bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II trial of docetaxel plus carboplatin versus docetaxel in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial.
Authors: Bouman-Wammes Esther W. , de Munck Linda , van den Berg H Pieter , Beeker Aart , Smorenburg Carolien H. , Verheul Henk M.W. , Gerritsen Winald R. , van den Eertwegh Alfonsus Johannes Maria 
Published: March 2017

166 Background: Docetaxel is the standard first-line chemotherapy for patients with castration resistant prostate carcinoma (CRPC). Docetaxel re-challenge has never been tested in a prospective randomized clinical trial. As some studies supported the addition of carboplatin to docetaxel in this setting, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel monotherapy in docetaxel pre-treated CRPC patients. Methods: Patients with CRPC with a progression-free interval (PFI) of at least 3 months after initial treatment with docetaxel were randomized between docetaxel 75mg/m2 or docetaxel 60mg/m2 plus carboplatin AUC 4, both plus prednisone in a 3-weekly schedule. Treatment was continued until progressive disease, unacceptable toxicity or completion of 10 cycles. The primary endpoint is progression-free survival (PFS) (PSA and/or RECIST). Secondary objectives are overall survival, toxicity, PSA response and quality of life. Results: As a result of insufficient recruitment, the study was discontinued early after inclusion of 75 patients, instead of the targeted 150 patients. The median PFS was comparable between both groups (docetaxel 12.7 months versus combination therapy 11.7 months p = 0.99), and no difference in OS was found (median OS 18.5 months versus 18.9 months, p = 0.88). Rates of PSA response were comparable (response/stable PSA in 42.1%/39.4% of the patients in the monotherapy arm versus 35.1%/48.6% in the combination arm, NS). The incidence of grade 3-4 infections and gastro-intestinal (GI) side effects was higher in the docetaxel plus carboplatin arm (GI side effects 0% versus 13.9% p = 0.03; infection 2.7% versus 16.7% p = 0.056). The difference in febrile neutropenia (0% versus 11.1%) is not significant. Conclusions: For patients with CRPC and an initial good response to docetaxel, re-treatment with docetaxel monotherapy is a feasible, save and effective treatment. Addition of carboplatin resulted in more toxicity. Docetaxel re-challenge is a viable therapeutic option for selected patients. Clinical trial information: NTR3070.
Phase Ib study of apalutamide (APA) with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Update on safety and efficacy.
Authors: Posadas Edwin M. , Chi Kim N. , De Wit Ronald , De Jonge Maja J. , Attard Gerhardt , Friedlander Terence W. , Yu Margaret K. , Hellemans Peter , Chien Caly , Abrams Charlene Connelly , Gonzalez Martha , Trudel Geralyn Carol , Chauhan Vijay , Jiao Juhui James , Saad Fred 
Published: March 2017

173 Background: APA and AA target the androgenreceptor (AR) axis via different mechanisms and may have complementary activity in mCRPC. APA is an advanced AR antagonist that targets the AR ligand-binding domain with high affinity (Clegg. Cancer Res. 2012). APA prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. This phase 1b study evaluates potential PK interactions between APA and AA + P. Here we report antitumor activity and safety of APA in combination with AA + P from 57 pts versus 29 pts presented at ASCO 2015 (NCT02123758). Methods: Pts with progressive mCRPC and ECOG PS ≤ 2 received AA (1000 mg/d) + P (5 mg BID) on Cycle 1 Day 1 (C1D1) with addition of APA (240 mg/d) on C1D8 in 28-day treatment (tmt) cycles. Efficacy assessment was based on RECIST 1.1 and PCWG2 criteria. Results: 57 pts started tmt on study; median tmt duration was 17 weeks. Median age was 70 years (range, 49-89) and median baseline PSA was 111 µg/L (range, 4-2597). Bone, nodal, and visceral disease were present in 50 (88%), 31 (54%), and 17 (30%) pts, respectively. 29 (51%), 29 (51%), and 23 (40%) pts were previously treated with a taxane, AA, or enzalutamide (ENZ), respectively. 47 pts discontinued tmt: disease progression (n = 39), consent withdrawal (n = 3), physician decision (n = 1), death (n = 1), and other (n = 3). In AA- and ENZ-naïve pts (n = 18), 67% had PSA decline ≥ 50%. In AA- or ENZ-treated pts (n = 39), 15% had PSA decline ≥ 50%. Most commonly reported ( > 10% of pts) drug-related AEs: fatigue (42%), diarrhea (21%), vomiting (21%), nausea (19%), hypokalemia (19%), decreased appetite (16%), hot flush (12%), abdominal pain (12%), and dysgeusia (11%). Grade ≥ 3 drug-related AEs reported in > 1 pt: fatigue (7%), hypokalemia (3.5%), hyponatremia (3.5%), and hypertension (3.5%). 1 pt discontinued study drug for grade 3 fatigue. Conclusions: Interim data indicate that 240 mg/d of APA with 1000 mg/d of AA + P has antitumor activity and an acceptable safety profile in mCRPC. Clinical trial information: NCT02123758. [Table: see text]
Circulating tumor DNA (ctDNA) and correlations with clinical prognostic factors in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Khalaf Daniel , Annala Matti , Beja Kevin , Vandekerkhove Gillian , Zulfiqar Muhammad , Finch Daygen L. , Oja Conrad D. , Vergidis Joanna , Gleave Martin , Wyatt Alexander William , Chi Kim N. 
Published: March 2017

