bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissecting the invasive potential of esophageal cancer by siRNA library screening.
Authors: Duggan Shane P , Phipps Sinead , Behan Fiona , Garry Catherine , Kelleher Dermot P
Published: February 2017

86

Background: The low survival for esophageal cancer is in part attributed to its high invasive potential and distant metastasis. In cancer, abnormal cell migration is an essential component of metastasis, and it is reasonable to consider that the conversion between different forms of morphology permits tumor cells to metastasise. Discovering regulators of esophageal cancer morphogenesis may aid in the development of novel targeted therapies that limit metastatic potential. Methods: GOhTRT cells were seeded and treated with siRNA (Human Druggable Genome, Dharmacon) by reverse transfection. Cells were fixed, immunostained for DNA, tubulin and actin and imaged with automated microscope. Cell images were processed using the InCell Analyzer software and the R statistical software systems CellHTS2 and RNAither. The effect of RNAi knockdown on cell viability and cell motility were assessed using MTT cell proliferation assay and scratch wound assay. Results: 127 gene candidates greatly exhibited effects on F-actin and α-tubulin area staining. This list was refined to six high quality candidates (RRM2, ITGB8, GPS1, SPRY1, NOL1 and MYO9B). Silencing of GPS1, MYO9B and SPRY1 increased the rate of migration in a scratch wound assay, with 86.98% ± 3.097%, 75.78% ±5.454% and 72.97% ± 5.463% (p =0.0022) respectively. There was no significant difference in cell viability absorbance values for siGPS1 (0.9037 ± 0.06575; p =0.1905) and siSPRY1 (0.9088 ± 0.09849; p =0.2985), which suggests that the increased rate of wound closure previously seen is by virtue of migratory signalling as oppose to an increase in cell proliferation. Cell viability was decreased considerably in siRRM2 cells (0.2492 ± 0.02798; p <0.0001) and siMYO9B (0.4048 ± 0.04663; p<0.0001) in comparison to siNT cells (1.046 ± 0.07712). Conclusions: In summary, this screen successfully identified high confidence hits associated with cytoskeletal remodelling, some of which are already associated with metastasis in literature and database searches. Further mechanistic studies and gene pathway analysis of candidate genes will provide novel therapeutic targets which can be utilised to block the spread of cancer in patients.
The nucleoside diphosphate kinase-A as a migration suppressor in gastric lymphoma.
Authors: Kim Jae J. , Kim Jin Il
Published: February 2017

87

Background: The nm23-H1 gene encodes the NDPK-A (nucleoside diphosphate kinase A) that contributes variably to the migration of cancer cell. To investigate the role of the NDPK-A in gastric lymphoma, we examined the expression of NDPK-A in two different cancer cell lines of the same gastric lymphoma patient. Methods: The primary cell line of gastric lymphoma, RF-1, was cultured from the primary gastric lymphoma site, and the other cell line RF-48 was metastasized to the peritoneum of the same patient after 6 months. We have generated stable gastric lymphoma transfectants, pIRES-NDPKA-GFP-neo, that constitutively over-express transfected and vector form of NDPK-A, in addition to a reporter, green fluorescent protein(GFP). The transfected gastric lymphoma cell migration assay was performed 24-well modified chemotaxis chambers with FluroBloc membrane. Results: In regard to the migration rate of the gastric lymphoma cell lines, RF-1 vector was 75.8±7.5%, RF-1 transfected was 54.4±12.3%, RF-48 vector was 84.7±15.4%, RF-48 transfected type was 62.3±9.2%, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. NDPK-A was presented more in RF-1 than RF-48, and presented more in the transfected type than the vector type, and concerning the migration rate, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. Conclusions: In regard to the migration rate of the gastric lymphoma cell lines, RF-1 vector was 75.8±7.5%, RF-1 transfected was 54.4±12.3%, RF-48 vector was 84.7±15.4%, RF-48 transfected type was 62.3±9.2%, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. NDPK-A was presented more in RF-1 than RF-48, and presented more in the transfected type than the vector type, and concerning the migration rate, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type.
Determination of dihydropyrimidine dehydrogenase (DPYD) gene single-nucleotide polymorphism (SNP) in Mexican patients with locally advanced esophageal carcinoma.
Authors: Ruiz-Garcia Erika , Lopez-Yañez Alicia , Caderillo-Ruiz German , Deneken Connie Zuratzi , Diaz Consuelo , Herrera MaryTere , Moreno Jesus Zamora , López-Basave Horacio Noe , De La Garza Jaime G. , Meneses-Garcia Abelardo , Astudillo Horacio
Published: February 2017

