bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarker patterns of localized and metastatic prostate cancer.
Authors: Feldman Rebecca , Reddy Sandeep K. , Gatalica Zoran , Mahanes Joanne R. , Myers Charles E. 
Published: February 2017

192 Background: Presence or absence of metastases is a determining factor for prostate cancer prognosis. Common sites of metastasis include bone (B), lymph nodes (LN) or visceral organs (V). We sought to determine theranostic biomarker differences between primary (P) and metastatic (M) specimens, with subset analysis for differences between metastatic sites. Methods: 497 prostate cancer cases referred to Caris Life Sciences between 2009 thru 2014 were evaluated. Specific testing was performed and included a multiplatform approach: sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: 58% (287/497) were M specimens, of which 23% (66), 24% (68) and 52% (149) were from B, LN and V, respectively. Significant differences for EGFR amplification/overexpression, low MGMT expression, TOPO1/2A overexpression and higher PTEN mutation rate were found in the M subgroup. These alterations indicate a role for EGFR/PTEN in progression of prostate cancer, and potential role of MAPK/PAM-targeted therapies, alkylating agents and topoisomerase inhibitors in M disease. Mutational profiles of the M subgroup are more genetically unstable exhibiting mutations in 60% of genes tested (notable events include APC & β-Catenin, PTEN, TP53 and BRCA1/2) vs. 30% observed in the P subgroup (p=0.0067). In the subset analysis, EGFR amplification was higher in B (29%) and V (24%) compared to LN (13%); (not significant). Low TS expression was more frequent in B vs. LN (p=0.004), TOPO2A overexpression was higher in V vs. B (p=0.0001) and there was a trend for PD1 positive infiltrating lymphocytes being more abundant in LN vs B (p=0.09). Interestingly, cMET overexpression (7/230) and amplification (1/162) were rarely observed across the cohort, providing support for the surprising failure of cabozantinib in castration-resistant prostate cancer. Conclusions: Our data indicate a role for multiplatform profiling to identify therapeutic options that are appropriate for subsets of patients. Molecular changes associated with M disease including EGFR, PTEN, MGMT and TOPO1/2A, present opportunities for developing therapeutic strategies which may include a combination of targeted therapies, as well as traditional cytotoxic chemotherapies.
Tracking clonal diversity in metastatic prostate cancer progression.
Authors: Hovens Christopher , Hong Matthew , Macintyre Geoff , Wedge David , Van Loo Peter , LunkePhD Sebastian , Alexandrov Ludmil , Slogget Clare , Cmero Marek , Mangiola Steafano , Lonie Andrew , Naeem Haroon , Sapre Nikhil , Phal Pramit , Kerger Michael , Pedersen John , Ryan Andrew , Haviv Izhak , Costello Anthony , Corcoran Niall 
Published: February 2017

193 Background: Genomic heterogeneity has been observed in a number of tumor types including prostate cancer. However, how subclonal tumor diversity changes during metastasis and progression to lethality remains unexplored. Large scale genomic analyses have reported the most prevalent somatic aberrations associated with the dominant clone of the tumor without permitting an analysis of subclonal complexity or how this complexity impinges on metastatic potential or resistance to treatment. Methods: To understand and track the evolution of lethal prostate cancer from initial therapy to end stage metastases, we performed longitudinal and multiregional sampling of tumors from 7 patients with lethal prostate cancer. We performed whole-genome sequencing, RNA sequencing, and SNP profiling. Computational approaches were used to reconstruct the genetic relationships and evolution of the tumors. These evolutionary tree reconstructions allowed us to observe the dynamics of chromoplexy and mutational processes along specific branches of tumor evolution. To refine the genetic landscape and spatial connections between subclones, we employed deep, targeted re-sequencing of variant loci in the original sequenced samples, in additional FFPE sites sampled from the organ confined tumors, and from blood. Results: We show that while all primary and metastatic prostate tumors share a single ancestral clone, metastases arise from subclones present at minor frequencies in the primary tumor. We reveal that individual metastases comprise mixtures of subclones indicative of intra-metastatic heterogeneity. We provide evidence for cross-metastatic site seeding and dynamic remolding of subclonal mixtures in response to therapy suggesting a distinct metastatic hierarchy. Ultra-deep sequencing of end-stage blood reveals the presence of diverse subclones with metastatic potential derived from various stages in the evolution of the tumor. Conclusions: Our results demonstrate unexpected complexity in the origins of both primary and metastatic prostate cancer, with distinct implications for treatment of advanced disease.
Clinical outcomes and safety in men ≥ 75 and < 75 years with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide in the phase 3 PREVAIL trial.
Authors: Graff Julie Nicole , Baciarello Giulia , Armstrong Andrew J. , Higano Celestia S. , Iversen Peter , Forer David , Mansbach Harry H. , Phung De , Tombal Bertrand F. , Beer Tomasz M. , Sternberg Cora N. 
Published: February 2017

