bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: A randomized, double-blind, placebo-controlled, phase 2 trial.
Authors: Noguchi Masanori , Arai Gaku , Egawa Shin , Ohyama Chikara , Naito Seiji , Matsumoto Kazumasa , Uemura Hirotsugu , Nakagawa Masayuki , Nasu Yasutomo , Eto Masatoshi , Suekane Shigetaka , Sasada Tetsuro , Shichijo Shigeki , Yamada Akira , Kakuma Tatsuyuki , Itoh Kyogo 
Published: February 2018

214 Background: A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase 2 trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances anti-tumor effects in patients with castration-resistant prostate cancer (CRPC). Methods: In this double-blind, placebo-controlled, randomized, phase 2 study, we enrolled chemotherapy-naïve patients with progressive CRPC from 10 medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to either KRM-20 combined with docetaxel and dexamethasone or placebo with docetaxel and dexamethasone. Patients initially received 5 weekly subcutaneous KRM-20 (20 mg) or placebo injections with daily oral dexamethasone (1 mg) following 5 courses of docetaxel (70 mg/m2 every 3 weeks). The primary endpoint was to compare each treatment for prostate-specific antigen (PSA) decline. Results: Between Jul 31, 2013 and Jul 11, 2014, 51 patients were enrolled to the trial: 25 were assigned to the KRM-20 arm, and 26 were allocated to the placebo arm. Mean % PSA levels from baseline in the KRM-20 arm significantly decreased during the treatment compared witht those in the placebo arm ( P = 0.028, MANOVA). Human leukocyte antigen matched peptide-specific immunoglobulin G ( P = 0.018) and CTL ( P = 0.007) responses in the KRM-20 arm significantly increased after the treatment. The appearance of myeloid-derived suppressor cells in the KRM-20 arm significantly decreased after the treatment ( P = 0.007). The addition of KRM-20 did not result in increased toxicity. There was no between-group differences in progression-free or overall survival. Conclusions: These findings suggest potential clinical benefits for the combined use of KRM-20 with docetaxel and dexamethasone in patients with CRPC. Clinical trial information: UMIN000011028.
Cabozantinib for metastatic castration-resistant prostate cancer (mCRPC) following docetaxel: Combined analysis of two phase III trials.
Authors: Pond Gregory Russell , Sonpavde Guru , Fizazi Karim , De Bono Johann S. , Basch Ethan M , Scher Howard I. , Smith Matthew Raymond 
Published: February 2018

225 Background: Two phase III trials, COMET-1 and COMET-2, have reported that cabozantinib did not extend overall survival (OS) outcomes compared to prednisone and prednisone plus mitoxantrone respectively, in unselected post-docetaxel patients with mCRPC. We conducted a retrospective analysis of a combined dataset of these trials in an attempt to identify a benefit in subsets of patients based on prognostic risk factors. Methods: Baseline characteristics and survival data were combined for COMET-1 and COMET-2. Prognostic ability of baseline factors on survival was evaluated using Cox proportional hazards regression models, which incorporated the factors in the modern post-docetaxel nomogram and overall bone scan lesion area (BSLA) by computer-assisted analysis. Regression models included trial as a stratification factor. Evaluation of potentially benefited subsets was performed by the use of interaction terms between the factors and cabozantinib. The hazard ratio between cabozantinib and comparator arms was evaluated after adjusting for baseline prognostic factors. All tests were 2-sided and a p-value ≤0.05 was considered statistically significant. Results: A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). Age, albumin, LDH and BSLA were statistically significant prognostic factors in addition to variables from the Halabi model (site of metastases, pain, docetaxel-free interval, ECOG-PS, hemoglobin, alkaline phosphatase, PSA). There was no consistent interaction effect on survival between cabozantinib vs. comparator arms for any prognostic group. After adjusting for multiple potential prognostic factors, treatment with cabozantinib vs. comparator was associated with an observed hazard ratio of 0.77 (95% CI = 0.65 to 0.92, p = 0.003) for survival. Conclusions: After combining data from both COMET-1 and COMET-2 trials, no differential effect of cabozantinib on survival was observed for any prognostic risk factor. A modest treatment effect of cabozantinib on OS was observed after controlling for multiple potential prognostic factors.