93

Background: Fluoropyrimidines as 5-fluorouracil (5-FU) and its prodrug capecitabine are chemotherapeutic drugs commonly used in the treatment of gastrointestinal cancer. Patients with deficiency of dihydropyrimidine dehydrogenase enzyme (DPD), which interfere with the pyrimidine metabolism, could be at risk toxicity (mild, severe or lethal) because 80-90% of the administered 5-FU is catabolized by DPD. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 72 Mexican patients with locally advanced esophageal cancer, DPD activity was evaluated through the detection of the seven most relevant DPYD SNPs (IVS14 + 1G>A; 85T>C/85T>T; 2657G>A; 2921A>T; 1679T>G; 2846A>T; and 496A>G). Results: We found that 20.83% (15/72) of our patients had three different polymorphisms: 9.72% (7/72) were positive for SNP 496A>G in heterozygous patients and 4.16% (3/72) in homozygous patients; 4.16% (3/72) were positive for SNP 2657G>A in heterozygous patients; 2.77% (2/72) were positive for SNPs 85T>C and 85T>T in heterozygous patients. The rest of patients 79.10% (57/72) were negative to these SNPs. Conclusions: This is the first study in Mexican population, determining DPYD SNPs. We found that frequency of SNP 85T>C and 85T>T is similar as Oriental race (2-3%), but contrast with Caucasians (0.19%). The SNP 2657G>A whose allelic frequency is unknown, in Mexicans is about 4%; meanwhile, for SNP 496A>G which Caucasian prevalence was reported 0.8%, in our Mexican sample was very high (14%). None of our patients even those with toxicity grade 3-4, were positive to the SNP associated to high toxicity (IVS14 + 1G>A). Because of this heterogeneity, know we are sequencing the complete gen.
FOrMAT: Feasibility of a molecular characterization approach to treatment of patients (pts) with advanced gastrointestinal (GI) tumors.
Authors: Moorcraft Sing Yu , Gonzalez de Castro David , Cunningham David , Walker Brian A , Hulkki Wilson Sanna , Diez Perez Javier , Peckitt Clare , Wotherspoon Andrew , Begum Ruwaida , Valeri Nicola , Gerlinger Marco , Braconi Chiara , Rao Sheela , Watkins David , Chau Ian , Starling Naureen
Published: February 2017

TPS227

Background: The molecular characteristics of a pt’s tumour can determine their suitability for treatment with targeted drugs. Several molecular alterations are only seen in a small percentage of pts and so it is often necessary to screen many pts to identify those who may benefit from targeted therapies. Testing each pt for multiple biomarkers is also increasingly important. Targeted next generation sequencing (NGS) can rapidly interrogate tumours for actionable genetic aberrations and therefore facilitate a personalised treatment approach. FOrMAT aims to assess the feasibility of delivering validated NGS results (to accredited standards) in a clinically meaningful timeframe and how this could be adopted into routine clinical practice in the United Kingdom’s National Health Service. Methods: FOrMAT (ClinicalTrials.gov identifier NCT02112357) is a single-centre translational study in pts with locally advanced/metastatic GI tumours (including gastroesophageal, pancreatic, biliary tract and colorectal). Targeted capture sequencing is performed on archival or fresh biopsy samples to detect mutations, copy number variations and translocations in 45 genes which have prognostic, predictive or pharmacogenomic significance or are targets in current/upcoming clinical trials. Results are discussed by a Sequencing Tumour Board to establish if a pt is potentially suitable for a targeted therapy (e.g. within another clinical trial, as part of standard of care or via a compassionate access program). Changes to pts’ treatment are not mandated. The primary endpoint is the percentage of pts in whom a currently actionable molecular alteration was detected. Secondary endpoints include evaluation of the time required to obtain sequencing results. Blood samples will be collected at baseline and at the time of each tumour response assessment for analysis of molecular markers, including ctDNA and microRNA. Pts may also consent to optional biopsies for exploratory research into tumour heterogeneity and development of pt-derived organoids. The study aims to recruit 200 pts over 2 years. Recruitment started in February 2014 and to date 56 pts have been recruited. Clinical trial information: NCT02112357.
The DASH Study: A phase 1b study of dalantercept plus sorafenib in advanced hepatocellular carcinoma.
Authors: Abou-Alfa Ghassan K. , Miksad Rebecca A. , Gutierrez Martin , Tejani Mohamedtaki Abdulaziz , Sharma Manish , Sun Weijing , Henderson Charles A. , Baron Ari David , Olowokure Olugbenga Olanrele , Pearsall R. Scott , Wilson Dawn , Korth Chris , Sherman Matthew L. , Pandya Shuchi Sumant
Published: February 2017

TPS495

Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalantercept plus sorafenib in subjects with advanced HCC is ongoing. The primary endpoint includes the evaluation of the safety and tolerability of dalantercept plus sorafenib and determination of the recommended phase 2 dose levels of the combination. Secondary endpoints include assessments of the pharmacokinetic profile of the combination, preliminary activity including response rate using RECIST 1.1 and time to progression, and pharmacodynamic biomarkers in the serum and tissue including ALK1 and BMP9 expression. In the first two cohorts of 3-6 subjects each, the dalantercept dose levels will be 0.6 and 0.9 mg/kg, respectively, administered subcutaneously (SC) every 3 weeks in combination with sorafenib 400 mg PO once daily. In cohort three, 3-6 subjects will receive dalantercept dose level 0.9 mg/kg SC every 3 weeks with sorafenib 400 mg PO twice daily. Patient safety data through day 22 will be evaluated prior to escalation to the next cohort. An expansion cohort will enroll 10-20 subjects at or below the maximum tolerated dose level. Key eligibility criteria: histologically confirmed advanced HCC, Child-Pugh A liver disease, ECOG performance status of 0-1, and no prior systemic therapy in the advanced setting. Clinical trial information: NCT02024087.
Phase II trial of temsirolimus (TEM) plus sorafenib (SOR) in hepatocellular carcinoma (HCC).
Authors: Kelley Robin Kate , Nimeiri Halla Sayed , Gordan John Dozier , Hwang Jimmy , McWhirter Ryan M. , Kanakamedala Advaita , Atreya Chloe Evelyn , Kulik Laura , Kircher Sheetal , Mulcahy Mary Frances , Benson Al Bowen , Venook Alan P.
Published: February 2017