200 Background: In the phase 3 PREVAIL trial, enzalutamide (ENZA), an androgen receptor inhibitor, improved overall survival (OS) and radiographic progression-free survival (rPFS) relative to placebo (PBO) in chemotherapy-naïve men with mCRPC. Methods: PREVAIL randomized 1,717 patients (pts) with asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC 1:1 to ENZA 160 mg daily or PBO. Coprimary endpoints were OS and rPFS. This prespecified analysis evaluated the impact of age (≥ 75 vs < 75 years) on efficacy and safety. Results: In PREVAIL, 609 (35%) pts were aged ≥ 75 years. This older subset had several poorer baseline prognostics relative to those aged < 75 years: worse ECOG performance status (ECOG 1: 45.0% vs 24.7%), higher prostate-specific antigen (PSA; 73.3 vs 37.3 ng/mL) and more cardiovascular disease (26.9% vs 16.5%). In both older and younger pts, ENZA improved OS, rPFS and time to PSA progression (Table). Pts aged ≥ 75 years in both the ENZA and PBO groups combined had a higher rate of grade ≥ 3 adverse events (46% vs 37% in younger pts) and among enzalutamide-treated men more older pts reported falls (any grade; ENZA 19% and PBO 8%) than younger pts (ENZA 7% and PBO 4%). Fewer pts ≥ 75 years received subsequent antineoplastic therapies. Conclusions: In PREVAIL, efficacy outcomes in elderly (≥ 75 years) and younger (< 75 years) pts with chemotherapy-naïve mCRPC were comparable and pts consistently benefited from ENZA treatment. Safety with ENZA was similar in both age groups, although older pts reported a higher incidence of falls and received fewer subsequent antineoplastic therapies. Clinical trial information: NCT01212991. [Table: see text]
Effects of radium-223 dichloride (Ra-223) with docetaxel (D) versus D on prostate-specific antigen (PSA) and bone alkaline phosphatase (bALP) in patients (pts) with castration-resistant prostate cancer (CRPC) and bone metastases (mets): A phase 1/2a clinical trial.
Authors: Morris Michael J. , Higano Celestia S. , Scher Howard I. , Sweeney Christopher , Antonarakis Emmanuel S. , Shevrin Daniel H. , Ryan Charles J. , Loriot Yohann , Fizazi Karim , Pandit-Taskar Neeta , Garcia-Vargas Jose E. , Lyseng Kari , Bloma Marianne , Aksnes Anne-Kirsti , Carrasquillo Jorge A. 
Published: February 2017

202 Background: Ra-223 is an approved α-emitter prolonging survival in CRPC with symptomatic bone mets. We conducted a phase 1/2a study examining the safety and antitumor effects of Ra-223 + D vs D alone, and previously presented data showing that Ra-223 + D is safe and well tolerated (ESMO 2014). Here we report the effect of Ra-223 + D vs D on bALP and PSA dynamics. Methods: D-eligible pts with progressing CRPC and ≥ 2 bone mets were randomized 2:1 to Ra-223 (50 kBq/kg q 6 wk × 5) + D (60 mg/m2 q 3 wk × 10) vs D (75 mg/m2 q 3 wk with step-down option to 60 mg/m2). bALP and PSA were recorded q 3 wk during first 6-wk cycle, then q 6 wk and q 3 wk, respectively, and analyzed at a central laboratory. Changes in both markers are described by the % of pts who achieved ≥ 30%, > 50%, and > 80% declines between baseline and the safety follow-up visit (3 wk post last D injection) as their best response; pts with elevated baseline bALP (≥ 21 µg/L) levels were included for the bALP analysis. bALP to below the upper limit of normal (ULN) was also recorded, regardless of % decline. Results: 46 pts (33 Ra-223 + D vs 13 D alone) were enrolled. As of October 2014, 21 (Ra-223 + D) vs 5 (D) pts had received all planned study treatment. Median (range) baseline PSA was 99 µg/L (3-1000) for Ra-223 + D pts and 43 µg/L (4-1042) for D pts. Maximal changes in PSA and bALP levels between baseline and safety follow-up are shown in Table. No pt had a bALP increase. Conclusions: Ra-223 + D appears to favorably impact posttreatment PSA and bALP declines. Ra-223 + D appears particularly effective at normalizing bALP levels vs D alone. The clinical benefits of such changes in serum markers will require validation in larger prospective studies. Clinical trial information: NCT01106352. [Table: see text]
Bone scan index as a biomarker to predict outcome in real-life mCRPC patients on abiraterone acetate: A multicenter study.
Authors: Reza Mariana , Ohlsson Mattias , Kaboteh Reza , Anand Aseem , Franck Lissbrant Ingela , Damber Jan-Erik , Budäus Lars , Eichenauer Till , Wollmer Per , Edenbrandt Lars , Tragardh Elin , Bjartell Anders 
Published: February 2017

