (SOC). We report comparative survival data for the two original comparisons that stopped accrual early at pre-planned lack-of-activity analysis based on failure-free survival (FFS): celecoxib (Cox) and celecoxib + zoledronic acid (Cox+ZA). Methods: SOC was HT for at least 2yrs; RT was encouraged for men with M0 disease. Stratified randomisation allocated pts 2:1:1 to SOC (control), SOC+Cox or SOC+Cox+ZA. Celecoxib (400mg) was given twice daily until 1yr. Zoledronic acid (4mg) was given for six 3-weekly cycles then 4-weekly until 2yrs. The primary outcome measure was death from any cause. This pre-planned analysis is triggered by analysis of the “original comparisons” that continued accrual through all activity stages. Analyses use Cox proportional hazards model and flexible parametric models, all adjusted for stratification factors. Results: 1,245 men were contemporaneously randomised to these 3 arms (Oct2005-Apr2011). Groups were well balanced: median age 65yrs; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly-diagnosed; median PSA 66ng/ml. Median follow-up was 62m. Grade 3-5 adverse events were seen in 35% SOC, 32% SOC+Cox, 32% SOC+Cox+ZA. There were 295 control arm deaths (82% PCa); median survival 68m. The adjusted HR was 1.00 (95% CI 0.82-1.22; p=0.99; median OS 69m) for SOC+Cox vs SOC; and 0.86 (95%CI 0.70-1.06; p=0.16; median OS 74m) for SOC+Cox+ZA vs SOC. Pre-planned analyses in men with metastatic disease showed HR 0.78 (95%CI 0.62-0.99) for SOC+Cox+ZA vs SOC. Further data will be shown. Conclusions: These data show no survival advantage for the addition of celecoxib alone for men starting long-term HT for the 1st time. However, the addition of celecoxib combined with ZA demonstrated a survival advantage for men with metastatic disease, in a pre-planned analysis, and requires further investigation. Clinical trial information: NCT00268476.
Enhanced overexpression of hypoxia-related miRNA-210 in primary tumor of metastatic prostate cancer.
Authors: Eminaga Okyaz , Fries Jochen , Woetzel Fabian , Warnecke-Eberz Ute , Neiss Susanne , Heitmann Michaela , Herden Jan , Engelmann Udo , Heidenreich Axel
Published: February 2017

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Background: miR-210 is a known transcriptional target of the hypoxia-responsive HIF-1α signaling pathway. However, the association between the expression of miR-210 and the tumor progression in prostate cancer (PCa) remains unclear. Methods: We isolated miRNA by miRNeasy FFPE kit (Qiagen, Hilden, Germany) from paraffin-embedded tissues of 87 prostate specimens with adenocarcinoma of the prostate cancer in different tumor stages, with high-grade prostatic intraepithelial neoplasia (HGPIN) and normal tissues. Organ-confined PCa was defined as PCa with pT2 tumor stage, Gleason score ≤ 7a and PSA level < 10 ng/ml. PCa with pT3/4 or Gleason > 7a was defined as advanced PCa. PCa with pN1 were considered as metastatic diseases. Additionally, 3 cases with castration-resistant prostate cancer (CRPC) were considered. Quantitative miR-210 expression data were acquired and analyzed using a real-time TaqMan-based PCR with the ABI Prism 7900HT (Life Technologies, Darmstadt, Germany). ANOVA and post hoc analysis according to Turkey were performed using SPSS 22 (IBM, Armonk, USA). For silico analysis, Diana tools were applied to determine target genes of miR-210 and related functions and pathways. All the statistical tests were two-sided, and the level of statistical significance was set at P < 0.05. The small nuclear U6 RNA was used as an endogenous control. Results: ANOVA revealed significant differences in expression levels of miR-210 according to the tumor progression. Interestingly, organ-confined PCa showed the lowest expression level of miR-210 in our analysis. No sig. differences in miR-210 expression between normal tissues, HGPIN and organ-confined PCa and between advanced PCa, metastatic diseases and CRPC were observed. However, miR-210 expression was significantly higher in metastatic diseases and CRPC in comparison to organ-confined PCa. The silico analysis showed that genes regulated by miR-210 were associated with homologous recombination, non-homologous end-joining, the cell cycle regulation and synthesis of DNA. Conclusions: We observed an enhanced overexpression of hypoxia-related miRNA-210 in primary tumor of metastatic prostate cancer and CRPC in comparison to organ-confined PCa.
Comorbidity and the receipt of curative therapy for favorable-risk prostate cancer prior to and following the publication of PIVOT.
Authors: Mihalcik Stephen A. , Chen Ming-Hui , Braccioforte Michelle H. , Moran Brian Joseph , D'Amico Anthony V.
Published: February 2017