TPS501

Background: The multikinase inhibitor SOR prolongs survival in patients with HCC not amenable to curative therapies. In HCC preclinical models, the combination of SOR with an inhibitor of the mammalian target of rapamycin (mTOR) pathway is synergistic, though single-agent mTOR inhibition did not improve survival in HCC patients after failure of SOR in a phase III trial. We previously completed a phase I study of the mTOR inhibitor TEM combined with SOR in 25 HCC patients which identified the maximum tolerated dose as TEM 10 mg IV weekly and SOR 200 mg PO BID. This two-center, phase II study was developed to examine the efficacy of the combination and to explore candidate biomarkers. The study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support, with activation October 2012. Methods: The study is registered on ClinicalTrials.gov (NCT01687673). Design: Single-arm, one stage phase II trial. Primary endpoint: Time to progression (TTP) by RECIST 1.1. Other endpoints: Progression-free survival, response rate, overall survival, proportion with alpha fetoprotein decline ≥ 50%, toxicity, hepatitis B virus reactivation rate, and exploratory biomarkers including mTOR pathway protein expression in tumor, circulating tumor cells, and blood and tumor micro-RNA profiles. Sample size: 25 evaluable patients are required to detect a difference between the null hypothesis of median TTP < 3 months versus alternate hypothesis of median TTP ≥ 6 months (a clinically-meaningful outcome in advanced HCC), with 1-sided significance level of 10% and power 88% under the exact test. Main eligibility criteria: HCC not amenable to curative therapies, histologically-confirmed, ≥ 1 untreated, radiographically-measurable site of disease. No prior systemic therapy. ECOG ≤ 1. Child-Pugh score ≤ 7 with bilirubin ≤ 2 mg/dL. Treatment and procedures: TEM 10 mg IVweekly plus SOR 200 mg PO BID in 28-day cycles, with collection of archival tumor samples and blood samples at baseline, on treatment, and at progression. Accrual:Sixteen of 25 planned evaluable patients have enrolled. An interim analysis for safety after 30% enrollment met pre-specified target to continue. Clinical trial information: NCT01687673.
A phase I dose-escalation trial of TH-302 with nab-paclitaxel and gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Olszanski Anthony J. , Wang-Gillam Andrea , Kwak Eunice Lee , Nazzal Kamal , Mehdi Fazal , Borad Mitesh J.
Published: February 2017

TPS505

Background: TH-302 is a hypoxia-activated, nitroimidazole-linked prodrug of bromo-isophosphoramide mustard (Br-IPM), which is released under hypoxic conditions. TH-302 is currently being studied in combination with gemcitabine (G) in a phase III trial in patients (pts) with advanced pancreatic adenocarcinoma (PDAC) (NCT01746979). Encouraging preclinical activity of TH-302 plus nab-paclitaxel (nab-P) and G provides a rationale for further study of this triplet (Sun JD et al, AACR Special Conference on Pancreatic Cancer 2014; abstract #B88). Methods: Clinical trial: NCT02047500. Open-label, phase I, dose-escalation trial of TH-302 plus nab-P and G in pts with previously untreated locally advanced or metastatic PDAC. Dose escalation: 3 + 3 design with one of 3 planned dose levels of TH-302 (170, 240 and 340 mg/m2) on days 1, 8, and 15 of a 28-day cycle, plus nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Expansion cohort (n≥15): TH-302 at the recommended phase II dose (RP2D) with nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Treatment will be continued until disease progression or intolerable toxicity. Primary objectives: To evaluate safety and tolerability, define the maximum tolerated dose and determine the RP2D of TH-302 in combination with nab-P/G. The primary endpoint is no. of pts with dose-limiting toxicities during the first 28 days. Secondary objectives: To evaluate overall safety of the triplet regimen, metabolic response rate using EORTC criteria for 18F-FDG PET, CA19–9 response rate (defined as >50% decline from baseline), and RECIST response rate of TH-302 plus nab-P/G. The pharmacokinetic (PK) profile of TH-302 and Br-IPM in the plasma of pts will also be evaluated, as will the effect of TH-302 on the PK of nab-P, and vice versa. Exploratory analyses include the association of pharmacogenomic markers, such as CYP2C9, BRCA1 and BRCA2, with PK, safety and efficacy. The association of potential hypoxia biomarkers (CA IX, GLUT1, VEGF, osteopontin) with antitumor activity will also be explored. The trial is in progress; 7 of an estimated 48 planned pts have been recruited (trial start Jan 2014, estimate end Aug 2016). Clinical trial information: NCT02047500.
Folfoxiri with or without cetuximab as first-line treatment of patients with non-resectable liver, only metastatic colorectal cancer and KRAS/NRAS wild type (FOCULM study).
Authors: Deng Yanhong , Wang Lei , Liu Guanjian , Hu Huabin , Cai Yue
Published: February 2017

