bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of combined sequential treatment of sipuleucel-T followed by enzalutamide in metastatic chemo-naïve castration-resistant prostate cancer: Results of single center of large urology group.
Authors: Mouraviev Vladimir , Pieczonka Christopher Michael , Telonis Dimitios , Albala David 
Published: February 2017

241 Background: The timing and sequencing of combination therapy is becoming of outmost importance for the treatment of mCRPC patients. As a result our hypothesis has been to layer on enzalutamide very quickly after the completion of sipuleucel-T. Methods: We collected the data of 84 patients with chemo-naïve mCRPC treated with sipuleucel-T at our practice from September 2011 to January 2014. Prior to the initiation of treatment the baseline status was recorded in all patients. We then selected and analyzed outcomes of 19 patients who received sequential enzalutamide treatment after completion of sipuleucel-T. The average timing for the initiation of enzalutamide was 2.5±1.6 months after completion of the immune therapy. We believe this to be a very unique cohort as all of these patients were treated with enzalutamide off label (i.e. pre-chemo). Results: The median time of enzalutamide therapy was 5.4 months (range: 1-13). In our cohort of 19 patients: 1 case showed radiographic full regression of metastatic lesions in bone, lung and lymph nodes. Another case showed radiographic full regression of bony metastatic lesions. 2 other cases – showed a partial regression radiographically of bony metastatic disease. 13 cases showed stable disease according to RECIST-criteria. The remaining 2 patients were deceased due to progression of mCRPC. The patients with full and partial response were in the lowest quartile of our cohort as defined as a PSA ≤ 3.87 ng/ml. On the contrary, all cases of progression and death were documented in highest (last) quartile as defined by a PSA level more than 84 ng/ml. Conclusions: Our experience demonstrates a promising effect using sequential sipuleucel-T immunotherapy followed by enzalutamide for mCRPC. To our knowledge this will be the first case of complete radiographic regression of lung, bone, and extensive lymph node disease. Currently there are studies undergoing that will hopefully validate our experience with using enzalutamide at the initiation of sipuleucel-T.
Trends in prescribing preferences (PPrefs) of U.S.-based oncologists for patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) following docetaxel (DO).
Authors: Ryan Charles J. , Kim Won , Buettner Arden , Britton Susan Lynne , Lankford Maria L. , Neely Doug B. , Green Mark R. 
Published: February 2017

243 Background: PPrefs of 467 US-based medical oncologists (MOs) in post-DO mCRPC pts were studied prospectively. A validated, proprietary, live, case-based market research tool was utilized with a core case scenario and 4 distinct treatment (Rx) outcomes following chemotherapy (CTx). Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case: 59 y/o status post (s/p) radical prostatectomy with PSA failure after 15 months (mo), s/p salvage pelvic radiation (RT) → presents with rise in PSA and 3.5cm pelvic lymph node 16mo following RT→ progresses through multiple Rx over the next 42mo, including combined androgen blockade, anti-androgen withdrawal, sipuleucel-T and abiraterone (ABI). Now starting DO CTx due to increasing bone metastases and bone pain (BP). PPrefs for 4 variant scenarios of DO CTx were probed: (1) DO 75 mg/m2Q3wk x 6 cycles (cy) →Resolution of BP/PSA response → DO held due to cumulative myelosuppression/fatigue. Pt more active off CTx, ECOG PS 1. 3mo later →asymptomatic 30% rise in PSA. (2) DO x 4 cy → decrease in PSA, BP, node size. Prior to cy 6, has asymptomatic PSA progression. (3) DO x 4 cy→ decrease in PSA, BP, node size. Prior to cy 6, has both PSA and BP progression. (4) DO x 2 cy → progression with increased BP, PSA, and pelvic nodal disease. Results: See Table. Conclusions: PPrefs after DO CTx were outcome-dependent. In the absence of BP, ENZ is the most common PPref, even in this ABI-refractory pt. PPref for R223 over 2nd line CTx in the acquired symptomatic resistance setting is notable. PPref for 2nd line CTx increases with rapid, symptomatic disease progression. [Table: see text]
Evaluating cell-free DNA genetic alterations in men with metastatic castrate resistant prostate cancer.
Authors: Gambhira Ratish , Ledet Elisa M. , Dotiwala Aryeneesh , Mandal Diptasri , Sartor Oliver 
Published: February 2017