Effect of HER3 dimer feedback upregulation via PI3K-AKT-mTOR pathway inhibition on androgen receptor (AR) stabilization in metastatic prostate cancer.
Authors: Galazi Myria , Salji Mark , Weitsman Gregory , Gomez Valentin , Leung Hing , Ng Tony 
Published: February 2018

226 Background: Metastatic castration resistant prostate cancer (CRPC) is dependent on persistent activation of the AR. In addition, the AR and PI3K-AKT-mTOR pathways have been shown to regulate each other through complex feedback mechanisms. Various early phase clinical studies are currently investigating the role of PI3K-AKT-mTOR pathway inhibitors in improving outcomes in metastatic CRPC. We hypothesise that the formation of a HER3 (human epidermal growth factor receptor) heterodimer, has an important role in regulating the AR and PI3K-AKT-mTOR feedback loop and that its detection can predict response to PI3K-AKT-mTOR pathway inhibition. Methods: LNCAP cells were stably lentiviral transduced with shRNA against HER3. The effect of PI3K-AKT-mTOR inhibition by DS7423, GDC0068, GDC0941 and Everolimus on AR and its direct target gene PSA was evaluated by western blot and real-time quantitative PCR. CWR22 and 22RVI mouse xenograft tumours were stained with fluorescently labelled antibodies for fluorescence lifetime imaging microscopy (FLIM) to assess HER2-HER3 dimerisation by FRET (fluorescence resonance energy transfer) using TRI2 software. Results: We show that there is a statistically significant increase in AR protein levels and PSA gene expression in LNCAP NTC vs HER3kd cells upon treatment with the dual PI3K-mTOR inhibitor DS7423. In addition, there is decreased inhibition of AKT phosphorylation in LNCAP NTC cells, whereas in the absence of HER3 there is complete abrogation of pAKT levels. The use of GDC0941 and Everolimus resulted in similar effect on AR in the LNCAP NTC vs HER3kd cells, however this is less prominent. The AKT inhibitor, GDC0068, has little effect on AR in the presence or absence of HER3. FLIM demonstrated increase in FRET as evidence of HER3 heterodimerisation in 22RVI compared to CWR22 xenograft tissue, showing that HER3 dimerisation emerges in metastatic prostate cancer that has progressed to a castrate resistant phenotype. Conclusions: Our results suggest that HER3 stabilises the AR upon PI3K-AKT- mTOR pathway inhibition and that detection of a HER3 heterodimer can be used as a predictive biomarker of response to these therapies.
Impact of enzalutamide (ENZA) vs. bicalutamide (BIC) on health-related quality of life (HRQoL) of patients (pts) with castration-resistant prostate cancer (CRPC): STRIVE study.
Authors: Concepcion Raoul , Armstrong Andrew J. , Karsh Lawrence Ivan , Holmstrom Stefan , Ivanescu Cristina , Dunshee Curtis , Agarwal Neeraj , O'Kelly Michael , Naidoo Shevani , Olsson Carl A. , Phung De , Ratitch Bohdana , Wang Fong , Kral Pavol , Penson David F. 