TPS798

Background: For liver limited metastatic colorectal cancers, complete resection of liver metastases is the only potentially curative treatment and can significantly improve overall survival. The current goal of medical treatment for colorectal cancer with initially unresectable liver metastases is to maximize the rate of secondary resection. This phase II study is to explore whether cetuximab in combination with FOLFOXIRI as first treatment could improve radical resectability in patients with KRAS/NRAS wild-type, unresectable liver - only metastases of colorectal cancer. Methods: The primary aim is to evaluate the percentage of patients who had a curative liver treatment following protocol treatment, i.e., liver metastases that can be completely resected and/or ablated with no evidence of residual malignant disease. Secondary aims include safty, objective response rate, overall survival, progression free survival, quality of life and an assessment of predictive molecular markers of response. 138 cases of patients met inclusion criteria and enrolled in the trial will be randomized to two therapy groups: experimental arm A (Chemotherapy with FOLFOXIRI + Cetuximab) or standard arm B (Chemotherapy with FOLFOXIRI). All patients will receive the study treatment regimen every 2 weeks, and a total of the maximum of 8 cycles. CT scan or MRI of the abdomen will be performed after 2 or 3 cycles of therapy to assess clinical response and resectability of liver metastases by multidisciplinary team including hepatic surgeon. If liver metastases are not deemed to be resectable at this assessment, but tumor assessment demonstrates stable disease or partial response, therapy will continue with re-assessment for clinical response and resectability after the next cycle. Clinical trial information: NCT02063529.
Evaluation of the contribution of individual gene groups to a 17-gene prognostic prostate cancer signature.
Authors: Knezevic Dejan , Lu Ruixiao , Burke Emily , Rothney Megan , Zhang Nan , Febbo Phillip G. , Lawrence H. Jeffrey
Published: February 2017

101

Background: A 17-gene biopsy-based RT-PCR assay (Oncotype DX Prostate Assay) has been validated as a predictor of adverse pathology and biochemical recurrence (BCR) in clinically very low to intermediate-risk prostate cancer patients. The assay measures expression of 12 cancer and 5 reference genes that are combined to calculate a Genomic Prostate Score (GPS; scaled 0-100), providing a biologic measure of tumor aggressiveness. The cancer genes represent four biological pathways: androgen signaling, stromal response, cellular organization and proliferation. We examined the effects of variation in quantitative expression of individual gene groups on GPS results and prediction of clinical risk. Methods: The first 3,500 tumor specimens processed in the Genomic Health Inc.’s reference laboratory were included. Expression of individual genes was measured and expression of the four gene groups and GPS calculated. For each gene group, GPS of patients with the lowest 5% expression levels were contrasted with GPS of patients with highest 5% expression levels. Results: Percentages of NCCN very low, low and intermediate patients were 28%, 37%, 30%; median age was 65. Mean and median GPS were 24.6 (SD 12.0) and 23 (range 0-90). Individual gene groups exhibited wide expression ranges (e.g. proliferation-16-fold difference (FD) vs. cellular organization > 8000 FD). Large differences in expression of each gene group were reflected in GPS values and, based on a prior clinical validation study, translate into large differences in BCR risk (Table). Conclusions: Each of the four gene groups show large variations in expression, meaningfully affect the GPS, and contribute to the prediction of PCa aggressiveness. [Table: see text]
IHC versus FISH for the detection of ERG rearrangements in prostate cancer.
Authors: Pestova Ekaterina , Zhang Ying , Barbanera William , Kaiser-Walters Kelly A. , Du Jing , Liu Ping , Buckingham Lela , Colpitts Tracey
Published: February 2017

102

Background: ERG rearrangements are present in about 50% of all prostatic adenocarcinomas (CaP). Using ERG break-apart fluorescence in situ hybridization (FISH) probes, several classes of ERG rearrangement patterns have been described: Edel, Esplit, and 2+Edel. Class ERG 2+Edel was reported to be associated with lethal disease and significantly worse clinical outcome in CaP, while prognostic significance of other classes of ERG rearrangements and of ERG protein expression remains controversial. In this study, we found that IHC cannot discriminate between various forms of ERG rearrangements including 2+Edel, while FISH can. Methods: Formalin fixed paraffin embedded (FFPE) histological specimens from 52 Radical Prostatectomy (RP) cases were used. FISH analysis was performed using Abbott Molecular dual-color break-apart probes for the 5' and 3' regions of the ERG gene. Percent of overall ERG abnormalities and percent of Class 2+Edel per specimen were calculated. ERG expression was evaluated using DAKO FLEX Monoclonal Rabbit Anti-Human ERG Clone EP111. For each slide, H scores (H score =intensity X percentage of positive cells) from both tumor areas and benign prostate epithelium areas were assigned. The IHC score was defined as “H score from tumor minus H score from benign prostate epithelium”. IHC score > 0 was considered positive. Statistical analysis was conducted using JMP 10. Results: Of the 52 RP cases, 9 had the ERG 2+Edel rearrangement (cutoff >2%), 25 had Edel or Esplit rearrangements (cutoff >45%), and 27 had no ERG rearrangements by FISH. The overall Percent Agreement (OPA) between the ERG IHC and FISH (any class of ERG rearrangements) was 90% with 95% Confidence Interval (CI) (79%, 96%). However, for the ERG 2+Edel group, the OPA between the ERG IHC and FISH 2+Edel was 71%, and 62% of IHC positives were false positive. Thus IHC does not discriminate between the 2+Edel, Esplit or Edel forms of ERG while FISH identifies each class of rearrangement. Conclusions: IHC assay allows the detection of overall ERG abnormalities, however it does not discriminate ERG Class 2+Edel, which is consistently reported to be of prognostic significance. Further studies are required to confirm prognostic utility of ERG rearrangements and protein expression in CaP.
Long-term bother profiles in patients with locally advanced prostate cancer treated with radiotherapy compared to men with localized prostate cancer treated with high-dose radiotherapy.
Authors: Lilleby Wolfgang
Published: February 2017

