bluuebunny/crossref_metadata_2025_split huggingface dataset:
Checkpoint kinase inhibition in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.
Authors: Atiq Mohammad Omar , Chakraborty Goutam , Nandakumar Subhiksha , Mazzu Ying Zhang , Stopsack Konrad H. , Yoshikawa Yuki , Lee Gwo-Shu Mary , Kantoff Philip W. 
Published: February 2020

150 Background: Poly ADP-ribose polymerase inhibitors (PARPi) have shown promise in the treatment of metastatic castration-resistant prostate cancer patients with DNA damage response defects . The phase 3 PROfound trial showed olaparib delayed the time to radiographic progression or death as compared with abiraterone or enzalutamide. In addition to olaparib, three other PARPi are in Phase 3 trials in prostate cancer (PC): rucaparib, talazoparib, and niraparib. Despite responses, resistance is common and treatment options for PARPi-resistant patients are limited. In this study, we observed de novo activation of checkpoint kinases (CHEK) in talazoparib-resistant (TR) PC cells. Therefore, we hypothesized that targeting CHEK may mitigate resistance to PARPi in PC. Methods: We developed TR human prostate cancer PC3 (low BRCA2 protein due to heterozygous deletion of BRCA2) cells. We performed phosphoproteomic analysis to identify possible mechanisms of talazoparib resistance in PC3 cells and validated the results with Western blot. Results: TR-PC3 cells proliferated slower and had a significant increase in the phosphorylation of CHEK2 compared to parental (p) PC3. Treatment with a CHEK2-selective inhibitor, CCT241533, did not affect cell growth in TR-PC3 cells. Conversely, treatment with a CHEK 1/2 inhibitor, prexasertib, led to significant cell growth inhibition in TR-PC3 at a much lower IG 50% concentration compared to pPC3. RNAi-mediated knockdown validated the superior efficacy of combined CHEK1 and CHEK2 inhibition since this combination produced the greatest cell growth inhibition seen in both TR-PC3 and de novo PARPi-resistant p22RV1. Treatment of pPC-3 and p22RV1 with combinations of talazoparib and prexasertib showed greater cell growth inhibition compared to either drug alone. Conclusions: Resistance to PARPi in PC cells with deletion of BRCA2 may potentially be overcome with CHEK inhibition. Moreover, our preliminary data suggested that the effect of PARPi and CHEK inhibitors on PARPi/CHEK inhibitor-naïve PC cells was greatest when used together, indicating that patients with PC may experience greatest anti-tumor activity of the two drugs when they are used in combination.
Multiregion expression profiling of prostate cancer from men randomized in the STAMPEDE trial: Stage I results of a multistage biomarker analysis.
Authors: Grist Emily , Parry Marina , Mendes Larissa , Lall Sharanpreet , Kudahetti Sakunthala C. , Santos Vidal Sara , Atako Nafisah B. , Anjum Mazna , Ishaq Sofeya , Todorovic Tamara , Huang Huei-Chung , Waugh David , Sweeney Christopher , Clarke Noel , James Nicholas D. , Berney Daniel , Parmar Mahesh K. B. , Davicioni Elai , Brown Louise C. , Attard Gerhardt 
Published: February 2020