244 Background: Personalizing CRPC therapy is desirable but difficult as biomarkers that have predictive value other than AR-V7 are scarce. Novel biomarkers that can be repetitively assessed via non-invasive methods may provide important insights into disease biology and therapeutic selection. Cell free DNA (cfDNA) is found in the blood of advanced cancer patients and potentially reflects tumor-related genetic alterations. Herein, we evaluated plasma cfDNA genetic alterations in men with CRPC. Methods: We isolated cfDNA from the plasma of 11 men with metastatic CRPC. Following library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data pre-possessing including alignment, duplicate removal, normalization and variant calling. Visualization and statistical analyses were performed with SNP & Variation Suite v8.x. Additional analyses will follow on translocations. Results: Preliminary analysis of cfDNA showed stopgain mutations in CDC27, FAM104B and non-synonymous mutations in HNRNPCP5, PDE4DIP, JTB and OR2B11. Additionally, insertions were annotated in CYP1B1, CD81, and HSP90AA1 along with CD24 deletion. These genetic alterations are not yet validated using PCR or direct tumor based nucleic acid assays. Missense mutations in HNRNPCP5, PDE4DIP and OR2B11 and a deletion in CD24 have been previously reported in the genetics literature when directly sequencing tumor DNA. Conclusions: When compared to published databases, these preliminary analyses suggest but do not prove that prostate cancer specific genetic changes are detectable in plasma cfDNA. Further characterization of these alterations, in larger matched germline/tumor/plasma samples may provide insights into tumor evolution in CRPC patients. We hypothesize that these genetic changes may contain important predictive and/or prognostic information.
Using radiogenomics to characterize MRI-guided prostate cancer biopsy heterogenity.
Authors: Stoyanova Radka , Pollack Alan , Lynne Charles , Jorda Merce , Erho Nicholas , Lam Lucia L.C. , Buerki Christine , Davicioni Elai , Ishkanian Adrian 
Published: February 2017

25 Background: Current methods for prostate cancer risk stratification are often insufficient to accurately predict outcome after definitive therapy. As tumor multi-focality and genetic heterogeneity can lead to diagnostic prostate biopsy sampling bias, we hypothesize that quantitative imaging with multiparametric (MP)-MRI will more accurately direct targeted biopsies to index lesions associated with highest risk clinical and genomic features, and improve accuracy of current risk classification systems. Methods: Regionally distinct prostate habitats were delineated on MP-MRI (T2w, perfusion and diffusion imaging). Directed biopsies were performed on 17 habitats from 6 patients using MRI-ultrasound fusion. Biopsy location was characterized with 51 radiographic features (including intensity, volume, perfusion, and diffusion paramters). Transcriptome-wide analysis of 1.4 million RNA probes was performed on RNA from each habitat. Genomics features with insignificant expression values (<0.25) and interquartile range <0.5 were filtered, leaving ~2K features. Results: High quality genomic data was derived from 17 (100%) biopsies and clustered by patient origin. Using only prostate cancer related genomic features for hierarchical clustering, samples clustered by Gleason score (GS), indicating these biopsies contain prognostic signal. Similarly, when principal component analysis was performed on 51 imaging features, the primary source of variance segregated the samples into high (≥7) and low (6) GS. Pearson’s correlation analysis identified 152 genomic features that were highly associated with the imaging features (|r| > 0.7). Furthermore, genomic features were found to be significantly enriched for prostate cancer related pathways (p < 0.05), representing a potential biologically meaningful link between imaging and genomic data. Conclusions: MP-MRI-targeted diagnostic biopsies can potentially improve risk classification by directing pathological and genomic analysis to highest risk index lesions. This is the first demonstration of a link between quantitative imaging features (radiomics) with genomic features in MRI-directed prostate biopsies.
Correlation between time to prostate cancer metastasis and overall survival after androgen-deprivation therapy initiation.
Authors: Valenca Loana Bueno , Werner Lillian , Xie Wanling , Nakabayashi Mari , Kantoff Philip W. , Pomerantz Mark M 
Published: February 2017