186 Background: Sequencing of ctDNA is a minimally invasive method to study somatic DNA alterations. Quantitation and characterization of ctDNA may correlate with tumor burden and poor risk clinical features, but this is unproven in mCRPC. Methods: We performed deep targeted sequencing of 73 mCRPC-related genes in plasma ctDNA from 136 treatment naïve mCRPC patients. Fraction of ctDNA was determined by quantifying somatic mutant allele frequency and the deviation from heterozygosity for germline single nucleotide polymorphisms at regions of somatic copy number alterations. Baseline clinical factors were correlated with ctDNA fraction and genomic aberrations. Results: ctDNA could be quantified in 86/136 (63%) patients. Increasing fraction correlated with elevated ALP (chi2, p < 0.001), LDH (p < 0.001) and presence of liver metastasis (p = 0.01). Patients with any one of these factors were more likely to have a ctDNA fraction ≥ 40% (67% vs 36% of patients with neither factor, p = 0.001) and less likely to have unquantifiable ctDNA (26% vs 49%, p = 0.006). A decreased ctDNA fraction was associated with metastases only to lymph nodes (p = 0.012). Among the most frequently aberrant genes were Androgen Receptor (AR), p53, RB1, and PTEN, present in 38%, 30%, 23% and 22% of patients, respectively. Aberrations were associated with poor prognosis factors, including: AR and p53 alterations, which both correlated with presence of liver metastasis (p = 0.020 and p = 0.004 respectively), elevated LDH (p = 0.001, p < 0.001), and presence of ≥ 10 bone metastasis (p = 0.018, p = 0.017); PTEN deletion which correlated with elevated ALP (p < 0.001), elevated LDH (p = 0.001), ≥ 10 bone metastasis (p = 0.009) and time to CPRC of < 12 months (p = 0.021); and RB1 correlated with ≥ 10 bone metastasis (p = 0.009). Conclusions: We found an association between poor prognostic factors and increasing ctDNA fraction in patients with mCRPC. Genomic aberrations, particularly alteration in AR, p53 and PTEN, correlated with poor prognostic factors. These data show that clinical factors may help predict ctDNA yield in patients with mCRPC, and also provide insight into the role of deleterious genetic alterations.
Effect of enzalutamide on sensitivity in prostate cancer cells to radiation by inhibition of DNA double strand break repair.
Authors: Ghashghaei Maryam , Muanza Thierry , Paliouras Miltiadis , Niazi Tamim 
Published: March 2017

