bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpreting survival outcomes for African-American (AA) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T (SIP-T) with number needed to treat to benefit (NNTB).
Authors: Moses Kelvin A. , Flanders Scott C. , Harmon Matthew , Chang Nancy N. , Rayford Walter , Quinn David I. , Sartor A. Oliver 
Published: March 2019

222 Background: AA men often present with more aggressive prostate cancer and are less likely to receive treatment, negatively affecting quality-of-life and overall survival (OS). Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Data from the PROCEED registry showed that OS for AA pts treated with SIP-T was 9.3 mo longer than OS for Caucasian pts. In a prior subgroup analysis of Phase III data, AA pts realized a 30.7-mo difference in OS with SIP-T vs. placebo (PBO). We calculated the NNTB to further interpret the OS benefit in AA pts. Methods: Data were pooled from 3 Phase III mCRPC SIP-T trials (D9901, D9902A, and IMPACT). The absolute risk reduction (ARR) is calculated from Kaplan-Meier estimates at 12-, 24-, and 36-mo for all SIP-T subjects, and an AA cohort, receiving ≥1 infusion. NNTB, the inverse of the ARR, represents the number of pts needed to be treated with SIP-T to prevent 1 additional death compared to PBO. All NNTB values are rounded up. Results: Of the 737 pooled mCRPC pts enrolled, 488 men were randomized to SIP-T (n=33 AA), and 249 to PBO. Baseline clinical characteristics between the SIP-T and PBO groups were well balanced; however, compared to overall SIP-T and PBO, AA SIP-T pts were more likely to have received prior chemotherapy, lower hemoglobin, and better performance status. The NNTB at 12-mo was the same (13) for both the pooled SIP-T and AA treated cohort. At 24-mo, the NNTB values were 10 for pooled and 5 for AA. At 36-mo, an NNTB of 8 (pooled) and 3 (AA) SIP-T treatments prevented 1 additional death (Table). Conclusions: This NNTB analysis shows a favorable survival benefit for AA men treated with SIP-T and all treated SIP-T subjects. NNTB values declined over 3-years, suggesting durability of clinical benefit with SIP-T, and that it may address a known survival disparity in AA with prostate cancer. Studies with larger sample sizes may confirm if AA pts derive a greater OS benefit from SIP-T. Clinical trial information: NCT00065442. [Table: see text]
Radium 223 treatment in metastatic castrate-resistant prostate cancer: Impact of sequencing on survival—Real-world outcomes from a single United Kingdom center.
Authors: Jiang Xue Yan , Atkinson Sarah , Cuming Sam , Burns Alexander , Pearson Rachel Anne , Frew John A. , Azzabi Ashraf S. , McMenemin Rhona Margaret , Pedley Ian David 
Published: March 2019

223 Background: Radium 223 (Ra-223) is a FDA and EMA approved alpha particle radiopharmaceutical used to treat men with metastatic castrate resistant prostate cancer (mCRPC) with symptomatic bone metastasis. In view of emerging systemic options, new EMA 2018 licence indication is for 3rd line onwards. We aim to evaluate the impact of systemic therapy sequencing on survival outcomes from a heterogeneous cohort of 228 patients treated with Ra-223 in a single UK centre. Methods: We prospectively collected data from 228 men underwent Ra-223 therapy for mCRPC between April 2014 and August 2018. Survival outcomes in relation to sequence of systemic treatment used prior to Ra-223 were analysed. Results: Medium age = 72 (51-87) years. Most patients (n = 142, 69%) received at least one systemic agent prior to Ra-223: docetaxel and/or cabaxitaxel chemotherapy (n = 60, 29%), abiraterone (n = 62, 30.1%) and enzalutamide (n = 67, 32.5%) in various sequences. No patients received concurrent Ra-223 /systemic treatment other than LHRH analogue. Key findings are summarized in table below. Conclusions: Our data demonstrated better survival trend in patients who received Ra-223 early. Patients who received prior chemotherapy have worse survival compared with those who were chemo-naïve likely due to bone marrow depletion. Ra-223 should not be offered to patients who have already had both cabaxitaxel and docetaxel as their medium survival is too poor to justify a treatment which takes 6 months to complete.[Table: see text]
Immunogenomic landscape of neuroendocrine prostate cancer (NEPC).
Authors: Ferguson Alison , Bhinder Bhavneet , Conteduca Vincenza , Sigouros Michael , Sboner Andrea , Nanus David M. , Tagawa Scott T. , Rickman David , Elemento Olivier , Beltran Himisha 
Published: March 2019