104

Background: We compared the long-term the bother profiles in patients with prostate cancer (T1-3 M0) consecutively referred to the OUS to definitive radiotherapy encompassing the prostate and pelvic lymph nodes (RT+IMRT) (N=90) or radiotherapy to the prostatic gland only (RAD) (N=180), applied with adjuvant androgen deprivation in all patients. Methods: After 36months 206 (76%) of the eligible men (RT+IMRT = 64 and RAD = 142) had completed the UCLA-PCI questionnaire at baseline, 12, 24 and 36 months. The bother scores were adjusted for significant differences in quality of life measured by the SF-12 instrument. Differences in the mean scores between the treatment groups were evaluated by the Mann-Whitney U test for skewed samples. Patients were similar in age and by the distribution of prognostic risk factors in both cohorts. Results: The longitudinal bother mean scores up to 36 months post-treatment for the main domains are reported. Significantly more RAD patients had less urinary bother at baseline compared to RT+IMRT patients. In both groups sexual bother was significantly increased over time. Thus, at 36 months mean scores for urinary, bowel and sexual bother appeared to be stable in both groups. However, despite of increased bowel bother at one year (p= 0.02) in the RT+IMRT group, bowel bother score improved in these patients compared to RAD at last observation (p= 0.25). Conclusions: The long-term bother profiles are similar in the RT+IMRT and RAD groups at 36 months follow-up. Modern radiotherapeutic techniques allow targeting of high-risk patients. Differences in organ function and bother can only be accomplished for by long-term health care assessment.
Association of neutrophil count with overall survival in localized prostate cancer.
Authors: Taussky Daniel , Bahig Houda , Delouya Guila , Bodson-Clermont Paule , Soulieres Denis
Published: February 2017

121

Background: Systemic inflammation has been linked to worse outcome in metastatic prostate cancer. This study analyzes the influence of complete blood count (CBC) on outcome after curative radiotherapy for localized prostate cancer. Methods: We reviewed our institutional database of patients with localized prostate cancer treated with either definitive external beam radiotherapy (EBRT) or brachytherapy from September 2001- June 2014. Data on pre-treatment CBC such as hemoglobin (Hgb), mean corpuscular volume(MCV) and platelet count (PLT) were available in 1,021 pts, neutrophil/lymphocyte ratio (NLR) in 1,015 pts. Univariate and multivariate cox proportional hazards models were used to analyze the influence of complete blood count parameters on overall and recurrence free survival (PSA nadir + 2 ng/mL). A p<0.05 was considered statistically significant. Results: Median follow-up was 44 months. 55 patients had biochemical recurrence and 68 patients died.On univariate analysis, increasing risk of biochemical recurrence was associated with a combination of all known risk factors as defined by the Cancer of the Prostate Risk Assessment (CAPRA) score, but not by age. When adjusting for age (p=0.009), CAPRA remained significant (p=0.0003) but no comorbidity or CBC. On univariate analysis for overall survival, CAPRA (p=0.0001) and neutrophil count (p=0.04, HR1.16, 1.01-1.34) as well as a cardiac history (p=0.009) were associated with increased risk of overall mortality. The first multivariate model was adjusted for age and included the CAPRA, comorbidity and CBC variables: age (p=0.006) and CAPRA (p=0.008) were prognostic, neutrophil count was borderline significant (p=0.056, HR 1.17, 0.99-1.37). In a second multivariate model without adjusting for age, neutrophil count was a significant prognostic factor for overall survival (p=0.032, HR 1.18, 1.01-1.38) as well as the CAPRA (p=0.005, HR 1.18, 1.05-1.33). Conclusions: In this testing cohort, neutrophil count was an independent risk factor for increased overall mortality in patients with localized prostate cancer. The influence of age on this prognostic factor will be further studied. A validation cohort is needed to corroborate these results.
Definitive treatment of localized prostate cancer: Time and geographic trends.
Authors: Tward Jonathan D. , Burt Lindsay , Shrieve Dennis C.
Published: February 2017