17

Background: On July 19, 2012, the Prostate Cancer Intervention versus Observation Trial (PIVOT) was published and reported that after a median follow up of 10 years, radical prostatectomy neither improved overall survival nor reduced prostate cancer (PC)-specific mortality in men with low-risk PC compared to watchful waiting. However, the trial’s applicability may be somewhat limited by the participants’ poorer-than-average overall health. This study aimed to evaluate the impact of the PIVOT by assessing practice patterns before and after its publication. Methods: Between October 1997 and May 2013, 6,818 men with low-risk (n = 5,081, 74.5%) or favorable intermediate-risk (N = 1,737, 25.5%) PC were treated with curative intent at the Chicago PC Foundation. We compared the proportions of these men with ≥2, 1, or 0 comorbid conditions, restricted to myocardial infarction, congestive heart failure, diabetes mellitus, and coronary artery disease. We assessed for a trend in these proportions by time tertile prior to the PIVOT’s publication and compared them one month following PIVOT to the final pre-publication time tertile. Results: Of 6,818 men treated with curative intent, 5,208 (76.5%), 1,307 (19.2%), and 293 (4.3%) had 0, 1, and ≥2 comorbidities, respectively. Prior to PIVOT, the proportion of men with the greatest comorbidity (≥2) increased by time tertile (3.5% vs. 4.2% vs. 5.4%; p = 0.002), while 1 month following publication, there was a decline in the proportion of men with the highest degree of comorbidity (5.4% vs. 2.9%; p = 0.05). In addition to the drop in men with greatest comorbidity, men treated following the publication of the PIVOT were also younger (median age 65.7 vs. 66.8 years; p = 0.04), more likely to be black or Hispanic (24.7% vs. 17.4%; p = 0.003), and more likely to have favorable intermediate than low-risk PC (36.1% vs. 28.4%; p = 0.007). Conclusions: Following the publication of the PIVOT, men with low or favorable intermediate-risk PC whose health was poorer than the national average were less likely to undergo curative treatment, whereas men at higher risk for harboring occult high grade PC despite favorable-risk indices were more likely to undergo curative treatment.
Aldo-keto-reductase 1C3 expression as an independent risk factor for occurrence of castration resistant prostate cancer in high risk prostate cancer treated with neoadjuvant therapy and prostatectomy.
Authors: Hashimoto Yasuhiro , Tanaka Toshikazu , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara
Published: February 2017

172

Background: Aldo-keto reductase family 1 member C3 (AKR1C3) is a key steroidogenic enzyme that is implicated in the development of castration-resistant prostate cancer (CRPC). In this study, we examined AKR1C3 expression in surgical specimens of high risk prostate cancer treated with neoadjuvant LHRH + EMP, and we investigate the correlation between the expression level of AKR1C3 and the occurrence of CRPC. Methods: High-risk Pca was defined by the D’Amico stratification system. A total of 103 patients with high-risk Pca were enrolled in this study. The LHRH + EMP therapy included the administration of the LHRH agonist and 280 mg/day of EMP for six months before the radical prostatectomy. BCR was defined as the prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after the prostatectomy. Castration-resistant prostate cancer (CRPC) is defined by PSA or radiographic progression in the castrate levels of testosterone ( < 50 ng/dL). Along with the routine pathological assessment, AKR1C3 expression was evaluated in tissue microarray analysis (TMA) in all patients. A multivariable Cox proportional hazards model was used to evaluate the association between CRPC and clinical data. Results: The average patient age was 67.2 (49 to 78), and the median initial PSA level was 18.8 ng/mL (4.2–95.6). At a median follow-up period of 79.5 months, BCR occurred in 41 patients (39.8%) and CRPC occurred in nine patients (8.7%). In TMA, overexpression of AKR1C3 was seemed in 14 patients (13.6%). 5-year CRPC free survival rate of AKR1C3(+) patients (64.2%) was significantly lower than that of AKR1C3(-) patients (97.6%). (Log-rank test: p < 0.001) On multivariable analysis, AKR1C3 expression is an independent risk factor for occurrence of CRPC in this study. (p = 0.044). Conclusions: Although the present study was small and preliminary, overexpression of AKR1C3 is an independent risk factor for occurrence of CRPC in the high risk prostate cancer treated with neoadjuvant LHRH + EMP and prostatectomy. Further study is warranted to elucidate its clinical significance.
Amiloride effects on abiraterone antiproliferative activity in prostate cancer cells in vitro and on clinical management of abiraterone induced mineralocorticoid excess syndrome.
Authors: Valcamonico Francesca , Bedussi Francesca , Galli Diego , Dalla Volta Alberto , Fragni Martina , Vezzoli Sara , Ferrari Vittorio D. , Lazzari Barbara , Ferrari Laura , De Ferrari Francesco , Memo Maurizio , Berruti Alfredo , Sigala Sandra
Published: February 2017