224 Background: Prostate cancer (PCa) shows limited clinical benefit from current immunotherapy strategies. NEPC is a histologic subtype of advanced PCa that most often arises clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance, but shares pathologic, clinical, and molecular features with small cell lung carcinoma (SCLC). We investigated the immune landscape of NEPC in relation to other PCa subtypes and SCLC to identify potential immunological targets. Methods: We evaluated RNA-seq from 190 patients comprising benign prostate (n = 29; 25 PCa matched), localized PCa (n = 68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n = 11), CRPC (n = 54), NEPC (n = 25) with follow-up data, and SCLC (n = 28) (Rudin et al., Nat Gen 2012). Additionally, 290 patients had WES data available for tumor mutational burden (TMB). Unsupervised clustering of FPKMs was performed to identify an immune rich cluster of 232 genes, which was used to categorize immune status and prioritize validation of select targets by IHC. Results: Median TMB of NEPC was similar to CRPC (38.0 vs 37.0 p= 0.44) but significantly lower than SCLC (38.0 vs 142.5, p< 0.001). Unsupervised assessment of T-cell related gene expression identified a predominantly cold immune status across subtypes, with hot (n = 8) tumors associated with metastatic tumors of the LN and bone. Worse overall survival was seen with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p < 0.001). Further analysis of NEPC showed lower expression of cytokines ( p< 0.01) and variation in checkpoint markers. Specifically, NEPC had significantly lower expression of PD1 in relation to CRPC ( p= 0.0001) and SCLC ( p = < 0.0001), higher PDL1 than CRPC ( p= 0.05) but comparable with SCLC ( p= 0.93) and lower PDL2 than PCa and SCLC ( p= 0.03; < 0.001, respectively). Conclusions: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. The inverse correlation between survival outcome and immune infiltration, as well as the novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC.
Results of a 50 patient single-center phase II prospective trial of Lutetium-177 PSMA-617 theranostics in metastatic castrate-resistant prostate cancer.
Authors: Hofman Michael , Violet John A , Hicks Rodney J , Ferdinandus Justin , Thang Sue Ping , Iravani Amir , Kong Grace , Ravi Kumar Aravind , Akhurst Timothy J. , Mooi Jennifer , Guo Christina , Tran Ben , Jackson Price , Scalzo Mark , Eu Peter , Williams Scott , Sandhu Shahneen Kaur 
Published: March 2019