217 Background: Bone Scan Index (BSI) is a quantitative measurement that reflects the tumor burden in bone calculated from bone scintigraphy. It also represents a prognostic marker in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Abiraterone acetate (AA) has showed to prolong survival before and after chemotherapy in this group of pts. In this study we evaluated the predictive value of BSI change as a biomarker of response in mCRPC patients on treatment with AA. Methods: We retrospectively studied 62 mCRPC pats who received AA following disease progression after chemotherapy at 3 different academic hospitals. Automated baseline and follow-up BSI data was obtained from images of whole-body bone scintigraphies performed before and during AA treatment. Data on clinical overall survival (OS), blood levels of prostate-specific antigen (PSA), alkaline phosphatase (ALP) and haemoglobin (Hb) at the time of baseline and upon follow-up was collected from medical records. The association between changes in these parameters at follow-up and survival was evaluated using Cox proportional-hazards regression models and Kaplan-Meier estimates of the survival function. Discrimination between prognostic variables was assessed using the concordance index (C-index). Results: Pts with an increase in BSI of > 0.3 (n=31) had 13% one year-survival rate compared to 42% for pts with improvement or stable disease according to BSI change at follow-up (BSI change < 0.3; n=31) (p< 0.001). Among all parameters evaluated (BSI, PSA, ALP, Hb) in a univariate Cox analysis, BSI change from baseline to follow-up presented the highest and strongest association with OS (C-index=0.7, Hazard ratio= 1.3 and p=0.0001). Conclusions: Increase in BSI of ≥ 0.3 is significantly associated with reduced survival in mCRPC pts under AA treatment following disease progression in a post-chemotherapy setting. BSI is a candidate biomarker to evaluate response and survival in this group, and change in BSI could be a valuable tool in monitoring pts with mCRPC on second-line therapies. BSI could then serve as a decision making tool supporting physicians to continue current treatment or to consider alternative therapies.
Impact of skeletal-related events on survival in patients with prostate cancer metastatic to bones.
Authors: McDougall Jean A. , Goulart Bernardo Haddock Lobo , Sullivan Sean D , McCune Jeannine S. , Bansal Aasthaa , Karnopp Andrew , Fedorenko Catherine R. , Valderrama Adriana , Seal Brian S. , Ramsey Scott David 
Published: February 2017

223 Background: Skeletal related events (SREs), defined as pathological fracture, spinal cord compression, surgery or radiotherapy to the bone, occur in nearly half of men diagnosed with metastatic prostate cancer. Accurate assessment of the risk of death associated with SREs is important to making decisions about the use of recently approved treatments, which have been shown to decrease the frequency of skeletal events, yet estimating the impact of SREs on survival presents several methodological challenges given the recurrent time-dependent nature of exposure. Methods: A cohort of men >65years of age, diagnosed with prostate cancer and bone metastasis between January 1, 2004 and December 31, 2009 was identified from the Surveillance Epidemiology and End Results (SEER) registries were linked to Medicare Parts A and B claims. The outcome of interest, death from any cause, was ascertained from SEER and survival time was calculated from the date of metastatic prostate cancer diagnosis. Multivariable Cox proportional hazards models treating the occurrence of an SRE as a time-dependent exposure were used to estimate the hazard ratios (HR) and corresponding 95% confidence intervals (CI) for the association between SRE occurrence, number, and type, and death. Results: Among 3,297 men with metastatic prostate cancer, 40% experienced ≥1 SRE during the observational follow-up period (median 19 months). Compared to men who remained SRE-free, cohort members who had ≥1 SREs had a two-fold higher risk of death (HR 2.2, 95% CI 2.0-2.4). Those whose first SRE was a pathological fracture had a 2.7-fold higher risk of death (HR 2.7, 95% CI 2.3-3.1), followed by spinal cord compression (HR 2.1, 95% CI 1.8-2.5), surgery (HR 1.8, 95% CI 1.5-2.2) and radiotherapy (HR 2.2, 95% CI 1.9-2.4). Compared to those experiencing only one SRE, men who experienced a second SRE of any type had double the risk of death (HR 2.2, 95% CI 1.9-2.6). Conclusions: SREs were associated with ≥50% reduction in overall survival. This finding is consistent across different types of SREs and supports using therapies to prevent or treat SREs in patients with prostate cancer metastatic to the bones.
Efficacy of a novel cytotoxic polybisphosphonate for treatment of bone metastasis in castration-resistant prostate cancer (CRPC).
Authors: Nilsson Sten , Lindberg Henriette , Thellenberg-Karlsson Camilla , Nyman Claes , Marquez Marcela , Lennartsson Lena , Blom René , Castellanos Enrique , Holmberg Anders R 
Published: February 2017