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Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptoms and signs was the primary end point. Results: Prednisone, spironolactone and eplerenone induced an increase in the LNCAP proliferation rate and antagonized the AA-induced reduction of the cell proliferation in a concentration-dependent manner, while PF-03882845 did not. Amiloride at high concentrations induced cell death. When combined with AA +/- prednisone, amiloride at low concentration did not interfere with AA anti-proliferative activity however an additive inhibitory effect was observed at higher concentrations. The association of amiloride with hydrochlorothiazide led to a complete disappearance of all clinical and biochemical signs of abiraterone induced MCES in the 5 treated patients. Conclusions: Amiloride and PF-03882845 do not negatively interfere with the AA inhibition of proliferative activity of prostate cancer cells in vitro. The association of amiloride plus hydrochlorothiazide is efficacious in the management AA induced MCES.
Screen failure rates in contemporary phase II/III therapeutic trials in genitourinary malignancies.
Authors: Wong Sarah E. , North Scott A. , Sweeney Christopher , Stockler Martin R. , Sridhar Srikala S.
Published: February 2017

176

Background: Screen failures cost effort, time and resources estimated at about $2000 per patient (Bienkowski RS et al 2008). There is little published data about the frequency or causes of screen failures in genitourinary (GU) cancer clinical trials. Methods: We reviewed published articles and contacted study investigators on 42 key phase 2 and 3 trials in advanced GU cancer run from 1999 to 2015. We sought data on the numbers and causes of screen failures. Screen failures were defined as individuals who underwent screening but were not enrolled in the trial. Results: Among all 11 phase 3 trials in prostate cancer, the mean screen failure rate was 25% (17.9%-30.3%). In 4 recent trials evaluating novel androgen receptor pathway targeted agents, abiraterone and enzalutamide before or after chemotherapy for castration-resistant disease, the mean screen failure rate was 28% (range 22% to 30%). Only 2 of 3 prostate cancer chemotherapy trials completed after 2008 collected screen failure data with screen failure rates of 18 and 21%. The main reason for screen failures among all prostate cancer clinical trials was ineligibility. Among 14 phase 3 trials in kidney cancer, 5 reported rates and the mean screen failure rate was 24% (range 21%-27%). The main reasons again were ineligibility, with a very small percentage due to patient refusal. Among 17 phase 2 or 3 trials in bladder cancer, 6 reported rates and the mean screen failure rate was 13% (range 2.04% - 22.8%). The main reasons were primarily ineligibility and patient refusal to a lesser extent. Only (16/42) 38% of the trials published screen failure rates-73% of those in prostate cancer (all completed after 2008), 29% in kidney cancer, and 24% in bladder cancer. Conclusions: Contemporary trials in GU cancer that collected screen failure data had fairly consistent failure rates of 20-30% in prostate and kidney cancer. Many trials did not collect data on the numbers of and reasons for screen failures. Greater standardization of definitions, methods and reporting are needed to better understand and improve screen failure rates in GU cancer trials.
Imaging characteristics of patients with prostate cancer who discontinued active holistic surveillance on 3T multiparametric prostate MRI.
Authors: Katz Aaron , Liu Corinne , Fontes Andrew S , Kosinski Kaitlin E.
Published: February 2017