153 Background: The PAM50 gene expression classifier stratifies localized prostate cancer into luminal A/B and basal subtypes: luminal A have superior prognosis compared to luminal B and basal. Drug response scores built using the NCI-60 cell lines predict luminal subtypes are more taxane sensitive compared to basal; luminal B is hypothesized to be the most proliferative and hormone responsive compared to the basal subtype. The STAMPEDE trial provides a framework to validate prognostic and predictive associations of the PAM50 test in tumors from men randomized to androgen deprivation therapy (ADT) alone or with docetaxel or abiraterone. We here present multi-region whole-transcriptome expression array data at completion of Stage I designed to confirm the feasibility of molecular subtyping STAMPEDE tumor blocks. Methods: In collaboration with Decipher Biosciences we generated clinical-grade whole-transcriptome expression array data (Human Exon 1.0 ST GeneChip) performed to CLIA standards on mRNA (from three 10 micron slides) from cancer-enriched areas and applied the PAM50 classifier. Results: As of January 2019, we retrieved blocks from 2012 men from an ITT population of 3879. For Stage I feasibility assessment, we sectioned diagnostic trans-rectal biopsies of the prostate from 50 randomly selected men treated with ADT. We extracted mRNA from 109 cores; > 92% cores (101) from > 94% patients (47/50) passed quality control. The prevalence of PAM50 subtypes was: 31 basal cases (62%), 18 luminal B (36%) and 1 luminal A (2%). 26 cases (52%) were identified as ETS-related gene (ERG) positive. More than one core was interrogated from 35/50 cases (range: 1-6 cores). ERG positive cores were homogeneous across cores from the same patient but PAM50 subtyping identified intra-patient variability across cores from the same case. Conclusions: We confirm the feasibility of expression profiling STAMPEDE tumor blocks and identify a low prevalence of luminal A subtype. Whereas ERG status is consistent across multiple cores, basal and luminal subtypes co-exist in the same prostate. Multi-region analysis will enable further refinement for individual patient classification.
AR-V7 and prediction of benefit with taxane therapy: Final analysis of PROPHECY.
Authors: Armstrong Andrew J. , Luo Jun , Anand Monika , Antonarakis Emmanuel S. , Nanus David M. , Giannakakou Paraskevi , Szmulewitz Russell Zelig , Danila Daniel Costin , Healy Patrick , Berry William R. , Wenstrup Rick , Scher Howard I. , Tagawa Scott T. , George Daniel J. , Halabi Susan 
Published: February 2020

184 Background: We previously found that men with AR-V7 (+) poor risk mCRPC have a low chance of benefit with abiraterone or enzalutamide. The benefits of subsequent taxane chemotherapy based on AR-V7 status may help inform treatment decisions. Methods: We conducted a multicenter prospective study of men with poor risk mCRPC (PROPHECY, NCT02269982) starting Abi or Enza and subsequent taxane chemotherapy. AR-V7 status from CTCs was assessed before abi/enza and again before taxane chemotherapy using the Epic nuclear protein assay or the Johns Hopkins Adnatest assay. The primary endpoint was to test the association of AR-V7 with radiographic/ clinical progression free survival (PFS) and OS with taxane chemotherapy, using the proportional hazards model, adjusting for Cell Search enumeration and clinical risk score. Results: We enrolled 118 men with mCRPC starting Abi/Enza; of these, 51 were evaluable with CTC AR-V7 testing and received subsequent taxane chemotherapy. With 50 PFS events, see table for final results. While AR-V7 positivity was associated with worse outcomes overall, AR-V7 (+) patients had similar PFS, OS, and confirmed >50% PSA declines adjusting for CTC enumeration and clinical prognostic factors. Concordance between the two AR-V7 assays pre-taxane was 0.78 (kappa 0.46). AR-V7 positivity increased at progression on abi/enza, but not following taxane chemotherapy. Conclusions: Men with AR-V7 positive mCRPC have poor outcomes, but may benefit from taxane chemotherapy after progression on abi/enza. AR-V7 may provide a helpful predictive biomarker to guide treatment with a second AR inhibitor or a taxane. Clinical trial information: NCT02269982. [Table: see text]
Prognostic value of novel inflammation index for patients with metastatic castration-resistant prostate cancer.
Authors: Yamada Yasutaka , Sakamoto Shinichi , Rii Junryo , Yamamoto Satoshi , Kamada Shuhei , Imamura Yusuke , Nakamura Kazuyoshi , Komiya Akira , Nakatsu Hiroomi , Ichikawa Tomohiko 
Published: February 2020