Published: February 2018

234 Background: In STRIVE pts with CRPC (M0 n = 139; M1 n = 257), median time to 10-point decrease from baseline in FACT-P total for ENZA vs. BIC was 8.4 vs. 8.3 months (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.70, 1.19; p = 0.49). That assumed missing data was missing at random (MAR) and censored pts with no deterioration in FACT-P at last assessment. As HRQoL may worsen after progression/adverse events, for all STRIVE pts we replaced the MAR assumption with assumptions more likely to reflect clinically plausible HRQoL decline. Methods: Analyses of HRQoL decline (minimum clinically important difference or higher decrease in FACT-P vs. baseline) used a missing not at random (MNAR) assumption using a pattern mixture model (PMM) via sequential modeling with multiple imputation when imputation varies by reason of treatment discontinuation. Analysis of time to first clinically meaningful deterioration vs. baseline used a piecewise exponential survival multiple imputation model with reason-specific ∆ adjustment patterns similar to PMM analysis. Results: PMM analysis showed differences at week 61 in mean HRQoL change from baseline favoring ENZA vs. BIC for 7 of 10 scores: physical (PWB), functional, emotional (EWB), and social (SWB) well-being; FACT-P trial outcome index; FACT-G total; FACT-P total (all clinically meaningful except PWB). In the piecewise exponential survival imputation model, ENZA had a significantly lower risk of first deterioration in FACT-P total (0.76 [0.60, 0.95]), FACT-G total (0.66 [0.52, 0.83]), Prostate Cancer Subscale (PCS) pain-related (0.78 [0.62, 0.97]), SWB (0.49 [0.38, 0.64]), and EWB (0.58 [0.45, 0.75]) vs. BIC. For remaining domain scores, ENZA reduces risk of first deterioration (HR < 1) but the 95% CI includes 1 (which means not significant); sensitivity analysis showed similar results. Conclusions: In STRIVE pts, declines in all FACT-P scores were smaller for ENZA vs. BIC up to week 61. Comparison of change from baseline at week 61 favored ENZA for 7 of 10 scores (6 clinically meaningful). ENZA had a significantly lower risk of first deterioration in FACT-P or FACT-G total, PCS pain-related, EWB, and SWB. Clinical trial information: NCT01664923.
Outcomes in patients (Pts) with advanced prostate cancer and inactivating germline mutations in BRCA2 or ATM.
Authors: Yip Steven , Khalaf Daniel , Struss Werner J. , Sunderland Katherine , Vandekerkhove Gillian , Warner Evan W , Annala Matti , Wyatt Alexander William , Chi Kim N. 
Published: February 2018

242 Background: Germline mutations in homologous recombination repair (HRR) genes, including BRCA2, are present in 6-12% of pts with metastatic castration-resistant prostate cancer (mCRPC). BRCA2 germline mutations are associated with high-grade and poor-prognosis localized disease, while outcomes in pts with advanced prostate cancer continue to be defined. Methods: Germline DNA from 536 consecutive mCRPC pts in our liquid biopsy program were screened for BRCA2 and ATM gene mutations using targeted sequencing. Kaplan-Meier curves were used to estimate the median time from androgen deprivation therapy (ADT) initiation to mCRPC, progression free survival (PFS) on first-line androgen receptor (AR) targeted therapy, and overall survival (OS). Outcomes in BRCA2 or ATM germline mutation carriers and a subset of the total sample of HRR wild-type (WT) pts, who had clinical data available (n = 113), were compared using the log-rank test. Results: 26/536 (4.9%) of pts had germline BRCA2 (n = 22) or ATM mutations (n = 4). After ADT initiation, HRR mutated pts progressed to mCRPC with a median time of 13.4 mo compared to 19.0 mo in WT pts (HR = 1.6, [95% CI 1.0-2.5], p = 0.03). HRR mutated pts had a median PFS on first-line AR-targeted therapy in the mCRPC setting of 3.3 mo versus 7.9 mo in WT pts (HR = 2.2, [95% CI 1.3-3.5], p = 0.002). OS for HRR mutated pts from the time of ADT was 57.7 mo in contrast to 104.9 mo in WT pts (HR = 1.8, [95% CI 1.0-3.4], p = 0.07). OS from time of CRPC was 29.7 mo in HRR mutated pts versus 50.3 mo in WT pts (1.6, [95% CI 0.8-2.9], p = 0.16). Conclusions: Germline HRR mutated pts perform poorly with shorter PFS on first-line AR-targeted therapy and time to mCRPC, in contrast to WT pts. These findings support the hypothesis that BRCA2 and ATM gene mutated pts have poor outcomes with current AR-targeted treatments and should be evaluated for alternate regimens.