18

Background: Early-stage patients with prostate cancer can decide to go on Active Holistic Surveillance (AHS) to avoid over-treatment of a disease that has a high probability of being indolent. These patients are also placed on a special diet with vitamin supplements. We evaluate the imaging characteristics of this particular set of patients with prostate cancer with early-stage disease who are on a special diet and vitamin supplements, discontinued AHS and received definitive treatment. Methods: 300 consecutive 3T Multiparametric Prostate MRI (MP-MRI) were identified from March 26, 2012, to June 29, 2015. 200 patients (age 44 to 84 years) were identified in the active surveillance program. 114 patients had an initial MP-MRI prior to starting AHS and had at least one follow up MP-MRI after beginning AHS. 14 (12%) patients (age 60 to 79 years) discontinued AHS due to changes on a follow up MRI suggesting clinically significant prostate cancer. The MRI imaging findings were evaluated and correlated with pathology results, if available. Results: Of 14 patients, 3 (21%) patients had an enlarging MRI lesion compared to a previous MRI, 2 (14 %) patients had a new MRI lesion(s) suspicious for cancer, and 9 (64%) patients had suspicion or confirmation of extracapsular extension. 7 (50%) patients had a biopsy after a follow up MP-MRI with 6 (43%) demonstrating tumor upgrading. Length of time on AHS ranged from 4 months to 110 months. Prostate-specific antigen (PSA) levels and PSA density prior to beginning AHS ranged from 4.8 to 12.0 and 0.04 to 0.39, respectively. All were treated with definitive treatment, majority with unilateral focal cryoablation. Conclusions: The small number of patients with worsening disease on follow-up MP-MRI supports the role of AHS in patients with early-stage prostate cancer. MP-MRI is a useful tool in following patients on AHS and can extract patients who potentially may have clinically significant cancer and who may benefit from definitive treatment.
Use of crowdsourced research to develop a prognostic model for first-line metastatic castrate resistant prostate cancer (mCRPC).
Authors: Zhou Fang Liz , Guinney Justin , Wang Tao , Bare J. Christopher , Norman Thea C , Bot Brian , Shen Liji , Winner Kimberly Kanigel , Friend Stephen Henry , Abdallah Kald , Stolovitzky Gustavo A. , Xie Yang , Costello James
Published: February 2017

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Background: Project Data Sphere, LLC (PDS) and Sage Bionetworks/DREAM have completed the “Prostate Cancer DREAM Challenge” (Challenge), a crowdsourced competition, using historical prostate cancer clinical trial data from PDS. The Challenge aimed to improve prognostic models for overall survival (OS) and to explore predictive models for treatment toxicity in mCRPC patients. Methods: Control arms of 4 randomized phase III trials (total 2,070 patients) were used as training and validation data sets for the Challenge: ASCENT2, MAINSAIL, VENICE and ENTHUSE33. All subjects were first line mCRPC patients receiving docetaxel treatment. Curated baseline clinical covariates (demographics, comorbidity, prior treatment, laboratory, lesion and vital signs) were modeled along with raw clinical data tables. The primary purpose of the Challenge was to develop a prognostic model for OS (SubChallenge 1). The models were scored using concordance index and integrated area under receiver operator curve (iAUC) from 6-30 months. The published mCRPC OS model of Halabi, et al., JCO, 2014, was used as the benchmark. Results: The Challenge attracted over 160 active participants who formed 50 teams that submitted final models for SubChallenge 1. Median iAUC was 0.76 (0.67-0.78) with a maximum score of 0.792. Over half (n = 35) of these models exceeded the published benchmark (0.743 iAUC). Teams explored new methodologies such as model-based imputation and machine learning techniques to develop the best performing models. Many leveraged raw clinical data sets to create their own covariates and expanded beyond existing prognostic models. Conclusions: The Challenge externally validated Halabi’s first line prognostic model. New prognostic models were proposed and validated with significant improvements over the benchmark. Further analyses are needed to examine the winning models for new prognostic factors and to validate them using additional trial data from PDS. The Challenge drove interest from cross-disciplinary teams of global experts to explore and enhance their technical abilities using real clinical data whilst serving as a vehicle to accelerate medical innovation.
Correlation between radiographic progression-free survival (rPFS) and overall survival (OS): Results from PREVAIL.
Authors: Morris Michael J. , Beer Tomasz M. , Loriot Yohann , Higano Celestia S. , Armstrong Andrew J. , Sternberg Cora N. , De Bono Johann S. , Tombal Bertrand F. , Parli Teresa , Bhattacharya Suman , Krivoshik Andrew P. , Phung De , Rathkopf Dana E.
Published: February 2017