212 Background: Inflammation process has been reported to be involved in the development of several types of cancer. Recently, a lung immune prognostic index (LIPI) combining with derived neutrophils/ (leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level was proposed as an useful prognostic marker for advanced non-small cell lung cancer. However, the prognostic value of this index has not been evaluated and we aimed to validate its prognostic ability in metastatic castration resistant prostate cancer (mCRPC). Methods: Clinical data of 248 mCRPC patients were retrospectively collected from multi-institutions. We obtained the clinical factors including age, PSA, Gleason score (GS), tumor stage, white blood cell (WBC) count, dNLR, hemoglobin (Hb), LDH, alkaline phosphatase (ALP) and C-reactive protein (CRP) levels. The prognostic index was defined as poor (high dNLR and LDH), intermediate (high dNLR or LDH) and good (low dNLR and LDH) groups. We analyzed the overall survival (OS) after CRPC using Cox proportional hazard models and the Kaplan-Meier methods. Results: The median age at CRPC and baseline PSA level were 75 years and 458.39 ng/ml, respectively. The median OS after CRPC were 31.7 months. In multivariate analysis, dNLR (≥1.48, HR=1.75, P=0.0096), LDH (≥upper limits of normal, HR=1.94, P=0.0015) and ALP (≥310U/l, HR=2.37, P<0.0001) were independent prognostic factors for OS. The good prognostic index group showed significantly longer OS after CRPC compared with the intermediate and poor groups with the median survival of 46.2, 28.9 and 16.6 months, respectively (shown in Table). Conclusions: Novel inflammation index combined with dNLR and LDH was an useful prognostic marker for mCRPC. Further study with a large scale and treatment specific analysis will be required.[Table: see text]
Evaluation of bone metastasis and prognosis of prostate cancer with bone metastasis during standard hormonal therapy and chemotherapy: A report of PROSTAT-BSI multicenter registry in Japan.
Authors: Mizokami Atsushi , Takahashi Satoru , Matsuyama Hideyasu , Kaneko Gou , Shiina Hiroaki , Ichikawa Tomohiko , Horikoshi Hiroyuki , Hashine Katsuyoshi , Sugiyama Yutaka , Miyao Takeshi , Kamiyama Manabu , Harada Kenichi , Ito Akito , Nakajima Kenichi ,   The PROSTAT-BSI Investigators
Published: February 2020

215 Background: Quantitative evaluation of the change of bone metastasis (bMet) has not been clearly defined during treatments in prostate cancer (PCa). As therapeutic effects of bMet have become quantified with scintigraphic bone scan index (BSI), we performed a nation-wide observational prospective study in patients who were treated by hormonal therapy (HTx) or chemotherapy (CTx). Methods: A total of 237 patients were recruited at 30 hospitals in Japan, and this report summarized baseline demographics and prognosis of 203 patients. All had bMet and underwent either standard HTx (group H) or docetaxel CTx (group C). Bone scans were performed with 99mTc-MDP. Patients were followed up for 3 years, and changes in biochemical and tumor markers during HTx and CTx were recorded in addition to skeletal-related events, recurrence, and death. Results: The basic characteristics of the patients (n=203) at the time of registration during December 2016 were as follows: mean age 71 ± 8 years; median BSI calculated on-site 3.0 ± 3.2% and median PSA was 265 ng/mL (22-2923 ng/mL) and 33 (3-537 ng/mL), for Group H and C (p=0.0014), respectively. BSI was comparable (H: 3.0 ± 3.4 vs C: 3.0 ± 2.8%, p=n.s.) between the two groups. A total of 54 patients (24%) died from PCa. BSI flare defined as increase at 3 months and decrease at 6 months was 13% and 31% (p<0.0069) for Groups H and C, respectively. When patients were classified into three groups with BSI <0.9 (low), 0.9-3.3 (intermediate), and >3.3% (high). Kaplan-Meier Survival analysis showed that mortality at 1100 days was 8%, 16%, and 35% for Group H (p=0.0097), and 50%, 55%, and 65% for Group C (p=ns) for the low, intermediate and high BSI group, respectively. In addition, patients who showed BSI decline >20% until 6 months showed better prognosis than those who did not (p<0.0001 and p= 0.038 and for Group H and C, respectively). Conclusions: The data of PROSTAT-BSI showed that BSI could be a good biomarker for prognosis in both Groups H and C, in particular for prognostic stratification of patients indicated for HTx. Six-month response of BSI by >20% indicated better prognosis in both groups. Clinical trial information: UMIN000007858.
Safety and effectiveness of radium-223 dichloride (Ra-223) in patients with mCRPC in real-world setting: A Japanese post-marketing study (PMS).
Authors: Takahashi Shunji , Kakehi Yoshiyuki , Masumori Naoya , Hosono Makoto , Kinuya Seigo , Okayama Yutaka , Sunaya Toshiyuki , Okumura Masafumi , Uemura Hirotsugu 
Published: February 2020