132

Background: Numerous definitive treatment options exist for localized prostate cancer. We evaluated how the distribution of treatments varied by geographic location and over time in a contemporary US population database. Methods: All subjects with NCCN clinical risk-stratifiable localized prostate cancer between the years 2004 and 2011 were identified in the Surveillance Epidemiology and End-Results Database. Descriptive statistics evaluating the relative distribution of therapies by geographic region and over time were performed. Results: There were 290,631 evaluable subjects identified. The Table shows trends in treatment over time for combined low, intermediate, high, and very high risk prostate cancer. The use of brachytherapy has been significantly declining between 2004 and 2011, and no definitive therapy has been increasing. In 2010-2011, regional prostatectomy use varied from a low of 18% (Rural Georgia) to a high of 57% (Iowa). No definitive therapy rates varied between 12% (Hawaii) and 35% (Rural Georgia). Analyses of regional variation at the State County level reveals significant variability in the ratio of subjects receiving surgery to radiation (e.g., State of Utah surgery:radiation ratio 0.25 (Beaver County) versus 3.06 (Toole County). Conclusions: There is marked regional variation of practice at both the county and state levels for localized prostate cancer definitive therapy. The use of radiotherapy has been declining between the years 2004 and 2011, and appears to be offset by increases in no definitive therapy. Prostatectomy rates remained stable. [Table: see text]
Racial/ethnic variation in a common genetic alteration in prostate cancer.
Authors: Sesterhenn Isabell , Young Denise , Chen Yongmei , Petrovics Gyorgy , Cullen Jennifer , Kagan Jacob , Srivastava Sudhir , Rosner Inger L. , McLeod David G. , Dobi Albert , Srivastava Shiv
Published: February 2017

14

Background: The molecular basis of racial/ethnic differences in the detection and outcomes of the carcinoma of the prostate (CaP) needs to be better defined to improve biomarkers and identify appropriate therapeutic targets. ETS-related gene fusions in proto-oncogenes (ERG, ETV1) are among the most common early oncogenic alterations described in CaP. Studies have highlighted the racial/ethnic variation in ERG fusion and ERG oncoprotein expression frequencies showing: the highest frequencies in Caucasian (CA) men, the lowest frequencies in Asian men, and intermediate frequencies in African American (AA) men. These differences persisted when patients were carefully matched for age and clinico-pathologic features. Building on previous work, the current study was conducted to evaluate ERG expression frequencies in a large cohort of AA and CA CaP patients. Methods: Patients enrolled at the Walter Reed National Military Medical Center who consented to provide radical prostatectomy (RP) specimens to the CPDR Tissue Bank and Clinical Database were evaluated. The current study included 443 AA and 696 CA patients. ERG oncoprotein expression was detected by immunohistochemistry using the 9FY mouse monoclonal anti-ERG antibody and was correlated with clinico-pathologic features and CaP outcomes. Results: Lower frequencies of ERG in the index tumors of AA men as compared to CA men (28.4% vs. 51.5%, p < 0.0001) were observed. Furthermore, AA men with higher grade CaP (Gleason 8-10) had even lower ERG frequency (16%), suggesting distinct molecular biologic features in aggressive CaP for AA men. A trend with age was observed for both racial groups, with younger CA showing higher ERG frequencies. At least one focus of ERG positive PIN was present in prostates with ERG positive tumors. In both CA and AA patients, a very low frequency (8%) of ERG expression was noted in anterior index tumors compared to posterior tumors. Conclusions: This study lends increasing support to differences of the most common early genomic alteration (ERG) between AA and CA CaP patients. The study also underscores the importance of identifying new or improving existing biomarkers with consideration of patient race/ethnicity.
Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Monk Paul , Liu Glenn , Stadler Walter Michael , Geyer Susan Michelle , Sexton Jennifer L. , Wright John Joseph , Villalona-Calero Miguel Angel , Wade James Lloyd , Szmulewitz Russell Zelig , Gupta Shilpa , Mortazavi Amir , Dreicer Robert , Pili Roberto , Cooney Matthew M. , Dawson Nancy Ann , George Saby , Garcia Jorge A.
Published: February 2017

146

Background: Tivantinib is a putative non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that has additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to castration resistance. Methods: 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival. PCWG2 guidelines were utilized for determining eligibility and progression. Results: Of the 80 pts enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluated. Median age was 67 yrs (range: 43 to 85). Baseline characteristics were balanced between arms for ECOG PS, Gleason score, PSA, LDH, hemoglobin, Alk Phos, prior treatment, bone and organ involvement. More African Americans and those with lymph node involvement were randomly assigned to placebo. Median follow up is 8.2 months (range: 1.4 to 27.6). To date 59 patients have progressed. Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.6 mo vs 3.8 mo, respectively; HR = 0.53, 95% CI: 0.32 to 0.89; p=0.015). Toxicity was mild overall. Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia were recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. 8 deaths (3 P and 5 tivantinib) have been recorded and were all considered unrelated to therapy. Conclusions: Tivantinib significantly improved PFS in men with asymptomatic or minimally symptomatic mCRPC. Given the favorable toxicity profile and evidence of anti-tumor activity, investigation of tivantinib with other agents may be a rational strategy. Clinical trial information: NCT01519414.
A phase III, multicenter, randomized, controlled study of maximum androgen blockade with versus without zoledronic acid in treatment-naïve prostate cancer patients with bone metastases: Results of ZAPCA study.
Authors: Kamba Tomomi , Kamoto Toshiyuki , Shimizu Yousuke , Namiki Shunichi , Fujimoto Kiyohide , Kawanishi Hiroaki , Sato Fuminori , Narita Shintaro , Satoh Takefumi , Saito Hideo , Sugimoto Mikio , Teishima Jun , Masumori Naoya , Egawa Shin , Sakai Hideki , Okada Yusaku , Terachi Toshiro , Ogawa Osamu ,   ZAPCA Study Group
Published: February 2017

