bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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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.
Short-course hormonal therapy and the risk of death from prostate cancer in men with intermediate-risk prostate cancer undergoing high-dose radiation therapy.
Authors: Keane Florence K. , Chen Ming-Hui , Zhang Danjie , Moran Brian Joseph , Braccioforte Michelle H. , D'Amico Anthony Victor
Published: February 2017

27

Background: We assessed the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable and favorable intermediate-risk prostate cancer (PC) who received dose-escalated radiotherapy (RT) with or without short-course androgen deprivation therapy (ADT). Methods: The cohort consisted of 2,668 men with intermediate-risk PC (71.3% favorable, 28.7% unfavorable) who were treated with dose-escalated RT with or without ADT (median 4 mos.) from 1997 - 2013. Fine and Gray's competing risks regression was used to assess whether ADT decreased PCSM-risk in an adjusted multivariable model (Table). An interaction term was included to assess for potential differences in the impact of ADT on PCSM risk in men with favorable versus unfavorable intermediate-risk PC. Results: After a median follow-up of 7.84 years, there were 393 deaths (14.73%), of which 33 were from PC (8.40%). There was significant reduction in PCSM-risk in men with unfavorable intermediate-risk PC who received ADT (AHR 0.39, 95% CI 0.16 to 0.92, P=0.033), but no significant difference in PCSM-risk in men with favorable intermediate-risk PC who received ADT (AHR 0.68, 95% CI 0.19 to 2.49, P=0.561). Conclusions: While ADT reduced PCSM-risk in men with unfavorable intermediate-risk PC, there was no significant improvement in men with favorable intermediate-risk PC, suggesting that for these patients ADT in addition to dose-escalated RT may not be required to minimize PCSM-risk. [Table: see text]
Dual targeting of the androgen receptor and hypoxia-inducible factor-1α pathways to synergistically inhibit castrate-resistant prostate cancer.
Authors: Figg William Douglas , Fernandez Elena V. , Reece Kelie M , Ley Ariel M , Troutman Sarah M , Sissung Tristan M. , Price Douglas K. , Chau Cindy H.
Published: February 2017

270

Background: Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). While enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and HIF-1α are key regulators of these processes, dual targeting of both signaling axis represents an attractive therapeutic approach. Methods: Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. Cells were stimulated with dihydrotestosterone (DHT) or the hypoxia mimetic cobalt chloride. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. Results: In prostate cancer cells, gene expressions of AR targets (KLK3, FKBP5, TMPRSS2) were repressed by HIF-signaling; conversely, HIF-1α target expressions (VEGF, ENO1, LDHA) were induced by DHT-mediated AR signaling. Treatment of CRPC cells with enzalutamide and chetomin or HIF-1α siRNA attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced VEGF protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells. Additionally, HIF-1α siRNA synergistically increased enzalutamide-induced apoptosis. Conclusions: Combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene specific HIF-dependent expression, prostate cancer cell growth, and apoptosis.
Characteristics of African Americans (AAs) treated with sipuleucel-T (sip-T): Comparison of clinical trial and real-world experience.
Authors: Tutrone Ronald F. , Ahaghotu Chiledum , Armstrong Andrew J. , Higano Celestia S. , Cooperberg Matthew R. , Belkoff Laurence H. , Olsson Carl A. , Goel Sanjay , Tyler Robert Claude , LIll Jennifer Susan , Gray Todd E. , McCoy Candice , Sartor A. Oliver
Published: February 2017