228 Background: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling targeted delivery of beta-radiation. We have previously reported favourable activity with low toxicity in a 30 patient study in men with metastatic castrate-resistant prostate cancer (mCRPC) and now report updated results including a twenty patient extension cohort. Methods: In this phase II trial, 50 pts with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints included imaging response, PSA PFS and OS. Cut-off for analysis 5 Oct 2018. Results: 76 men were screened to identify 50 patients eligible for treatment. Median PSA doubling time was 2.6 months. The majority of patients had received prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline ≥ 80%. 27 patients had measurable soft tissue at baseline and 56% of these patients had a partial or complete response by RECIST 1.1. The most common toxicities attributed to LuPSMA were transient G1-2 dry mouth in 68%, G1-2 nausea in 48%, and G1-2 fatigue in 36%. G3-4 toxicities attributed to LuPSMA were infrequent with thrombocytopenia in 10% and anaemia in 10%. Median PSA PFS was 6.9 months (95% CI 6.0-8.7) and median OS was 13.3 months (95% CI 10.5-18.0). Upon subsequent progression, further LuPSMA was administered to 14 patients (median 2 cycles commencing 359 days from enrolment); PSA ≥ 50% response occurred in 9 patients (64%). Conclusions: This expanded 50 patient cohort confirms high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies. In patients who subsequently progressed and were administered further LuPSMA, high response rates were also observed. These results have provided the basis for randomised controlled trials currently underway. Clinical trial information: ACTRN12615000912583.
The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as a biomarker of taxane resistance in castration-resistant prostate cancer.
Authors: Reig Òscar , Marin Mercedes , Mila Maria , Font Albert , Domenech Montserrat , Rodriguez Vida Alejo , Carles Joan , Suárez Cristina , Gonzalez del Alba Aranzazu , Jiménez Natalia , Victoria Iván , Sala Nuria , Ribal Maria Jose , López Sandra , Etxaniz Olatz , Maroto Pablo , Fernandez Pedro L. , Prat Aleix , Mellado Begona 
Published: March 2019

235 Background: TMPRSS2-ERG expression at peripheral blood has been correlated with lower docetaxel benefit. This multicenter study prospectively assessed the role of TMPRSS2-ERG mRNA as a taxane-resistance biomarker in blood and retrospectively in tumors, and explored the impact of prior abiraterone/enzalutamide (A/E) in castration-resistant prostate cancer (CRPC) patients and in vitro. Methods: TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with PSA-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. ERG knockdown, combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Results: In the multivariate analysis prior A/E (HR: 1.833; P = 0.005) and blood TMPRSS2-ERG (HR: 2, 95%CI; 1.1-3.67; P = 0.018) , were independently associated to lower PSA-PFS. In patients without prior A/E, both blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 2.92; P = 0.014 and HR 1.82; P = 0.045, respectively) to taxanes. This was not observed in patients with prior A/E. There was a significant interaction between blood TMPRSS2-ERG detection and prior A/E related to PSA-PFS (P = 0.032) and RX-PFS (P = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced neuroendocrine markers and reduced E-cadherin expression. Conclusions: Prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.
Adverse events of special interest assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials.
Authors: TOMBAL Bertrand F. , Armstrong Andrew J. , Barrus Jeffrey Kent , Beer Tomasz M. , Chowdhury Simon , Evans Christopher P. , Heidenreich Axel , Higano Celestia S. , Kamba Tomomi , Lin Ping , Nikolayeva Natalia , Sugg Jennifer , Steinberg Joyce Leta , Taplin Mary Ellen , Saad Fred 
Published: March 2019