Prostate cancer presentation, treatment selection, and outcomes among men with HIV/AIDS: A clinical, stage, and age-matched analysis.
Authors: Ruden Maria , Olivares Christopher , Fakhoury Mathew Q , Vidal Patricia Q , Hollowell Courtney MP , Psutka Sarah P 
Published: February 2018

245 Background: The clinical presentation, oncologic outcomes and the optimal management of prostate cancer (PC) among human immunodeficiency virus-seropositive (HIV+) men are poorly described. Our objective was to compare the clinical characteristics, treatment decisions and oncologic outcomes in a contemporary series of HIV+ and HIV negative (HIV-) men with PC. Methods: Clinical data for 3135 men treated for PC at Cook County Hospital (2000-16) were reviewed. HIV+ patients (N = 46) were matched 1:2-3 by age and clinical stage to HIV-negative controls (N = 137). Clinicopathologic features, primary treatment, and oncologic outcomes were compared with Kaplan Meier and Cox proportional hazards analyses. Results: HIV- and HIV+ patients were similar with respect to median age (58.2 vs. 57.2 years, p = 0.2), initial PSA (10.6 vs. 10.5 ng/mL, p = 1), clinical stage (94% cT1/2 vs. 88%, p = 0.4), 8% cN1 vs. 6.5%, p = 1; 10.9% cM1 vs. 10.9%, p = 1), ECOG performance status (0-1 in 99% vs. 100%, p = 1). Among HIV+ men, 67.4% had a history of AIDS, and 91.3% were on HAART at diagnosis with median viral load and CD4+ count of 40 copies/mL and 400 cells/mm3. Median time from HIV diagnosis to PC diagnosis was 8.6 years. Among men with localized disease (N = 153), HIV+ men (N = 37) were more likely to receive radiation therapy (59.5% vs. 44.8%) or no therapy at all (13.5% vs. 4.3%) and less likely to receive surgery (16.2% vs. 30.2%), or to initiate active surveillance (10.8% vs. 16.4%; p = 0.04 overall) than HIV-. There were no differences in rates of biochemical recurrence (Hazard ratio [HR] 0.79; p = 0.6), clinical progression (HR 0.89, p = 0.8), castration resistance (HR 0.71, p = 0.1), or PC-death (HR 3, p = 0.1). However, HIV+ status was associated with an increased risk of all-cause death (HR 2.89, p = 0.04) with median follow-up of 4.2 years (range 0-14). Conclusions: Matched by age and stage, HIV+ men with localized PC were observed to receive surgery and definitive treatment overall at significantly lower rates than HIV- controls. Oncologic outcomes were similar between HIV+ and HIV- men. Further research is necessary to define optimal PC treatment selection in men with HIV.
Outcomes of metastatic castration resistant prostate cancer (mCRPC) patients with DNA repair germline mutations (gDDR) following first taxane-based treatment.