236 Background: A cytostatic polybisphosphonate was developed for Tx of mCRPC. It has a) anti-resorptive effects, osteoclast inhib., b) tum. cell spec./tox, confirmed in in-vivo models. Tox. study shows high tolerability. Animal PK study has shown T½ < 3 hrs; principal accumulation in liver, spleen, kidneys. Methods: Clin phase I/IIa (clinicaltrials.gov NCT01595087): Prim obj: to define MTD of ODX given every 3rd week. Sec. obj: OS, bone metab. and resp. markers, PSA, QoL and PK. Explorative in vitrostudies (basis for rand. phase IIb trial in pts. with docetax-res. mCRPC). A docetax-resist. cell-line was developed from DU145 in escalating conc. of docetax, then continuous growth in docetax 500 µg/ml. Cells subj. to cytotox. exp. with ODX (iCELLigence system and fluorom microculture cytotox assay). Results: Clin Phase I/IIa first-in-man trial (clinicaltrials.gov NCT01595087): 17/28 patients rec. 4-7 doses every 3rd week. No DLTs; max dose adm.: 3.0 mg/kg: no drug-related SAEs. Tx was well tolerated. Efficacy and QoL data w. considerable variability as to be expected in this population of pts. w. mCRPC. Max blood conc. ODX: 110-160 fmol/mL; 85-90 % cleared within first 1 hr. Efficacy of ODX in docetax-res DU145TR: A dose-dependent cytotox effect seen when adding ODX in “sub-clin.” doses. All cells were apparently killed in the clin. relevant dose 6 uM. Conclusions: ODX is a novel drug cand. w. high cytotox. efficacy in vivo and in vitro, even in highly docetax-res. cells. Animal studies and Phase I trial show excellent tolerability. Studies now ongoing to elucidate whether short-term treatment is as efficacious as continuous treatment and whether some cells de facto may develop resistance also to this new treatment concept. A multicenter rand. double-blind pbo. controlled trial (EudraCT 2014-002054-39) starts Q4 2014 in mCRPC pts failing docetax and/or cabazitaxel AND abiraterone and/or enzalutamide. Clinical trial information: NCT01595087.
Evaluation of 3 T pelvic MRI imaging in prostate cancer patients receiving postprostatectomy IMRT.
Authors: Verma Vivek , Gay Hiram Alberto , Chen Ling , Michalski Jeff M. , Grubb Robert L. 
Published: February 2017

242 Background: The purpose of the study was to evaluate the utility of a 3 T pelvic magnetic resonance imaging (MRI) in detecting a local recurrence in post-prostatectomy prostate cancer patients prior to receiving adjuvant or salvage intensity-modulated radiation therapy (IMRT). Methods: Ninety prostate cancer patients status post-prostatectomy with rising prostate-specific antigen (PSA) had a 3 T pelvic MRI prior to IMRT. The following variables were analyzed for predicting positive findings on MRI: initial presenting and initial post-op PSA, PSA at the time of imaging, PSA velocity, surgical margins, Gleason score, pathological stage, pre-RT digital rectal examination, and type of surgical prostatectomy. Results: The only significant variable predictive of a positive MRI was positive margins. Specifically, 15 of 46 (33 %) patients with positive margins had a positive MRI, while 5 of 44 (11 %) patients with negative margins had a positive MRI. In the MRI positive group, the location of the positive findings on MRI corresponded with the pathology report in 9 of 12 (75 %) cases. Conclusions: Post-prostatectomy patients with pathologic positive margins are three times more likely to have positive findings on a 3 T MRI. [Table: see text]
Prior and concurrent use of abiraterone and enzalutamide with Ra-223 in an expanded access setting.
Authors: Sartor A. Oliver , Fernandez Daniel Celestino , Morris Michael J. , Iagaru Andrei , Brown Alan , Almeida Fabio , Sweeney Christopher , Smith Matthew Raymond , Dicker Adam , Wong Yu-Ning , Shore Neal D. , Gratt Jeremy , Petrenciuc Oana , Vogelzang Nicholas J. 
Published: February 2017