208 Background: Prostate cancer is the second leading cause of cancer-related deaths amongst men in North America. Data suggests that, following radiation therapy (XRT), androgen receptor (AR) enhances DNA damage repair and contributes to resistance of prostate cancer (PCa) cells to XRT. At present AR-pathway inhibition is the mainstay treatment of metastatic castration resistance prostate cancer (mCRPC). Enzalutamide (ENZA), a potent AR inhibitor is one of the approved drugs in this setting. The purpose of this study was to assess the potential radiosensitization of ENZA and its mechanism of action in hormone resistant PCa cells. Methods: The effect of ENZA alone or in combination with XRT was assessed on hormone-sensitive, (HS: LNCaP, PC3-T877A) and insensitive PCa cells (HI: PC3, PC3-AR V7, C4-2) using viability and clonogenic assays, cell cycle arrest and DNA damage analysis. Results: MTT assay demonstrates that ENZA significantly inhibits the proliferation of HS PCa cells in a dose dependent manner whereas CRPC required ENZA in combination with ADT (androgen deprivation therapy). Additionally, clonogenic assay proves that concurrent administration of ENZA or ADT+ENZA and XRT led to a supra-additive antitumor effect with the dose enhancement factor of 1.76±0.008 in LNCaP, 1.65±0.01 in PC3-T877A and 1.35±0.003 in C4-2 respectively at surviving fraction of 0.1. This effect was not observed in PC3 and PC3-AR V7 cells pre-treated with ENZA (in all cases DEF = 1 at SF = 0.1). Additionally, the level of γH2AX increased in HS cells and CRPC cells treated with ENZA/ADT+ENZA and XRT when compared to XRT alone. The enhanced H2AX activity remained unchanged up to 24 hours after combination treatment. Furthermore, there is an initial inhibition of DNA-PKcs in HS and CRPC cells treated with ENZA/ADT+ENZA administered before XRT. Conclusions: Our data suggest that the higher efficacy of ENZA/ENZA+ADT and XRT could be partially due to inhibition of DNA damage repair. Our results demonstrated a significant enhancement of XRT efficacy and confirms the rational for the ongoing combination clinical trials with XRT.
A phase II trial of zoptarelin doxorubicin in castration- and taxane-resistant prostate cancer.
Authors: Yu Steven , Athreya Kanthi , Liu Stephen V. , Schally Andrew V. , Groshen Susan G. , Tsao-Wei Denice D , Quinn David I. , Dorff Tanya B. , Xiong Shigang , Pinski Jacek , Engel Jurgen 
Published: March 2017

210 Background: Luteinizing hormone-releasing hormone receptors (LHRH-R) are expressed in ~86% of prostate cancers, with sustained expression despite prolonged exposure to LHRH agonists. Limited expression of LHRH-R on normal cells suggests LHRH-R may be a therapeutic target for prostate cancer. Zoptarelin doxorubicin is a cytotoxic hybrid molecule linking doxorubicin to an LHRH analog that selectively targets doxorubicin to cancer cells expressing LHRH-R. Methods: This Phase 2 trial evaluated the clinical benefit of zoptarelin doxorubicin for metastatic castration-resistant prostate cancer (mCRPC) following androgen deprivation therapy and ≥1 taxane-based regimen. The primary endpoint was clinical benefit (CB) defined as progression-free survival (PFS) per RECIST v1.1 at 12 weeks with no dose-limiting toxicities (DLT) or other toxicities resulting in treatment cessation. Secondary endpoints were time to overall progression, response rate, pain response, overall survival (OS), and PSA response. Results: Of 25 patients enrolled, 20 had ≥1 measurable lesion at baseline with PFS ≥12 weeks achieved in 56% and PSA response of PR (4%) and SD (84%). Median PFS and OS were 3.8 and 6.0 months, respectively. Reduced pain was reported by 59%. Treatment was well tolerated, with no cardiotoxicity and neutropenia (all grades) the most common hematologic adverse event. Conclusions: This phase 2 trial demonstrated clinical benefit in 56% of patients with no DLT or other toxicity requiring treatment termination. These results suggest a role for zoptarelin doxorubicin for mCRPC following progression on second- and third-line hormonal therapy. Clinical trial information: NCT01240629. [Table: see text]
Investigating RUNX1 and RUNX2 in prostate cancer.
Authors: McKillop Anne Jane , Edwards Joanne , Johnson Emma , Mason Susan , Cameron Ewan R , Blyth Karen 
Published: March 2017