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Background: In PREVAIL, enzalutamide (ENZA) significantly improved OS (hazard ratio [HR] 0.71; P < 0.0001) and rPFS (HR 0.19; P < 0.0001) compared with placebo in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Using data from the final analysis at 439 rPFS events we showed a strong correlation between investigator and central review. Here we report sensitivity analyses (SAs) from the final analysis of investigator-assessed rPFS and the association between investigator-assessed rPFS and OS. Methods: The coprimary endpoint of rPFS was defined as time from randomization to the earliest objective evidence of centrally assessed radiographic progression, defined by PCWG2 guidelines for bone disease and RECIST v1.1 for soft-tissue disease, or death within 168 days of treatment discontinuation. Bone progression was captured using a validated bone scan data capture assay. Four SAs were performed on investigator-assessed rPFS to evaluate the impact of: (1) progression in bone, (2) clinical progression, (3) a required confirmatory scan for soft-tissue disease progression, and (4) all deaths, regardless of length of time after study drug discontinuation. Associations of investigator-assessed rPFS and OS were calculated using Pearson’s correlation coefficient, Spearman’s rho, and Spearman’s rho estimated through the Clayton copula. Results: Treatment effects remained significant with each SA, with HRs of (1) 0.21 (95% confidence interval [CI] 0.18, 0.27), (2) 0.21 (95% CI 0.17, 0.26), (3) 0.23 (95% CI 0.19, 0.30), and (4) 0.23 (95% CI 0.19, 0.30) (P < 0.0001 for each). Results of rPFS and OS associations are presented in the table below. Conclusions: SAs of rPFS in PREVAIL demonstrated a robust and consistent treatment benefit with ENZA. We observed a modest association between rPFS and OS. However, some unaccounted factors, such as post-protocol treatment, could have reduced the strength of the association of rPFS and OS in the placebo arm. Clinical trial information: NCT01212991. [Table: see text]
MLL translocation in two castration-resistant prostate cancer (CRPC) patients.
Authors: Chowdry Rajasree Pia , Ledet Elisa M. , Phelan Mary C. , Sartor A. Oliver
Published: February 2017

186

Background: The mixed-lineage leukemia (MLL) protein is a histone methyltransferase that regulates multiple genetic elements. Chromosomal rearrangements of the MLL gene result in expression of MLL-fusion proteins that occur in a subset of acute leukemias and are associated with poor prognosis. The MLL protein complex has been shown to interact with the androgen receptor via the MLL-menin subunit and, in model systems, MLL-menin inhibition blocks CRPC growth. We describe 2 cases of metastatic CRPC with a translocation in the MLL gene. Methods: In our institution, fluorescence in situ hybridization (FISH) testing of bone marrow specimens is routinely performed using the MLL Breakapart probe from Cytocell, Ltd (Cambridge, UK). The probe consisted of an 87 kb segment labeled in red that covered a region telomeric to the MLL locus and a 168 kb segment labeled in green centromeric to MLL. The FISH assay was performed according to manufacturer’s instructions. Results: MLL translocation was found coincidentally in 2 patients. The first was a 50 year old male with CRPC who had progressed on abiraterone and multiple chemotherapy regimens. A bone marrow biopsy was done to evaluate pancytopenia and pathology revealed metastatic prostate cancer marrow infiltration, without any evidence of leukemia or myelodysplasia. FISH studies revealed a rearrangement of the MLL locus using the MLL Breakapart probe. The second patient was a 77 year old male with metastatic CRPC who had also progressed through multiple hormonal and chemotherapy regimens. Bone marrow biopsy was done to evaluate thrombocytopenia and pathology revealed metastatic prostate cancer occupying nearly 100% of the marrow. Cytogenetics revealed complex karyotype and FISH was positive for MLL gene rearrangement by the same assay. There was no evidence of leukemia or myelodysplasia in either case. Conclusions: Translocation of the MLL gene is well documented in leukemia but has not been described in CRPC. Additional studies are warranted regarding the frequency and importance of this potential therapeutic target.
Initial results of patients with early-stage prostate cancer on active holistic surveillance.
Authors: Katz Aaron , Fontes Andrew S , Kosinski Kaitlin E.
Published: February 2017

19

Background: There is currently no consensus on how active surveillance should be utilized in order to optimize the benefit of patients with prostate cancer (PCa) to prevent overtreatment. Our institution’s protocol, known as Active Holistic Surveillance (AHS) integrates MRI screening in the place of serial biopsies. Nutritional supplements and lifestyle changes are also suggested in order to provide a holistic way to reduce progression. We look to compare definitive treatment rates of our cohort on AHS to other publications in the literature. Methods: A retrospective chart review was conducted on 200 patients placed on active surveillance for low and low-intermediate risk PCa under D’Amico criteria from February 2002 to July 2015. Enrollment criteria was defined by clinical stage (T1c), PSA under 20 ng/mL, diagnosis of a Gleason 6 or Gleason 7 with a tumor volume of >50%, and a PSA doubling time of greater than 1 year. The main objective of the study was to evaluate the rate of patients discontinuing AHS to receive definitive therapy and reasons for leaving our AHS protocol. Results: 200 patients (age 44-84 years) have a median follow-up of 40 months (range 4-161). A total of 24 out of 200 patients (12%) moved on to definitive treatment. For patients on AHS before 2010 until 2012, the rates of definitive treatment were 0%. In 2013, 8 patients (4%) received definitive treatment. In 2014, 12 patients (6%) received definitive treatment. In 2015, 4 patients (2%) received definitive treatment to date.The average treatment rate per year is 4%. Reasons for 24 patients discontinuing AHS included biopsy progression (16.67%), MRI progression (29.17%), MRI progression with biopsy confirmation (29.17%), patient preference (20.83%), and 1 patient was deceased due to an unrelated illness (4.17%). Conclusions: Low rates of discontinuation compared to other publications in the literature demonstrate that AHS can be a successful protocol for low-risk and low-intermediate risk PCa patients, and that a holistic approach can be beneficial to active surveillance patients.
Integration of bone scan (BS) and computerized tomography (CT) findings as an endpoint to assess bone metastasis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Parker Scott J. , Pond Gregory Russell , Sonpavde Guru , Alex Anitha , Heilbrun Marta Elise , Agarwal Neeraj
Published: February 2017