237 Background: Androgen receptor inhibitor enzalutamide improves survival in patients with metastatic CRPC (mCRPC) and reduces risk of metastasis or death versus placebo in patients with non-metastatic CRPC (nmCRPC). This post hoc analysis evaluated the incidence of adverse events (AEs) of special interest reported with enzalutamide versus placebo in CRPC trials. Methods: Safety data from four Phase 3, placebo-controlled enzalutamide trials in men with CRPC (PROSPER, nmCRPC, NCT02003924; PREVAIL, mCRPC, NCT01212991; AFFIRM, mCRPC, NCT00974311; and 9785-CL-0232, mCRPC, NCT02294461) were assessed for AEs of special interest, including ischemic heart disease (IHD) [defined by narrow Standardised MedDRA Queries “Myocardial Infarction”/“Other Ischemic Heart Disease”], falls, and fractures. Data were reported as overall incidence and adjusted for treatment exposure (per 100 patient-years), and summarized as follows: patients receiving enzalutamide (n = 2799) and placebo (n = 1898) in all four Phase 3 trials. Results: Median treatment duration was 13.73 months with enzalutamide and 4.80 months with placebo in the combined Phase 3 trials. Overall incidence of IHD was higher with enzalutamide versus placebo in the combined Phase 3 trials (Table), remaining higher once adjusted for treatment exposure (2.5 with enzalutamide vs. 2.2 with placebo). Similarly, exposure-adjusted rate of falls and fractures were also higher with enzalutamide versus placebo (Table). Clinical trial information: NCT02003924 (PROSPER); NCT01212991 (PREVAIL); NCT00974311 (AFFIRM); NCT02294461 (9785-CL-0232). Conclusions: In this combined analysis of CRPC trials, incidences of IHD, falls, and fractures were higher with enzalutamide versus placebo in all patients. Efforts to identify patients at high risk for these AEs and reduce their risk, e.g. via exercise and cardiovascular risk reduction, are important in these patients, particularly in elderly men and those with cardiovascular comorbidities.[Table: see text]
Methylation-associated miR193b silencing activates master drivers of aggressive prostate cancer.
Authors: Mazzu Ying Zhang , Chakraborty Goutam , Yoshikawa Yuki , Nandakuma Subhiksha , Armenia Joshua , Jehane Lina E. , Lee Gwo-Shu Mary , Mucci Lorelei , Kantoff Philip W. 
Published: March 2019

240 Background: Epigenetic changes in DNA methylation, histone modifications and miRNA expression have major roles in prostate cancer (PC) initiation and progression. Previous screening for epigenetically regulated miRNAs in PC revealed hypermethylation of the miR-193b promoter, but no related functional studies in PC have been reported. Methods: Methylation was measured by methylation-specific PCR. Quantitative RT-PCR was used to validate the regulation of potential miR-193b targets. Luciferase reporter assays were applied to detect the regulation of miR-193b-targets. The promoter methylation status was modified by DNMT and HDAC inhibitors (5-azacytidine and mocetinostat). Results: miR-193b level is inversely correlated with the degree of its promoter’s methylation in the TCGA cohort. Distinct miR-193b promoter methylation patterns were detected in multiple normal and PC cell lines. Overexpression of miR-193b in PC cells with low miR193b level induced cell growth inhibition, apoptosis, or inhibition of invasion. Previously reported top 150-downregulated genes by miR-193b in liposarcoma showed a high correlation with PC progression in multiple PC cohorts. We further identified FOXM1 and RRM2 as the direct targets of miR-193b. Knockdown of FOXM1 and RRM2 in PC cells phenocopied miR-193b with respect to inhibition of invasion and induction of apoptosis. Furthermore, combination treatment with DNMT and HDAC inhibitors released the methylation-regulated silencing of miR-193b in PC cells, resulting the inhibition of FOXM1 and RRM2 expression. Conclusions: We revealed the tumor suppressive function of miR-193b in PC. Overexpression of miR-193b in PC cells with low miR193b level induced cell growth inhibition, apoptosis, or inhibition of invasion. A gene set identified in liposarcoma cells by overexpression of miR-193b showed a high correlation with PC progression in multiple PC cohorts. FOXM1 and RRM2 may be the key targets of miR-193b in PC. Our findings suggest that methylation-silencing miR-193b in PC may release the inhibition of some key oncogenes to contribute PC progression, which could provide a possible therapeutic mechanism for PC therapy.
The effect of a structured exercise intervention on CTCs and platelet cloaking in patients with metastatic prostate cancer.
Authors: Brady Lauren , Hayes Brian , Sheill Grainne , Baird Anne-Marie , Guinan Emer M. , Stanfill Bryan , Vlajnic Tatjana , Casey Orla , Greene John Patrick , Allott Emma , Hussey Juliette M. , Cahill Fidelma , Van Hemelrijck Mieke , Peat Nicola , Rudman Sarah Maria , Mucci Lorelei , Sheils Orla , John O'Leary , McDermott Ray , Finn Stephen P. 
Published: March 2019