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Background: AA men are underrepresented in randomized clinical trials (RCTs) for prostate cancer, despite an almost 2-fold greater incidence in AA vs Caucasian populations. Sip-T is an autologous cellular immunotherapy approved by the FDA and EMA for the treatment of certain patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. AA enrollment in three sip-T phase 3 RCTs was 5.8% (n=43). While no definitive conclusions were drawn, median overall survival (OS) suggested AAs benefit from sip-T. PROCEED, an ongoing phase 4 registry, expanded efforts to increase AA enrollment to better characterize this population and the safety, product parameters (PP), and OS of AAs treated with sip-T. Methods: PROCEED enrolled 1973 pts treated with commercial sip-T within 6 months of registration. Efforts, such as selecting racially diverse sites and highlighting AA enrollment in PROCEED communications and investigator meetings, were used to boost AA enrollment. Baseline Gleason score, Eastern Cooperative Oncology Group performance status (ECOG), prostate-specific antigen (PSA), and alkaline phosphatase (ALP) were compared between RCTs and PROCEED. Safety and survival analyses are ongoing. Results: PROCEED AA enrollment was 11.7% vs 7.1% US RCT nonwhite enrollment rate and approaches the US AA population of 13.7%. Baseline AA pt characteristics were: lower median PSA and ALP levels in PROCEED vs RCTs, higher ECOG >0 in PROCEED vs RCTs, and higher Gleason score ≥8 in PROCEED vs RCTs (Table). Conclusions: Efforts to boost AA enrollment in PROCEED to a proportion comparable to the US AA population succeeded. The lower baseline PSA of AAs in PROCEED is similar to the PSA observed in the entire PROCEED population. Safety, PP, and OS will be reported with longer follow-up. Clinical trial information: NCT01306890. [Table: see text]
Pretreatment neutrophil/lymphocyte ratio (NLR) prior to steroids as a prognostic factor in metastatic castrate refractory prostate cancer (mCRPC) patients treated with taxanes.
Authors: Chan David , McLachlan Jennifer Mary , Crumbaker Megan , Marx Gavin M.
Published: February 2017

273

Background: The neutrophil/lymphocyte ratio (NLR) has been demonstrated to be a prognostic factor in multiple malignancies. Prior analyses have demonstrated conflicting results in correlation between NLR and overall survival (OS) in mCRPC. Prednisone and dexamethasone, commonly used in chemotherapy regimens for prostate cancer, have been demonstrated to affect neutrophils and hence NLR. We investigated the correlation between pre-dexamethasone NLR and OS in patients with mCRPC. Methods: We performed a retrospective single-center study of patients with mCRPC who received taxane-based chemotherapy (docetaxel or cabazitaxel) between 9/2005 and 12/2012. Patients were included if blood test results were available between 3 and 28 days prior to commencement of chemotherapy. Baseline demographics and NLR were correlated with OS using a Cox proportional hazards model. Results: 42 patients were included, 9 of whom were still alive, with median age 70 and median follow-up 23.1 months. Median OS was 24.1 months. 36 were commenced on docetaxel-based chemotherapy and 6 on cabazitaxel-based chemotherapy. Considering NLR as a categorical variable, OS was significantly better in patients with NLR<5 (n=28) compared to those with NLR>5 (n=14), with median OS 32mo vs 15.4mo and HR 2.155 (95% CI 1.072-4.332, p=0.0007 by log-rank test). In multivariate analyses, NLR (p=0.008) and age (p=0.048) were independent predictors of overall survival. In sensitivity analyses, when including NLRs within 48 hours of chemotherapy initiation, the correlation between NLR and OS was only marginally significant (p=0.048). Conclusions: HighNLR is an adverse prognostic marker for decreased overall survival in mCRPC patients undergoing taxane-based chemotherapy. Previous conflicting results regarding its value may be related to the effect of steroids on NLR.
Biweekly cabazitaxel as post-docetaxel treatment for metastatic castration resistant prostate cancer (mCRPC): Findings from an early safety analysis of the Prosty II trial.
Authors: Kellokumpu-Lehtinen Pirkko-Liisa Irmeli , Marttila Timo , Hervonen Petteri , Kataja Vesa V , Utriainen Tapio , Luukkaa Marjaana , Taalikka Mikko , Kautio Anna-Liisa
Published: February 2017