236 Background: In order to assess safety and effectiveness of Ra-223 in real-world setting, a PMS has been conducted under Japanese regulation for Good Post-marketing Study Practice. Methods: This was a prospective, single-arm, observational study of patients (pts) with mCRPC. The planned sample size was 300. In this primary analysis, clinical outcomes during the 6 month observational period up to 1 month after the last injection of Ra-223 were assessed. An exploratory subgroup analysis was performed according to symptom status at baseline (asymptomatic (AS) or symptomatic (S): WHO's cancer pain ladder 0 or >1). Results: A total of 334 pts were enrolled from Jun 2016 to Nov 2017. As of May 2019, data for 273 pts were available (table). The incidence of drug-related any treatment-emergent adverse events (TEAEs), hematologic TEAEs, and skeletal-related events were 27%, 18%, and 3%, respectively. Fractures were reported in 3 pts, but all were judged not related to Ra-223 by investigators. At the subgroup analysis, baseline characteristics for AS-group seemed more favorable than those in S-group (table). More pts in AS-group completed 6 cycles of Ra-223, and incidence of drug-related TEAEs appeared lower in AS-group compared with S-group. More than 90% of pts did not experience pain progression during 24 weeks, regardless of their symptoms status. Conclusions: During the 6 month observational period, no new safety concerns related to Ra-223 treatment were reported. Asymptomatic patients were more likely to complete treatment and experience fewer TEAEs, possibly reflecting less advanced disease. A follow-up observation up to 3 years is on-going.[Table: see text]
The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study.
Authors: Hatakeyama Shingo , Okita Kazutaka , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara 
Published: February 2020

238 Background: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. Methods: We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. Results: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio: HR 0.84, P = 0.530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR 0.82, P = 0.650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR 1.58, P = 0.384). Conclusions: The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.
Real-world management of advanced prostate cancer: A Canadian comparison of academic specialists and community-based prostate cancer physicians.
Authors: Hotte Sebastien J. , Finelli Antonio , Chi Kim N. , Canil Christina M. , Fleshner Neil , Kapoor Anil , Kolinsky Michael Paul , Malone Shawn , Morash Chris , Niazi Tamim , Noonan Krista , Ong Michael , Pouliot Frederic , Shayegan Bobby , So Alan , Sorabji Delna , Hew Huong , Park-Wyllie Laura , Saad Fred 
Published: February 2020

29 Background: The Canadian GU Research Consortium recently conducted a consensus development conference with 27 academic prostate cancer (PC) specialists leading to 31 consensus recommendations. We conducted a survey to compare community-based practice with the consensus recommendations on the management of metastatic castration sensitive prostate cancer (mCSPC), metastatic castration resistant prostate cancer (mCRPC) and non-metastatic castration resistant prostate cancer (nmCRPC). Methods: An 87-item online questionnaire was sent to 600 Canadian community urologists, medical oncologists, radiation oncologists, and general practitioner oncologists involved in the treatment of PC. Results: Seventy-two physicians responded to the questionnaire (12% response). A discordance of >25% was observed in 15 of 31 recommendations (48%). Among the areas of discordance were treatment approach for patients with nmCRPC and PSADT < 10 months who are negative for metastases on conventional imaging but metastatic on PET-based imaging. Of the academic physicians, 89% indicated treating with agents approved for nmCRPC compared to 50% of community physicians (p=0.0005). Important discrepancies were also observed across academic and community physicians for radiation to the prostate for low-volume mCSPC which was 74% vs 27%, (p<0.0001) respectively; criteria for stopping therapy in mCRPC in which 78% of academic physicians favored continuation of therapy in the event of PSA progression only, compared to 24% of community physicians. Sequencing of therapy after prior apalutamide for nmCRPC using subsequent docetaxel treatment was observed in 81% of academic physicians vs 35% of community physicians, (p<0.0001), and use of genetic testing was favored by 74% of academics vs 36% of community physicians, (p<0.0001) for newly diagnosed metastatic prostate cancer. Conclusions: The areas of discordance between a national sample of community-based PC physicians and academic consensus recommendations represent potential areas for education, practice tools and future research.
Late toxicity and quality of life from GETUG-AFU 22 study.
Authors: Latorzeff Igor , Guerif Stephane , Pelissier Sandra , Meyer Emmanuel , Fraisse Julien , Supiot Stephane , Crehange Gilles , Lagneau Edouard , Ronchin Philippe , Benyoucef Ahmed , Hasbini Ali , Pommier Pascal , De Laroche Guy , Salomon Laurent , Sargos Paul 
Published: February 2020