232 Background: Prostate cancer is the most commonly diagnosed cancer in men and is increasing in incidence. Current treatment for metastatic disease is initially hormone treatment and chemotherapy. While this produces a response in the vast majority of patients, it is not curative. Novel therapeutic agents could provide a further treatment strategy and it is therefore important to understand the molecular pathways which contribute to this disease. The RUNX family of genes have been implicated as both oncogenes and tumor suppressors, with their role being context dependent. It has been reported that RUNX2 may have a tumor suppressor role in early stage prostate cancer but that this may switch to an oncogenic role in later stage disease. Methods: This project examines the expression of both RUNX1 and RUNX2 in a tissue microarray (TMA) of human prostate cancers. In parallel to the human studies both RUNX1 and RUNX2 were investigated in murine models of prostate cancer. Results: Analysis of the TMA showed that increasing levels of RUNX2 were associated with increasing Gleason grade, shorter time to relapse and poorer survival; the opposite effect was seen in RUNX1, where low levels of protein expression correlated with shorter survival. In concordance with the human results, reducing levels of RUNX2 in mouse models was associated with delayed tumor initiation, and smaller, less cystic tumors at endpoint. The opposite effect was seen with Runx1 where low levels resulted in more aggressive and invasive disease. Finally, when loss of both genes was combined in a model with loss of Pten and stimulation of WNT, survival was significantly reduced compared to controls. Conclusions: This study suggests that RUNX2 expression may correlate with a poorer prognosis in prostate cancer, while expression of RUNX1 is likely to be associated with an improved outcome.
Histone demethylase KDM7a to control androgen receptor activity in hormone-sensitive prostate cancer.
Authors: Kang Minyong , Jeong Chang Wook , Lee Kyoung-Hwa , Ku Ja Hyeon , Kim Hyeon Hoe , Kwak Cheol 
Published: March 2017

262 Background: Prostate cancer can be controlled by androgen-hormone treatment until the cancer becomes refractory. It is believed that hormone sensitivity is largely dependent on androgen receptor (AR) activity. Here, we investigated the molecular mechanism whereby androgen receptor activity is regulated by histone demethylase KDM7a, which demethylates histone H3K9 and H3K27. Methods: The LNCaP, PC3, and DU145 cell lines were cultured at 37 °C in 5% CO2 in Minimum Essential Medium alpha, which was supplemented with 10% fetal bovine serum. We engineered AR-positive LNCaP cells to stably express a short-hairpin RNA against KDM7a mRNA from a lentiviral vector. To examine the mechanisms of AR regulation by KDM7a, we used various techniques of molecular biology, such as real-time PCR, western blot, and chromatin immunoprecipitation assay. Also, we performed immunohistochemical staining by using prostate cancer tissue microarray. Results: By measuring AR downstream gene expression following androgen stimulation, we found that a KDM7a-deficient cell line showed lower AR downstream gene expression compared to a control cells. KDM7a knock-down in LNCaP cell line caused decreased cell proliferation, compared to control cell line. Silencing KMD7a in AR insensitive cell lines did not cause differences in cell proliferation. Western blot analysis with modified-histone antibody revealed that the KDM7a-knock-down LNCaP cell line had increased H3K27 dimethylation. We confirmed KDM7a binding on AR target-gene promoters after hormone stimulation in chromatin-immunoprecipitation experiments. And increased H3K27 di-methylation was observed in KDM7a knock-down LNCaP stable cell. Finally, we observed that the KDM7a protein was significantly upregulated in prostate cancer tissue (compared to control tissue), and that this difference correlated with the Gleason score. Conclusions: These data suggested that KDM7a is potentially a good therapeutic target for prostate cancer drugs and can be used as potentially a good prognostic indicator for prostate cancer and related treatment strategies.
Abiraterone acetate with prednisone and cabazitaxel as subsequent treatment after first-line docetaxel in metastatic castrate-resistant prostate cancer (mCRPC): Final efficacy and safety analysis of the CAPRO study.
Authors: Gonzalez del Alba Arancha , Puente Javier , Sala Nuria , Mendez Maria Jose , Pinto Alvaro , Rodriguez Sanchez Angel , Cuevas Sanz Jose Miguel , Muñoz del Toro Jacobo , Ruiz Pedro , Garcia Angela , Vazquez-Estevez Sergio 
Published: March 2017