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Background: Docetaxel (D) administered at 2-week intervals was better tolerated than the standard 3-week D in mCRPC. In addition, the overall survival was better with the 2-weekly D dosing in our Prosty I trial (Kellokumpu-Lehtinen et al. Lancet Oncol 2013;14:117-124). The aim of the Prosty II trial was to evaluate the safety of 2-weekly cabazitaxel (C) as post-docetaxel treatment for m CRPC. The safety of the first 40 patient (pts) is reported below. Methods: 40 pts were allocated to receive C 16 mg/m² i.v. d1 and d14 q4 wks. At baseline, WHO performance status was 0 in 33% of pts and 1 in 67% of pts and the median serum PSA level was 342 µg/L (range 3.7-2425)). The primary endpoint was safety. Study identifier: NCT01558219. Results: A total number of 144 cycles of C were administered. No prophylactic G-CSF was used. The most common Grade 3/4 adverse events (AE, expressed as % pts experienced Grade3 or Grade 4 AE) were neutropenia 12.5/2.5%, pain 12.5/0%, fatique 5/2.5%, anemia 5.0/0%, neutropenic infections 2.5/0%, leucopenia 2.5/0%, mucositis 2.5/0%, increase of alkaline phosphatase 5/0% and limb edema 2.5/0. In addition one Grade 4 pulmonary embolism and one intracerebral hemorrhage occurred. In one pt, cancer related bone fracture occurred during the second C cycle (Grade 4 AE). Altogether up to cycle 6 no AE was reported in 1 pt (2.5%), Grade 1 AE in 3 pts (7.5%), Grade 2 in 17 pts (42.5%), Grade 3 in 13 pts (32.5%) and Grade 4 in 5 pts (12.5%). Conclusions: Biweekly cabazitaxel seems to be well tolerated treatment for heavily pretreated advanced mCRPC patients.
Opioid use among prostate cancer patients with bone metastases.
Authors: Yaldo Avin , Wen Lonnie Kent , Ogbonnaya Augustina , Valderrama Adriana , Kish Jonathan K , Eaddy Michael , Kreilick Charles , Seal Brian S.
Published: February 2017

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Background: Bone metastases (mets) occur in ≥90% of men with castrate-resistant prostate cancer (PC), causing significant pain and resource use. Opioids are frequently used in managing pain throughout the course of care, but few studies have quantified the incremental use of opioids after the onset of bone mets. This study describes treatment patterns and incremental use of opioids among PC patients diagnosed with bone mets. Methods: Prostate cancer patients (ICD9=185.xx or 233.4) newly diagnosed with bone mets (ICD9=198.5) from 2006-2012 were identified from MarketScan databases. Patients were required to be ≥40 years, continuously eligible for medical and pharmacy benefits ≥12 months pre and ≥6 months postdiagnosis, and without evidence of other primary cancers during the study period. Patients were initially categorized as non-users of opioids (<10 days use), short-term users (≥10 but <60 days use), or long-term users (≥60 days use), and further by presence of skeletal-related events (SREs). Type of opioid therapy, proportion of time on opioids, morphine equivalent dose, and NSAID use were evaluated pre and postdiagnosis. Results: There were 4,476 patients identified for inclusion; 438 (9.8%) had an SRE. Mean age was 72 and 1.6% had chronic pain at baseline. The proportion of opioid users increased from 25.2% at baseline to 32.9% after diagnosis (P<0.0001). Among opioid users, the proportion of long-term users increased from 29.9% to 45.5% (P<0.0001). Use of monotherapy short-acting opioids decreased (pre 79.0% vs post 71.9%; P<0.0001), with a corresponding increase in mixed-action opioids (pre 13.3% vs post 23.4%; P<0.0001). Mean morphine equivalent dose (pre 7.1mg vs post 9.9mg; P<0.0001) and proportion of time on opioid therapy also increased substantially (pre 28.3% vs post 54.7%; P<0.0001). NSAID use decreased after bone met onset (pre 21.9% vs post 15.5%; P<0.0001). Opioid use and radiation therapy were more evident in patients with SREs (opioids 21.9%, opioids + radiation 32.6%, radiation 29.5%), and mean morphine equivalent dose was 10.8mg. Conclusions: Long-term opioid use and dose significantly increased after bone met onset in PC. Novel strategies that mitigate bone pain and minimize opioid use should be evaluated in this population.
Testing a prognostic model in patients with metastatic castrate resistant prostate cancer (MCRPC) treated prechemotherapy with abiraterone.
Authors: Pan Shermaine , Prasad Kellati , Hall Emma , Swindell Ric , Charnley Natalie
Published: February 2017