Authors: Puente Javier , Romero-Laorden Nuria , Vallespin Garcia Elena , Piulats Josep M. , Saez M Isabel , Fernandez Parra Eva , Perez Valderrama Begona , Borrega Pablo , Cendon Ylenia , Ibáñez Kristina , Lainez Nuria , Heras Lucia , Velez Edelmira , Almagro Elena , Zambrana Francisco , García Domínguez Rocío , Contreras Jose Antonio , Lapunzina Pablo , Olmos David , Castro Elena 
Published: February 2018

247 Background: Germline DDR have been identified in up to 12% of mCRPC patients. Initial results from various retrospective series have reported discordant impact in clinical outcomes associated to these gDDR following conventional treatments. PROREPAIR-B (Castro et al ESMO 2017) is the first prospective study to address this question. In this planned sub-analysis, we report mCRPC treatment outcomes associated to taxanes. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received docetaxel or cabazitaxel as first-taxane were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM and PALB2 and other gDDR on cause-specific survival (CSS), progression free survival (PFS), time to PSA progression (bPFS) and response to the first administered taxane as 1st or 2nd line therapy. Results: 326 (12 BRCA2, 8 ATM and 1 BRCA1 mutation carrier [gMUT]) out of 419 patients were eligible for this analysis. Diagnostic characteristic included Stage IV 51%, G8-10 60%. At the time of taxane initiation median PSA was 30.1 ng/mL, 84%, 48% and 11% of patients had bone, nodal and visceral metastases. CSS from first-taxane were not significantly different between gMUT and non-carriers (NC) (16.9 vs 23.2 m, p > 0.05). However, in BRCA2 carriers was significantly shorter than in NC (13.1 vs 23.3 m, p = 0.026). Despite a trend to higher PSA response rates in gMUT compared to NC (n = 288, 63% vs 42%, p = 0.07, BRCA2 55%, p > 0.05), PFS were not significantly different between both groups (7.2 vs 7.8 m, p > 0.05), with a trend to shorter survival in BRCA2 carriers (4.5 vs 7.4 m, P = 0.11). Conclusions: These results suggest that DDR mutation carriers respond to taxanes with similar time to progression compared to NC, with the exception of BRCA2 carriers, who despite to the initial response to taxanes, presented worse survival outcomes. This highlights the need for close monitoring and novel therapies in this population. Clinical trial information: NCT03075735.
Molecular profiling of liquid biopsies from patients (pts) with bone metastatic castration-resistant prostate cancer (BM-CRPC) treated with radium-223 (RA-223) to reveal differential enrichment for markers that correlate with overall survival (OS).
Authors: Corn Paul Gettys , Subudhi Sumit Kumar , Araujo John C. , Vardaki Ioulia , Aparicio Ana , Tu Shi-Ming , Pagliaro Lance C. , Zurita Amado J. , Logothetis Christopher , Panaretakis Theocharis 
Published: February 2018

259 Introduction: RA-223 prolongs OS in BM-CRPC pts but predictive markers are lacking. We hypothesized that molecular profiling of plasma-derived extracellular vesicles (EVs) from BM-CRPC pts treated with RA-223 would predict efficacy and inform development of combinations. Methods: Paired baseline (BL) and end of treatment (EoT) blood samples were collected from 25 pts treated with RA-223. Pts were stratified by median OS into 3 groups: 1) 6.3 months (range 3.3-8.5, n=5 pts, UnFav OS), 2) 18.2 months (range 12.6-19.4, n=7 pts, Middle OS) and 3) 27.6 months (range 23.1-33.8, n=13 pts, Fav OS). EVs were isolated from plasma and analyzed for specific proteins and RNA transcripts. Marker profiles by domain and analytic method were determined in pts from the stratified OS groups. Results: At EoT, there is enrichment of RNA transcripts and proteins involved in regulating immune responses, DNA Damage Response (DDR) and bone metabolism (Table). By benchmarking molecular signatures in pts with UnFav Os and Fav OS, we could analyze the molecular profiles of pts in the Middle OS group and stratify them to UnFav OS or Fav OS groups. Conclusion: Plasma-based molecular markers are predictive for RA-223 efficacy. An association between OS and immune and DDR profiles in men with BM-CRPC may indicate mechanism of action and identify subsets most likely to benefit. These preliminary results provide rationale for combination therapy with RA-223 and immune-checkpoint blockade or PARP inhibition. Clinical trial information: NCT02135484. [Table: see text]
Oncological and postoperative outcome of salvage PSMA-radioguided surgery in recurrent prostate cancer.