191

Background: Progression of bone metastasis in mCRPC is assessed solely by BS findings and correlates modestly with overall survival (OS). Given the lack of reliability of BS findings and the ready availability of routinely performed CT scans, which commonly identify bone metastases, we aimed to better assess progression in bone by integrating BS and CT findings and to explore their association with OS. Methods: Data were obtained from patients treated at the University of Utah receiving docetaxel-based chemotherapy (D) or post-docetaxel therapy with orteronel (O). Patients with both baseline and on-therapy CT and BS within 90 days were eligible for analysis. CT and BS underwent central radiology review for bone lesions by a single radiologist. Progressive disease (PD) was defined as ≥ 1 new lesion. Survival was measured from start of therapy. Cox proportional hazards regression was used to explore potential prognosticators of overall survival (OS). Statistical significance was defined as 2-sided p < 0.05. Therapy was a stratification factor. Results: Twenty-eight patients were evaluable including 18 patients receiving D, and 10 receiving O post-docetaxel. The mean age of these patients was 71.4 years and median (95% CI) overall survival was 18.4 (9.7-35.4) months. Four patients had PD on both BS and CT, while 2 (7%) had PD on CT but not BS and 3 had PD on BS but not CT. Patients with PD on BS or CT had worse OS (HR = 2.68, 95% CI = 1.04-6.90, p = 0.041) than those with no PD on either CT or BS. Looking at individual lesions, 4 (14%) patients had new lesions identified on CT which was not observed using BS, and they were associated with worse OS (HR = 3.72, 1.01-13.66, p = 0.048). Conversely, no significant difference in OS was observed for 4 patients with lesions identified on BS which were not observed using CT (HR = 2.67, 0.58-12.32, p = 0.21). Conclusions: This hypothesis-generating study suggests that CT can complement and enhance the ability of BS to capture PD and predict OS. Integration of BS findings using Prostate Cancer Working Group (PCWG)-3 guidelines to define PD and CT bone findings should be investigated in a larger study as an intermediate endpoint.
Analysis of the PROCEED registry by baseline prostate-specific antigen (PSA) quartiles: Preliminary analysis of real-world sipuleucel-T (sip-T) use.
Authors: Higano Celestia S. , Armstrong Andrew J. , Cooperberg Matthew R. , Concepcion Raoul S. , Tutrone Ronald F. , Olsson Carl A. , Pieczonka Christopher Michael , Shore Neal D. , Chang Nancy N. , LIll Jennifer Susan , Sartor A. Oliver
Published: February 2017

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Background: Sip-T is an FDA-approved, autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Post-hoc analysis of the phase 3 IMPACT study revealed that compared with the highest baseline PSA quartile, patients (pts) in the lowest quartile treated with sip-T had a larger overall survival (OS) benefit, suggesting sip-T is most beneficial if administered earlier in the treatment of mCRPC (Schellhammer et al., Urology. 2013.). This analysis evaluated pt characteristics by PSA quartiles in PROCEED (NCT01306890). Methods: Pts enrolled in PROCEED with baseline PSA and ≥ 1 sip-T infusion were included in this analysis. PSA values were divided into quartiles, and trends in baseline pt characteristics were evaluated as well as time to first anticancer intervention (tACI) with approved mCRPC therapies (docetaxel [D], cabazitaxel, abiraterone [abi], or enzalutamide [enz]) following sip-T treatment. Radium-223 was approved too late in the conduct of PROCEED to be included in the tACI analysis. Results: PSA quartiles from 1880 eligible PROCEED pts were lower than those of IMPACT (Table). Pts in the highest PROCEED quartile were older, more likely to have ECOG performance status ≥ 1, > 10 bone metastases, visceral metastases, and higher ALP and LDH, and lower hemoglobin compared with the lowest PROCEED quartile. More African American men and greater prior systemic therapy use were observed in the highest PSA quartile. Following sip-T, the median tACI (11.0, 8.2, 7.6, and 6.6 mos) was inversely proportional to PSA quartile. Conclusions: Lower baseline PSA values in PROCEED relative to IMPACT suggest that in a real-world setting, clinicians are using sip-T earlier in the treatment of mCRPC. Pts in the lowest PSA quartile had the best prognostic features and longest tACI. Additional patient follow-up is ongoing to evaluate OS and survival by quartile from PROCEED. Clinical trial information: NCT01306890. [Table: see text]
Effect of a new type androgen receptor antagonist, TAS3681, on ligand-independent AR activation through its AR downregulation activity.
Authors: Kajiwara Daisuke , Minamiguchi Kazuhisa , Seki Masanao , Mizutani Hiroya , Aoyagi Hiroki , Okajima Shigeo , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu
Published: February 2017