150

Background: Zoledronic acid (ZA) is proved to be useful for the prevention of skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases, but its early use combined with androgen deprivation therapy (ADT) in men with hormonal treatment-naïve prostate cancer and bone metastases is controversial. Methods: A total of 227 men with hormonal treatment-naïve prostate cancer and bone metastases were randomly assigned in a 1:1 ratio to receive zoledronic acid (4mg intravenously every 4 weeks up to 2 years) along with ADT (LH-RH analogue + bicalutamide, MZ group) or ADT alone (MAB group). Stratification factors were PSA (<200ng/ml vs. ≥200ng/ml), EOD (extent of diseases) grade (1,2 vs. 3,4) and Gleason score (<7 vs. ≥8). The primary end point was time to treatment failure (TTTF), defined as 3 consecutive rise of PSA from the nadir, clinical progression, SRE, death or cessation of protocol therapy for any reason. Results: The median follow-up was 41.1 months. The median TTTF was 12.4 months in MZ group (95% CI, 10.6 to 16.6) and 9.7 months in MAB group (95% CI, 8.9 to 12.6; hazard ratio, 0.754; 95% CI, 0.567 to 1.003; log-rank P= .051). In a subset of men with baseline PSA levels <200ng/mL, the median TTTF was 23.7 months in MZ group (95% CI, 15.2 to 31.3) and 9.8 months in MAB group (95% CI, 6.6 to 17.0; hazard ratio, 0.575; 95% CI, 0.354 to 0.933; log-rank P= .023). An exploratory multivariate analysis using Cox proportional hazards model identified MZ group, age less than 80, and EOD ≤2 as independent factors associated with better TTTF. Conclusions: In men with hormonal treatment naïve prostate cancer with bone metastases, concurrent use of ZA with ADT did not show a significant advantage over ADT alone regarding TTTF. However, in a subgroup of men with lower baseline PSA levels, ZA significantly prolonged TTTF, compared with ADT alone. Clinical trial information: NCT00685646.
Assessment of corticosteroid (CS)-associated adverse events (AEs) with long-term (LT) exposure to low-dose prednisone (P) given with abiraterone acetate (AA) to metastatic castration-resistant prostate cancer (mCRPC) patients (Pts).
Authors: Fizazi Karim , Chi Kim N. , De Bono Johann Sebastian , Gomella Leonard G. , Miller Kurt , Rathkopf Dana E. , Ryan Charles J. , Scher Howard I. , Shore Neal D. , De Porre Peter , Londhe Anil , McGowan Tracy , Pehlivanov Nonko , Charnas Robert Louis , Todd Mary Beth , Montgomery Robert B.
Published: February 2017

169

Background: AA is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs survival of mCRPC pts. A low dose of P is given when AA is administered to mCRPC pts. LT use of moderate-/high-dose CS has an established AE profile. We investigated whether LT use of low-dose P with or without AA led to CS-associated AEs. Methods: 2,267 mCRPC pts in COU-AA-301 and COU-AA-302 received 5 mg bid P, representing 2,006 pt-yrs of P exposure. 1,333 pts received AA + P. We utilized an inclusive Standardized MedDRA Queries–oriented approach to identify 112 preferred terms for known CS-associated AEs from both databases. CS-associated AEs during 3-mo exposure intervals and across all exposure to P were assessed. Results: The overall incidence of CS-associated AEs for any P exposure was 25%, 26%, and 23% for all pts, AA + P, and P alone, respectively. The incidence of grade ≥ 3 CS-associated AEs with any P exposure was 5%, 5%, and 4% for all pts, AA + P, and P alone, respectively. The most common grade ≥ 3 CS-associated AEs occurring in ≥ 0.1% of all pts were hyperglycemia (2%), cataract (0.4%), diabetes mellitus (0.4%), gastrointestinal hemorrhage (0.3%), adrenal insufficiency (0.1%), hip fracture (0.1%), melena (0.1%), and spinal osteoporotic compression fracture (0.1%). The overall incidence of weight increase (grade 1/2 only) was 4%, 4%, and 5% for all pts, AA + P, and P alone, respectively. Most were grade 1 (3.4%).When assessed by duration of exposure (3-mo intervals up to ≥30 mo), grade ≥ 3 CS-associated AEs fluctuated between 1% and 2%, but no discernable trend was observed. The observed change in weight from baseline showed no apparent increase over time. Conclusions: With over 2,000 pt-yrs of exposure, low-dose P given with or without AA is associated with an overall low incidence of CS-associated AEs. The frequencies of CS-associated AEs were low with increased duration of exposure to P. Clinical trial information: NCT00638690 , NCT00887198 .
Prostate cancer incidence in 340 hypogonadal men treated with testosterone undecanoate injections (TU) for up to 7 years: Observational data from a registry study.
Authors: Haider Ahmad
Published: February 2017