253 Background: The aim of this prospective early-access program (EAP) was to monitor acute and long-term safety of Ra-223 CL2. The ALSYMPCA RA-223 phase III trial was completed prior to abiraterone (Abi) and enzalutamide (Enza) approval. Herein we provide experience with RA-223 in relationship to Abi and Enza. Methods: Symptomatic bone metastatic CRPC pts in the US who were ineligible for or had prior docetaxel were enrolled. Treatment included Ra-223 50 kBq/kg IV q4weeks for 6 cycles concomitant with standard of care medications. Analyses were conducted to assess safety and overall survival (OS) in pts with prior and concurrent Abi and Enza. Results: Of 184 treated, 120 (65%) had prior and 35 (19%) pts had concurrent Abi; 59 (32%) had prior and 25 (14%) pts had concurrent Enza. Baseline characteristics were generally balanced in the overall and across prior and concurrent groups. Pts with no concurrent Abi or Enza had a similar OS to the overall group (Abi 16m, Enza 17m, overall 17m). Due to a small number of events (7 Abi, 6 Enza), a median value was not calculated for the concurrent groups. 8 deaths occurred during treatment none were related to RA-223. The rate of Grade 3-5 AEs was similar across concurrent (Abi 37%, Enza 36%) and prior groups (Abi 43%, Enza 42%) vs overall 41%. Most frequently occurring Gr 3-4 events were anemia (Abi 17%, Enza 8%, overall 11%), thrombocytopenia (Abi 6%, overall 3%), and back pain (Enza 8%, overall 4%). Conclusions: In this EAP, Ra-223 concurrently administered with either abiraterone or enzalutamide was safe and well tolerated adding important information on concurrent use of RA-223 and hormonal agents. Clinical trial information: NCT01516762. [Table: see text]
Effect of radium-223 dichloride (Ra-223) on risk for and duration of hospitalization in ALSYMPCA by docetaxel (D) subgroup.
Authors: Cislo Paul , Reuning-Scherer Jonathan D. 
Published: February 2017

254 Background: In ALSYMPCA, the first-in-class alpha-emitting radiopharmaceutical Ra-223 significantly improved overall survival vs placebo (pbo) and was well tolerated in patients (pts) with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no visceral metastases regardless of prior D use. To understand whether treatment (tx) benefit in prior and no prior D subgroups relates to differences in health care resource utilization, hospitalization and other resource use were evaluated. Methods: Hospitalization, nursing home visit, home health care and adult day care services use, and physician visit data were captured. To account for differences in observation time due to differing survival, resource use was annualized for each pt. Mean number and duration of encounters/year were compared using t-tests. To compare tx groups based on rate of use/year, incidence rates and ratios were calculated using a generalized estimating equation regression model with covariates. Results: For prior D pts, hospitalization incidence rates for Ra-223 vs pbo were 1.18 vs 1.70 (incidence rate ratio = 0.69; 95% CI, 0.53-0.90; P = 0.006) and mean hospitalization days/year were 8.53 vs 16.51 (P = 0.001). Among prior D pts with ≥1 hospitalization, mean hospitalization days/year for Ra-223 vs pbo were 19.65 vs 33.02 (P = 0.003). For no prior D pts, hospitalization incidence rates for Ra-223 vs pbo were 1.02 vs 1.10 (incidence rate ratio = 0.92; 95% CI, 0.66-1.29; P = 0.643) and mean hospitalization days/year were 7.53 vs 12.11 (P = 0.027). Among no prior D pts with ≥1 hospitalization, mean hospitalization days/year for Ra-223 vs pbo pts were 19.12 vs 26.61 (P = 0.063). The only other tx differences were nursing home days/year and day care services/year in the no prior D subgroup, but t-test and regression results were inconsistent. Conclusions: In the prior D subgroup, Ra-223 pts experienced 8.0 fewer hospitalization days/pt/year, driven by a 31% reduction in hospitalization and shorter duration among pts hospitalized. In the no prior D subgroup, Ra-223 pts experienced 4.6 fewer hospitalization days/pt/year, primarily driven by a shorter duration among pts hospitalized. Clinical trial information: NCT00699751.