199

Background: Two new therapies, enzalutamide and abiraterone, directed at the androgen receptor (AR) signaling axis, represent important advances in the management of castration-resistant prostate cancer (CRPC). However, eventually almost all of patients acquire resistance to these drugs by a variety of mechanisms. Ligand independent AR activation such as induction of AR splice variants and AR overexpression are major issues of current CRPC progression. In the present study, we report the biological characterization of TAS3681, which is a new AR antagonist with AR downregulation activity, and propose this concept as a potential new approach for the treatment of CRPC. Methods: For assay of AR transactivation, prostate cancer (PCa) cells were transiently transfected with androgen-responsive reporter gene construct. The transfected cells were treated with growth factor and cytokine in steroid-depleted media, and luciferase activity was measured. To evaluate the effect of TAS3681 on AR and c-Myc protein expression, PCa cells were treated with TAS3681 in steroid-depleted media. AR and c-Myc protein levels were determined by western blot. Real-time PCR was used to analyze the mRNA levels of c-Myc and c-Myc target gene. Chromatin immunoprecipitation was performed to determine the enrichment of AR at the element. Results: TAS3681 dose-dependently reduced AR protein levels in PCa cells. In contrast to enzalutamide, TAS3681 suppressed androgen-independent AR transactivation by growth factor and cytokine. In PCa cells which express full-length AR and splice variant AR-v7, TAS3681 suppressed AR-v7 target gene expression through downregulation of AR-v7. Moreover, TAS3681 reduced expression of c-Myc, critical driver of androgen-independent mechanisms of PCa progression, via AR downregulation activity. In addition, real-time PCR assay showed the transcriptional suppression of c-Myc and its target gene by TAS3681. Conclusions: TAS3681 exhibits suppressive effects on ligand-independent AR activation via AR decreasing activity. These finding suggest that TAS3681 could be a candidate of breakthrough therapy for resistance to current AR pathway target drugs.
A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.
Authors: Dhawan Mallika Sachdev , Lee Mina , Bryce Alan H. , Weinberg Vivian K. , Ryan Charles J. , Derleth Christina Louise , Harzstark Andrea Lynne , Small Eric Jay , Aggarwal Rahul Raj
Published: February 2017

202

Background: Cabazitaxel and prednisone (Cbz/pred) extend survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred(CAMP). Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 23 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3-791.2). There were 2 DLTs (sepsis and febrile neutropenia) observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (n = 4). There was 1 DLT (febrile neutropenia) observed with Cbz 20 mg/m2 (N = 12), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ³ 3 related adverse events were hematologic (neutropenia, n = 9; thrombocytopenia, n = 3; febrile neutropenia, n = 3). The median number of treatment cycles was 7.5 (range 2-16), and 2 pts remain on study. Greater than or equal to 50% maximal PSA declines from baseline were observed in 12 of 19 evaluable pts(63%). The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable control of disease observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.
An analysis of sodium 18f-fluoride PET/CT and prostate specific antigen (PSA) changes in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Strauss Julius , Ahlman Mark , Karzai Fatima , Heery Christopher Ryan , Cordes Lisa M , McMahon Sheri , Couvillon Anna , Rauckhorst Myrna , Thomas Chrisa , Theoret Marc Robert , Marte Jennifer L. , Millo Corina , Lindenberg Maria Liza , Turkbey Ismail B. , Choyke Peter L. , Figg William Douglas , Schlom Jeffrey , Dahut William L. , Gulley James L. , Madan Ravi Amrit
Published: February 2017