331 Background: Radical prostatectomy (RP) is recommended as a standard treatment for localized prostate cancer. However no recommendations exist for pts with immediate detectable PSA after RP. Methods: Pts with localized prostate cancer, treated by RP (R0 or R1), with a PSA level post-RP ≥0.2 ng/mL and ≤2 ng/mL at randomization and N0 M0 on imaging were included. Pts were randomized (1:1) to radiotherapy (RT) alone (RT arm) or 6 months degarelix hormone therapy (HT) with RT (RT+HT arm). RT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint was event-free survival (EFS). Acute and late toxicities were evaluated as secondary endpoints and scored using CTCAE V4.0 scale. Quality of life (QOL) was assessed with QLQ-C30 and QLQ-PR25 questionnaires at 12 and 24 months. Late toxicity was reported at 24 months. Results: From Jan-2013 to Sept-2015, 125 pts were included (RT arm: 64 pts; RT+HT arm: 61). Median follow up is 38 months (31.4; 44). The baseline characteristics are well-balanced between two arms: median age was 66 yrs (50-77), all men having an ECOG ≤1 (ECOG 0 in 92%), a median Gleason score of 7 (3-9), a median PSA of 0.3 ng/mL (0.09-1.82) post-RP and 0.6 ng/mL (0.12-3.65) at randomization. All pts received 33 Fr of RT. In the RT+HT arm 98.4% of pts received the 6 months of HT planned. All pts were eligible for safety analysis. At 24 months, no difference in late genitourinary (GU) or gastrointestinal (GI)toxicity was observed between the two arms (p=0.145) Grade 3 late toxicities were reported for 15/125 pts (12%): 8/64 pts (6.5%) in the RT arm and 7/61 pts (5.5%) in RT+HT arm (NS) and no toxicity grade >3 was observed. Evaluation of QOL was assessable at 12 and 24 months of FU for 80%/89% pts and 59%/77% pts in RT/RT-HT arms respectively. At 12 months QLQ-PR25 HT related symptoms was significantly more important in the RT-HT arm (p=0.04). At 24 months no significant difference in QLQC-30 or QLQ-PR25 analysis was reported. Conclusions:, At 24 months in this phase II trial no significant difference in GI/GU toxicity and.QOL was observed between the two arms. GETUG-AFU 22 efficacy analysis is still pending. Clinical trial information: NCT01994239.
Predicting radiation-induced immune trafficking and activation in localized prostate cancer.
Authors: Williams Scott , Keam Simon P. , Halse Heloise , Nguyen Thu , Mitchell Catherine , Caramia Franco , Byrne David , Haupt Sue , Ryland Georgina , Darcy Phillip K. , Sandhu Shahneen Kaur , Blombery Piers , Haupt Ygal , Neeson Paul J. 
Published: February 2020

340 Background: Prostate cancer is frequently cured with high-dose rate brachytherapy as a front-line treatment. However, a significant number unfortunately develop intrinsic resistance. Although considered to be an immune-excluded tissue, immune responses are implicated in driving tumour-eradication in prostate cancer. This has not been proven, and yet is used as the rationale for numerous clinical trials combining radiation and immunotherapies. We hypothesise that there is a predictable but differential relationship between radiation and the immune responses in prostate cancer that could be used to fulfil a clinical need - identifying patients that would benefit from immune intervention in conjunction with radiation. Methods: We present here the results of comprehensive immunological profiling of a cohort of world-unique pre- and post-radiation tissues from 24 patients (RadBank cohort). These were assessed using pathological classification, tissue segmentation (cancer/surrounding stroma), multiplex IHC, gene expression profiling, T-cell receptor sequencing, and spatial computational analysis. Results: Our data resolved three classes of prostate cancer tissue based on immune infiltrate level, immune-activation and -checkpoint gene signatures, spatial clustering and T cell clone sequencing: We have begun to resolve clear patient and clinical classifiers based on immune responses to radiation, and identified patients groups likely to benefit from immune therapy alongside radiation. Conclusions: Importantly, these classifications are associated with baseline gene expression profiles that may be used for pre-clinical stratification and more sophisticated treatment paradigms.