243 Background: Physical activity has been described as an effective adjunct for improving quality of life in patients with metastatic prostate cancer (PrCa). Circulating tumor cells (CTCs) are a morphologically distinct set of cancer cells, involved in disease progression. Platelet cloaking, the surrounding and subsequent attachment of platelets to CTCs, has been proposed as effective in aiding extravasation, thus enhancing metastatic spread. The ExPeCT (Exercise, Prostate Cancer and Circulating Tumor Cells) trial aimed to examine the impact of a structured exercise intervention on the mechanisms of metastasis, including CTC cloaking, in patients with metastatic PrCa. Methods: ExPeCT was a multi-center, randomized trial for patients with metastatic PrCa (n=61). Participants were randomized to either control or exercise arms. Participants in the exercise arm (n=29) completed six months of prescribed aerobic exercise. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analyzed for the presence of CTCs, CTC clusters and platelet cloaking. Results: No significant difference in CTC number between the exercise and control arms was observed (p=0.2630), however significant alterations in CTC number were observed within group over time (p<0.001). Platelet cloaking was modelled as a binary response (presence/absence). A trend towards higher levels of platelet cloaking in the control group was observed (p=0.1005). Further, all findings were compared to a range of clinical variables. CTC clusters were positively correlated with PSA levels (p=0.0393) and a positive correlation between CTC number and white blood cell count (p<0.001) was determined. Conclusions: No significant relationship between CTCs and physical activity was observed, however the exercise program was well tolerated by ExPeCT participants. This study has, for the first time, shown platelet cloaking of CTCs in metastatic PrCa, in addition to a significant positive correlation between CTCs and white blood cells. These findings provide critical insight into immune crosstalk and the metastatic cascade in metastatic PrCa. Clinical trial information: NCT02453139.
Aberrations in androgen receptor ctDNA varies by race in metastatic castrate-resistant prostate cancer.
Authors: Christensen Bryce Raymon , Ledet Elisa , Vu James , Steinwald Peter , Chapman Lynne , Ko Leta , Ranasinghe Lahiru , Schiff Joshua , Moses Marcus Marie , Cotogno Patrick , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Sartor A. Oliver 
Published: March 2019

247 Background: Characterization of circulating free DNA (ctDNA) may aid understanding of the pathophysiology of metastatic castrate resistant prostate cancer (mCRPC). The goal of this study was to evaluate and compare somatic alterations in ctDNA between African-American (AA) and Caucasian (C) mCRPC patients. Methods: 24 AA were retrospectively case-matched by prior treatment with 45 CA mCRPC; ctDNA was assessed with Guardant360 assay (Guardant Health, Redwood City, CA). Mutant allelic fraction, mutations, and gene amplification were compared. Results: Prior to testing, 6 AA pts and 12 CA pts had 0 lines of CRPC therapy, 7 AA pts and 10 CA pts had 1-2 lines, 5 AA and 17 CA had 3-4 lines, 5 AA and 2 CA had 5-6 lines, and 1 AA pt and 4 CA pts had >6 lines. The median Gleason score was 8, regardless of race. The median ctDNA mutant allelic fraction was 0.40% for AA pts and 0.60% for the CA pts. Mutations and/or amplifications in individually assessed genes are shown in the Table. No statistically significant differences were detected except for the androgen receptor (AR) gene where alterations (mutations and/or amplifications) were more frequent in AA as compared to C (p=0.04). Conclusions: AR alterations were more commonly detected in ctDNA in AA men as compared to C suggesting that AR driven pathophysiology may predominate in this setting. Additional analyses with a larger cohorts are warranted. Data from prospective trials in mCRPC using abiraterone/prednisone (George et al. LBA 5009, ASCO 2018) similarly suggest that mCRPC may be comparatively more AR driven in this racial setting. Alterations in ctDNA compared between AA and C men with mCRPC. [Table: see text]