203

Background: Recently there has been growing evidence that 18F-Fluoride PET/CT has increased sensitivity relative to technetium-99m diphosphonate (Tc-99m MDP) bone scan for evaluating metastatic bone disease. This analysis studied changes in 18F-Fluoride PET/CT and evaluated associations with PSA changes for mCRPC patients (pts) on enzalutamide (enz). Methods: As part of a randomized phase II study evaluating enz with or without vaccine therapy, men with mCRPC electively underwent 18F-Fluoride PET/CT at 3 month (mos) intervals [NCT01867333]. At these points serum PSA was collected. Data was taken on max SUV and volume of presumed cancerous lesions and a variable, ΣSUV*Volume, was calculated which was defined as the sum of the products of SUV max and volume of cancerous lesions. Results: At the time of our analysis, 19 pts had PSA and PET/CT data for at least 2 time points within 1 year of initiating therapy. The median baseline PSA was 19.6 ng/ml (0.76-587). All pts had predominantly bone disease with 10 having small volume lymphadenopathy. Only 1/19 pts progressed by PSA Working Group criteria. An analysis found that 18/19 pts (95%) had an association between changes in PSA and ΣSUV*Volume. Of these 18 pts, 13 had a major ( > 50%) and 1 had a minor ( > 30%) PSA response and all 14 had an accompanying decrease in ΣSUV*Volume. For 11/14 pts with PSA responses, the change in ΣSUV*Volume paralleled the change in PSA at all time points, while for 3 pts an associated change between ΣSUV*Volume and PSA was delayed by 3 mos. 4/14 pts had short term responses lasting only 3 mos followed by PSA increases. For these 4 pts the changes in ΣSUV*Volume paralleled PSA changes, decreasing at 3 mos and increasing thereafter. Finally 4/18 patients had no PSA response to therapy. All 4 pts had increases in ΣSUV*Volume which paralleled rising PSA values. Conclusions: Preliminary data from a small cohort suggests that findings on 18F-Fluoride PET/CT are associated with PSA changes. This represents a substantial difference from standard Tc-99m MDP and further suggests that 18F-Fluoride PET/CT may provide a more sensitive analysis of bone disease. Additional data from this and other studies are required.
Regulation of steroid-5-alpha-reductase 2 (SRD5A2) in human prostate by epigenetic modifications.
Authors: Olumi Aria F. , Ge Rongbin , Wang Zongwei , Wu Shulin , Tabetabaei Shahin , Wu Chin-Lee
Published: February 2017

204

Background: 5-alpha reductase type 2 (SRD5A2), an enzyme that is critical for prostatic development and growth. We have found that many aging prostate tissues do not express the enzyme. We previously showed that expression of SRD5A2 is not static and epigenetic modulations by DNA methyltransferase and pro-inflammatory cytokines play important roles in silencing of SRD5A2. Here we wished to define the methylation pattern and identify specific CpG dinucleotides that are methylated in the SRD5A2promoter region. Methods: Ninety six prostate samples from patients were obtained by transurethral resection of prostate (TURP). Methylation of SRD5A2 promoter was assessed using Methylated CpG Island Recovery Assay (MIRA). Bisulfide conversion of Genomic DNA was performed using Epimark bisulfide conversion kit. Primers for bisulfide sequencing were designed using MethPrimer software and bisulfide sequencing was performed using 3730XL DNA Sequencers. Binding of histone demethylase to promoter DNA was analyzed by ChiP assay. Results: We randomly selected 3 TURP samples with methylated SRD5A2 promoters and 3 TURP samples with un-methylated SRD5A2 promoters, and then bisulfide conversion and sequencing were performed to verify the methylation pattern of CpG dinucleotides on SRD5A2 promoter. We found that bisulfide sequencing analysis of SRD5A2 promoter was consistent with MIRA analysis. To further analyze the mediators of SRD5A2 promoter region, we show that TNF-alpha up-regulates expression of Snail protein, which is a central regulator of both DNA methylation and histone methylation, and increases the binding of H3K9me to SRD5A2promoter region, but not H3K27me or H4K20me. Conclusions: Methylation of SRD5A2 promoter, which is regulated by DNMT1, proinflammatory cytokines and the histone methylase, H3K9me, accounts for suppression of SRD5A2 in many adult human prostate tissues. Bisulfide conversion and sequencing confirm and focus the specified CpG dinucleotides that are methylated enabling us to evaluate mechanisms and patterns of SRD5A2 promoter methylation in order to study the functional significance of SRD5A2 methylation. Grant support: NIH/R01 DK091353.