17

Background: Concerns regarding the safety of testosterone treatment, particularly regarding prostate cancer (PCa) in middle-aged and elderly men, still hamper the use of testosterone in hypogonadal men. In this study, we investigated prostate parameters incl. incidence of PCa in hypogonadal patients on long-term treatment with TU. Methods: In a prospective, cumulative registry study, 340 men (age: 57.37 ± 7.03 years) with testosterone ≤12.1 nmol/L received TU 1,000 mg every 12 weeks following an initial interval of 6 weeks for up to 7 years. Prostate volume (PV) and PSA were measured and digital rectal examination (DRE)/ transrectal ultrasound (TRUS) performed before treatment initiation and then regularly every 3-6 months. In case of suspected PCa, biopsies were performed. Results: PV increased from 28.96 ± 10.41 to 29.88 ± 13.85 ml by model-adjusted 2.59 ± 0.2 ml (p<0.0001). This increase was statistically significant compared to the previous year for the first four years. PSA increased from 1.74 ± 0.94 to 1.96 ± 1.03 ng/ml by model-adjusted 0.23 ± 0.52 ng/ml (p<0.0001). 53 biopsies were performed in testosterone-treated patients. Of these, 5 (9.4%) were positive and 48 (90.6%) negative. The proportion of PCa in testosterone-treated patients in our registry study was 1.5% with an incidence of 30.7 per 10,000 patient years. In hypogonadal patients without testosterone treatment, 314 biopsies were performed. Of these, 111 (35.4%) were positive and 203 (64.6%) negative. In eugonadal patients, 584 biopsies were performed. Of these, 263 (40.4%) were positive and 321 (55%) negative. In total, 951 prostate biopsies were performed in our practice from 2004 through 2013, of which 379 (39.9%) were positive and 572 (60.1%) negative. Conclusions: Long-term treatment with TU in hypogonadal men undergoing regular monitoring according to EAU guidelines does not increase the incidence of PCa.
Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer.
Authors: Singh Harpreet , Madan Ravi Amrit , Dahut William L. , O'Sullivan Coyne Geraldine Helen , Rauckhorst Myrna , McMahon Sheri , Heery Christopher Ryan , Schlom Jeffrey , Gulley James L.
Published: February 2017

172

Background: Results of recent clinical trials have intensified interest in immunotherapy in oncology. A number of cancer immunotherapies have been approved recently, while others are in late stage clinical development. The poxvirus-based active immunotherapy, PROSTVAC is generally well tolerated and is currently being evaluated in a global Phase 3 randomized, placebo-controlled trial. Ipilimumab, an approved immune checkpoint inhibitor in melanoma, is also being evaluated in a Phase 3 trial in chemo-naïve mCRPC. Methods: Results of two Phase 2 trials in men with mCRPC who were treated with PROSTVAC alone were compared with results from a Phase 1 combination study in mCRPC patients treated with PROSTVAC plus escalating doses of ipilimumab. Patients were enrolled in the Phase 1 combination study when docetaxel was the only FDA-approved mCRPC treatment that improved overall survival (OS). Results: In a multicenter Phase 2 trial, 125 men were randomized 2:1 to receive PROSTVAC or placebo. Patients treated with PROSTVAC had improved OS compared to placebo (25.1 vs 16.6 months; HR 0.56; 95% CI 0.37-0.85).Similar data was seen in a second phase 2 trial of PROSTVAC, where 32 patients with mCRPC had a median OS of 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months. Conclusions: The comparison of data from three independent trials of PROSTVAC active immunotherapy in three similar patient populations provides hypothesis-generating data that the addition of an immune checkpoint inhibitor may have a positive effect on overall survival through a potential synergy in mechanism of action. The updated long term survival data is further evidence of improved OS with PROSTVAC. Future randomized trials are being planned to prospectively evaluate this hypothesis. Clinical trial information: NCT00113984.
Dynamic changes in biomarkers for immune response to sipuleucel-t (SipT) for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Hepgur Mehmet Faith , Dorff Tanya B. , Cai Jie , Reed Mary , Chan Betty , Quinn David I.
Published: February 2017

181

Background: SipT prolongs OS in asymptomatic or minimally symptomatic CRPC without regularly inducing PSA declines. Elevated CD54 count, CD54 upregulation (UPREG) and total nucleated cells (TNC), markers of immune activation in the product, have been shown to correlate with longer survival. We prospectively collected clinical characteristics and inflammatory markers as part of an audit to identify possible predictors of immune response in patients receiving SipT. Methods: 92 men with CRPC had blood drawn routinely before and after SipT treatment at USC. Circulating tumor cells (CTC), PSA, prostatic acid phosphatase (PAP), albumin (Alb), hemoglobin (Hb), serum alkaline phosphatase (SAP), LDH, C-reactive protein (CRP) and β2-microglobulin (β2m) were evaluated in a reference lab. SipT product parameters, CD54, UPREG and TNC were measured by Dendreon. These datasets were analyzed using Spearman coefficients for continuous variables and the Kruskal-Wallis test for categorical variables. Results: 92 pts who received SipT were included. Median age was 69 (48-90). 43% had Gleason 8-9. 42% had ECOG Performance Status (PS) 0, 44% PS 1, and 13% PS 2. 26% had received prior chemotherapy and 18% had used opioids. 84% had bone mets, 42% had lymphadenopathy, and 12% had visceral mets. Increases in the PSA, PAP, LDH and Alb was directly correlated with increased CD54 counts, increases in the CTC was directly correlated with increased TNC, whereas decrease in SAP was correlated with increased upregulation of dendritic cells. Conclusions: Our results show that increased tumor markers immediately after treatment are more common in high CD54 product pts. This may represent a “flare” due to immune activation. [Table: see text]