250 Background: Currently,overall survival (OS) is used to determine treatment efficacy in trials for advanced prostate cancer (PC). Reliable intermediate endpoints could hasten drug development efforts. We therefore sought to determine the association between an intermediate endpoint—time to metastasis (TTM)—and OS in PC patients receiving androgen deprivation therapy (ADT) for biochemical recurrence (BCR). Methods: The Dana-Farber PC database identified 415 patients who received ADT for non-metastatic BCR with median 6.4 years follow-up. Associations between TTM and OS were measured from (i) time of ADT initiation (n=398) and (ii) time of castration-resistance (n=247) using a non-parametric Kendall tau rank correlation for bivariate time to event outcomes. A Cox regression model was used to assess the association of development of metastasis and OS for landmark timepoints. Results: Among 398 subjects analyzed from start of ADT, 180 (45%) developed metastases with median TTM 6.25 years. A total of 152 (38%) died, with a median OS of 8.5 years. For men developing metastases within five years of ADT initiation, hazard ratio (HR) for mortality was 7.42 (p<0.0001, 95% CI 4.18-13.17). Among 247 subjects assessed from time of castration resistant PC (CRPC), 172 (70%) developed metastases with a median TTM 2.6 years. In this subgroup, 140 (56%) patients died with median OS 5.25 years. For men developing metastases within three years of developing castration-resistance, HR for mortality was 5.25 (p<0.0001, 95% CI 3.20-8.61). Overall, correlation between TTM and OS from ADT initiation and OS was 0.25 (P<0.0001, 95% CI 0.20-0.29). Correlation between TTM and OS from CRPC was 0.32 (P<0.0001, 95% CI 0.25-0.37). Conclusions: TTM was significantly correlated with OS in PC patients treated with ADT for BCR. Prospective data in a large validation cohort will help determine whether TTM is suitably predictive of OS to serve as a primary endpoint in clinical trials.
Radical prostatectomy as a component of multimodal therapy for highly selected M1 prostate cancer patients.
Authors: O'Shaughnessy Matthew , Eastham James Andrew , Bochner Bernard H. , Laudone Vincent Paul , Carver Brett Stewart , Sjoberg Daniel , Scardino Peter T. , Scher Howard I. , Touijer Karim A. 
Published: February 2017

251 Background: Men who present with limited metastasis at the time of prostate cancer (PCa) diagnosis are typically managed with systemic therapy alone and the primary site of disease is not addressed. Systemic therapy with recently approved agents has been shown to improve survival in men with metastatic PCa; however the role of local therapy remains untested. Here, we examine the role of definitive surgical treatment of the primary tumor in a multimodal approach to highly selected patients with oligometastatic disease to maximize local and systemic cancer control. Methods: 20 patients with limited metastatic burden underwent RP as a component of multimodal therapy. Baseline characteristics, details of management, surgical outcomes, and disease progression defined as initiation of chemotherapy, new metastasis, or reinitiation of ADT were characterized. Results: Median age at RP was 61 years. Metastatic burden was assessed with whole body imaging; 17 of 20 patients had bone metastases (mets) (median 1, IQR 1,3) and 7 of 20 patients had retroperitoneal node mets. No patients had visceral mets. All patients had RP and pelvic lymph node dissection; 4 patients also had retroperitoneal lymph node dissection. There was one grade III surgical complication. 75% of patients reported continence within 12 months of RP. Patients received RT to bone (n=10), bone and pelvis (n=4), or no RT (n=6). Median neoadjuvant ADT was 4 months (IQR 3, 5) for all patients and neoadjuvant + adjuvant ADT was 9 months (IQR 6, 10) in 11 patients who discontinued ADT. At median follow-up of 19 months (IQR 10, 33) since RP, 12-month PFS was 65% (95%CI 35, 84). Among the 11 patients who discontinued ADT, 5 were non-castrate and had no evidence of disease progression. 4 patients had continuous ADT due to disease progression. There were no local recurrences after surgery. Conclusions: Multimodal therapy that includes RP is feasible and well-tolerated with acceptable low rate of surgical complications and good return of urinary continence. ADT was discontinued in a limited number of patients without signs of disease progression at short-term follow-up. Further evaluation of this therapeutic strategy should be considered in a prospective clinical trial.
Variation in TRMT11 gene as a prognostic marker in advanced-stage castrate-resistant prostate cancer (CRPC) patients.
Authors: Zhang Ben Yiming , Riska Shaun M. , Mahoney Douglas W. , Ribeiro Ricardo Jorge Teixeira , Medeiros Rui , Monteiro Catia , Cerhan James Robert , Costello Brian Addis , Dronca Roxana Stefania , Quevedo Fernando , Pitot Henry Clement , Moynihan Timothy J. , Mauricio Joaquina , Fraga Avelino Manuel , Calais Da Silva Fernando Eduardo , Kochuparambil Samith Thomas , Kohli Manish 
Published: February 2017

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]
Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model.
Authors: Moore William R. , Norris John D. , Wardell Suzanne , Eisner Joel Robert , Hoekstra William J. , Schotzinger Robert J. , McDonnell Donald P. 
Published: February 2017