276 Background: Abiraterone acetate + prednisone (AA) and cabazitaxel (CB) have shown an improvement in overall survival after Docetaxel (DOC) in (mCRPC)1,2. There is little evidence about the optimal sequencing treatment in prospective trials. In this final analysis we now compare the efficacy of AA and CB as second line (2L) treatment in mCRPC patients (pts) in routine clinical practice (RCP) in Spain. Methods: The CAPRO study is a prospective multicenter national observational descriptive study. The primary endpoint was to describe the management in 2L mCRPC pts after DOC in RCP. bPFS (biochemical progression free survival) and PFS (clinical or radiological progression free survival) were assessed by the Kaplan-Meier method. Results: 150 patients were recruited (Jul 2013-Jan 2015). At median follow-up of 7.8 mo (IQR 4.2-12.8) 67% (n = 100) of the pts received AA, 29% (n = 44) CB, and 4% (n = 6) other treatments as 2L. PSA response > 50% was 47.3% and 32.3% for AA group and CB group respectively (p = 0.146). Median bPFS was similar between the AA and the CB group (9.19 mo [95% CI 6.84-11.55] vs 9.92 mo [95% CI 6.08-13.76]; hazard ratio 0.779 [95% CI 0·49–1.24]; p = 0·29), whereas median PFS was significantly longer in the AA group than in the CB group (8.74 mo [95% CI 6.54-10.94] vs 6.41 mo [95% CI 4.99-7.82]; hazard ratio 0·56 [95% CI 0·38–0·85]; p = 0·005). A difference was observed in bPFS and PFS depending on the time of progression to first line (during treatment, < 3 or more than 3 mo) for both AA and CB. The most common toxicities of special interest (all grades/grade 3–4 as % of pts) were fatigue (31/1% in the AA group vs 54/4% in the CB group), oedema (15/0% AA group vs 13/4% CB group), hypertension 7/1% AA group, diarrhea (8/0% AA group vs 31/4% CB group), vomits (9/2% AA group vs 11/0 CB group) and neutropenia 7/4% CB group. Conclusions: In this final analysis AA was the 2L treatment of choice in routine clinical practice in Spain during the period of time in which the study was conducted. PSA response and bPFS were similar between AA and CB, whereas PFS was significantly longer in the AA group. There were no new safety signals observed.
Quality of life (QL) of patients (pts) treated for muscle invasive bladder cancer (MIBC) with radiotherapy (RT) +/- chemotherapy (CT) in the BC2001 trial (CRUK/01/004): Analysis of impact of treatment at an individual level.
Authors: Huddart Robert Anthony , Hall Emma , Miranda Miguel , Crundwell Malcolm , Jenkins Peter , Rawlings Christine Lisa , Tremlett Jean , Hendron Carey , Lewis Rebecca , Porta Nuria , Hussain Syed A. , James Nicholas D. ,   on behalf of the BC2001 Investigators
Published: March 2017

292 Background: BC2001 showed that adding 5FU+MMC CT (cRT) to RT significantly improved locoregional disease free survival [James 2012] & using reduced high dose volume RT (RHDVRT) rather than standard RT (stRT) did not reduce late side effects [Huddart 2013]. Here we report the impact of treatment on QL at the individual level. Methods: 458 (pts) were randomised to RT (178) vs. cRT (182) (CT comparison) &/or to stRT (108) vs. RHDVRT (111) (RT comparison). Pts completed Functional Assessment of Cancer Therapy-Bladder (FACT-BL) questionnaires at baseline (bl), end of treatment (EoT), 6, 12, 24, 36, 48 & 60 months (m). Mean changes from bl were compared between randomised groups. A minimal clinically relevant change from bl score was defined as 3 points in bladder cancer subscale (BLCS) & 7 points in total FACT-BL (TOTAL). The proportion of pts with an improvement, no difference & worsening at 12m were compared by Chi squared/Fishers exact test (1% significance). Results: Data were available for 331 (92%) & 204 (93%) pts at bl & 181 (50%) & 107 (49%) at 12m for the CT & RT comparison respectively. QL scores were significantly reduced at EoT but recovered to bl levels by 12m with no significant difference in TOTAL or BLCS mean change scores between randomised groups. By EoT ~60% pts reported worsening of QL. At 12m & beyond, whilst mean change scores were not different to bl, ~30-40% reported worsening of QL (-) with a similar proportion reporting an improvement (+) (Table 1). No statistically significant differences were found between randomised groups. Conclusions: Following (c)RT a significant proportion of pts have a decline in QL at EoT but after 12m overall QL is, on average, similar to bl. At an individual level approximately equal proportions of pts report an improvement in QL as report a worsening. There is no evidence of additional impairment in QL by the addition of CT to RT. Clinical trial information: ISRCTN6832433. [Table: see text]