Authors: Horn Thomas , Rauscher Isabel , Eiber Matthias , Wester Hans-Juergen , Schottelius Margret , Heck Matthias Michael , Gschwend Juergen E. , Maurer Tobias 
Published: February 2018

270 Background: Positron-emission tomography (PET) directed against PSMA allows detection of even small metastatic prostate cancer (PC) lesions at low PSA values. In a subset of patients (pts) with recurrent PC salvage surgery might be beneficial. To facilitate removal during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (PSMA-RGS). Methods: 121 consecutive patients with recurrent PC (PSA median: 1.13 ng/ml, range: 0.00 – 13.90 ng/ml; 9 pts under androgen-deprivation therapy) and soft-tissue lesions on 68Ga-PSMA PET after radical prostatectomy underwent 111In- or 99mTc-based PSMA-RGS between April 2014 and May 2017. The rate of complete biochemical response (cBR; PSA < 0.2ng/ml) was determined 6-16 weeks following PSMA-RGS. Biochemical recurrence-free survival (bRFS), PC-specific treatment-free survival and postoperative complications were evaluated. Results: Metastatic soft-tissue lesions from PC metastases could be removed in 120/121 pts (99.2%). One patient died six days postoperatively from a pulmonary embolism, five patients were lost to follow-up. Eleven pts suffered from Clavien grade III complications within 90d from surgery. In 75 out of 115 (65.2%) pts cBR was achieved. cBR was more likely in patients with a preoperative PSA level < 1.13 (76.3% vs. 52.7%) or a single anatomical location of recurrence (71.9% vs. 58.8%). Median bRFS was 5.1 months. At the time of analysis, 15 pts exhibited an ongoing cBR for at least 12 months (range: 12-32 months). A significantly longer bRFS was achieved in pts with a preoperative PSA < 1.13 ng/ml (median 14.9 vs 3.2 months, p = 0.02). In pts with a single compared to multiple location of recurrence we observed a trend towards a longer median bRFS (8.2 months vs. 3.5 months, p = 0.08). After one year of follow-up, 61.6 % of pts did not receive any further PC-directed treatment. Conclusions: PSMA-RGS is a promising tool to enhance intraoperative detection of metastatic lesions in PC with an acceptable complication rate. It leads to a high number of biochemical response with substantial duration in a subset of pts. Our data showed that bRFS was highest in patients with a low preoperative PSA and a single anatomical site of recurrence.
Serum neuroendocrine (NE) markers and clinical characteristics of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in men with metastatic castration resistant prostate cancer (mCRPC): Data from the West Coast Prostate Cancer Dream Team.
Authors: Aggarwal Rahul Raj , Zhang Li , Beer Tomasz M. , Youngren Jack , Stromlund Alise , Bell Alexander , Foye Adam , Playdle Denise , Alumkal Joshi J. , Reiter Robert Evan , Gleave Martin , Evans Christopher P. , Thomas George V. , Huang Jiaoti , True Lawrence D. , Rettig Matthew , Lara Primo , Chi Kim N. , Small Eric Jay 
Published: February 2018

278 Background: Detection of t-SCNC in mCRPC patients relies primarily on histopathologic evaluation (Histo) of a metastatic tumor biopsy (bx), likely leading to underdiagnosis. The clinical features of t-SCNC and the diagnostic utility of serum NE markers (neuron-specific enolase (NSE) and chromogranin (CGA)) were evaluated. Methods: Eligible patients (pts) underwent a metastatic bx at one of 5 centers. Histo was performed by 3 independent pathologists (JH, GT, LT). NE markers were evaluated in a central lab (lower limit = 1 ng/mL). Kruskal-Wallis and chi-square test were used to compare continuous and categorical variables, respectively. Receiver-operative-curve (ROC) analysis of serum NE markers was undertaken. Results: 160 consecutive pts with available Histo and NE markers were included. t-SCNC was found in 27 pts (17%). Detection of t-SCNC was observed in all bx sites, including liver (14%), lymph node (19%) and bone (14%). Clinical features are shown in the Table. By ROC analysis, if both serum NSE was > 6.05 ng/mL and chromogranin was > 3.1 ng/mL, the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the detection of t-SCNC were 95%, 50%, 98%, and 22%, respectively. Conclusions: Many of the classic features of de novo SCNC, including low PSA levels, do not reliably distinguish t-SCNC. In contrast, serum NE markers have diagnostic utility with high sensitivity and NPV, but low specificity and PPV. Heterogeneous NE differentiation may partially account for these findings. Clinical trial information: NCT02432001. [Table: see text]