263 Background: MDV3100 inhibits binding of androgens to AR and abiraterone is known to block androgen production through CYP17 inhibition; both are effective treatments for castration-resistant prostate cancer (CRPC, yet cross-resistance to both agents is problematic. The AR mutations F876L and T877A increase resistance to MDV3100 (M) or abiraterone (A), respectively. A regimen resistance is likely mediated through T877A activation by stimulatory progesterone (P4), pregnenolone (P5), or prednisone. The oral, non-steroidal L-inhibitor, VT-464, in phase 2 CRPC studies without prednisone coadministration, does not increase P4 or P5. Methods: The effects of VT-464, A, and M on AR transcription activity and cell proliferation were assessed and compared using reporter assays, and their oral effects in an M-resistant (F876L) human tumor mouse model were also assessed. Results: VT-464 competitively antagonized (Schild analysis) wild-type AR (IC50 =18 µM) and its potency was not decreased by AR overexpression (VCaP IC50=7.4μM). VT-464 fully antagonized AR T877A (IC50=0.52 μM) and inhibited LNCaP cell (AR T877A mutation) proliferation (IC50=0.70 μM) with potency similar to M. In contrast to M, VT-464 fully inhibited F876L (IC50=2.5 μM). VT-464 did not activate any AR forms up to the highest concentration tested (60 μM). In vivo, greater F876L tumor inhibition was observed with oral VT-464 compared to oral M or abiraterone acetate. Conclusions: VT-464 more potently antagonized mutated AR forms associated with A or M resistance than wild-type; AR antagonism contributed to xenograft activity and appears relevant to its clinical pharmacology. Due to its high L inhibition selectivity and potent mutant AR antagonist activity, VT-464 has a suitable profile for the treatment of early- or late-stage CRPC patients. VT-464 has advanced into phase 2 studies funded by Innocrin (NCT#02012920), the NCI (NCT02130700), and PCF in M- and A-resistant populations.
Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: Long term outcome of the Temporary Authorization for Use program in France.
Authors: Houede Nadine , Beuzeboc Philippe , Gourgou Sophie , Tosi Diego , Moise Laura , Gravis Gwenaelle , Delva Remy , Flechon Aude , Latorzeff Igor , Ferrero Jean-Marc , Oudard Stephane , Tartas Sophie , Laguerre Brigitte , Topart Delphine , Roubaud Guilhem , Agherbi Hanane , Rebillard Xavier , Azria David 
Published: February 2017

264 Background: COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a temporary use authorisation (TUA) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TUA. Methods: Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TUA for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors. Results: Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years. Conclusions: Biochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders’ patients could beneficiate from AA for more than 3 years.
Phase 1/2 trial of cabazitaxel with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone acetate: Phase 2 results.
Authors: Mateo Joaquin , Fizazi Karim , Pezaro Carmel Jo , Loriot Yohann , Mehra Niven , Albiges Laurence , Bianchini Diletta , Varga Andrea , Ryan Charles J. , Petrylak Daniel Peter , Shen Liji , Zhang Jenny , Attard Gerhardt , De Bono Johann Sebastian , Massard Christophe 
Published: February 2017

268 Background:Abiraterone acetate (A) and cabazitaxel (C) improve survival for patients with mCRPC. We conducted an open-label trial of A+C to assess the antitumor activity and tolerability of the combination in patients (pts) previously treated with docetaxel (D) and A (NCT01511536). Here, we report results for the phase 2 part of the study, after the combination MTD was established (Massard C, et al. ASCO 2013). Methods: Pts received A (1,000 mg QD) and C (25 mg/m2 every 3 weeks) with prednisone/ prednisolone (5 mg BID). Eligibility criteria included prior D and prior A for at least 3 months, disease progression by rising PSA, ECOG PS 0–1 and no prior C or mitoxantrone. The primary endpoint was PSA response rate (PSA-RR: ≥50% decrease confirmed ≥3 weeks later). A 1-sided exact test was planned to test a null hypothesis of PSA-RR 25%, with a type 1 error of 0.05. With a sample size of 26, this test would have a power of 83% under the alternative hypothesis of PSA-RR 50%. Secondary endpoints included progression-free survival (PFS), duration of response, radiological-RR, overall survival and safety. Results: Twenty-seven pts were treated in this phase 2 part of the study. The median time on A prior to A+C was 8.3 months (range 3.1–29.8). All pts previously received D and A; 4 pts (15%) had also received prior treatment with enzalutamide. The median number of C cycles administered was 7 (range 1–21). Main treatment-emergent adverse events (AE) Grade≥3 were neutropenia (15 pts; 55%; 1 pt [3.7%] had febrile neutropenia), fatigue (4 pts; 15%) and sepsis (3 pts; 11%). Seven pts (25.9%) required a dose reduction of C due to AE, but all patients received ≥80% of the planned dose intensity. Of 26 pts evaluable for the primary endpoint, 12 achieved a PSA response (PSA-RR 46.2%; 95% CI 26.6–66.4%), and therefore the null hypothesis was rejected (p<0.01). Median PSA-PFS was 6.9 mo (95% CI 4.1–10.2 mo). Three out of 14 pts (21%) with measurable disease achieved a partial response per RECIST 1.1. Conclusions: The combination of abiraterone and cabazitaxel is well tolerated and demonstrated antitumor activity in the post-docetaxel, post-abiraterone setting. Clinical trial information: NCT01511536.