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Background: There is a need for prognostic models in metastatic prostate cancer to determine optimal treatment pathways on development of castrate resistance. Abiraterone is an androgen biosynthesis inhibitor. Efficacy was proven in patients with MCRPC prechemotherapy in the COU-AA-302 trial with PSA PFS 11.1 months (Raj et al New Eng J med 2013). We have previously investigated prognostic factors in MCRPC (Charnley et al J Clin Oncol 2014). We reported a prognostic model which predicts that if alk phos rise ≥100 in the preceding 3 months and/or Hb<11 there is no response. The model was correct in 78.9% of responders and 55% of non responders (overall 66.7%). We test the model in an independent group of 81 patients prechemotherapy, some from a different treating centre. Methods: 81 patients with metastatic CRPC received abiraterone 1g daily prechemotherapy. Response to abiraterone was defined as a 50% reduction in PSA. Alk phos rise ≥100 in the previous 3 months and Hb<11 were related to PSA response. Results: 19 patients had both alk phos rise ≥100 in the preceding 3 months, and Hb<11. None of these patients had a PSA response. For the 31 patients with no risk factors 66% of cases responded. The predictive model was correct in 66% of true responders, and 85.3% of non responders, 74.1% overall. Conclusions: In this group of 81 patients with castrate resistant metastatic prostate cancer a previously defined model, which incorporates alk phos rise ≥100 in the preceding 3 months and/or Hb<11 is 74.1 % accurate in an independent group of patients. No patients with both alk phos rise>100 in the preceding 3 months, and Hb<11, responded to abiraterone. The model has potential in guiding treatment pathways on development of castrate resistance in prostate cancer, but needs to be tested in a greater number of patients.
Characterization of differences between prostate cancer (PCa) patients presenting as de novo versus primary progressive metastatic disease.
Authors: Finianos Antoine Nafez , Gupta Kanika , Meshikhes Mariam , Shimony Maya , He Chao , Guebre-Xabiher Hiwot , Simmens Sam , Aragon-Ching Jeanny B.
Published: February 2017

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Background: In 2014 alone, 29,480 men are projected to die of PCa (Cancer Statistics, 2014).Approximately 4% are metastatic on presentation (de novo, dn) while a subset of men progress on to metastatic disease during the course of their disease (primary progressive, pp). We sought to characterize and compare differences in disease characteristics and outcomes between those who present as dn vs pp metastatic disease in our institution. Methods: A retrospective chart review of dn vs pp metastatic patients for the past 2 years was undertaken. Characteristics such as demographics, Gleason score, duration of hormone sensitivity, and treatment, were obtained. T-test and Fisher’s exact test were used to test differences in patient and disease characteristics between dn and pp metastatic patients. Results: Preliminary results on 10 de novo and 13 primary progressive patients are presented herein. Statistically significant differences were noted for median age at diagnosis: de novo 66.5 years of age (range=48-71) vs primary progressive 58 years of age (range 42-77), p=.05; Median duration of hormone sensitivity: de novo 149.5 days (range=91-440) vs primary progressive 444.5 days (range 91-3041), p = 0.0002; Median Gleason Score: de novo 9 (range 6-10) vs primary progressive 8 (range 6-9), p = .002. Although there was a tendency towards higher mean and median of PSA levels for the de novo (225.16 and 50 ng/ml, respectively) vs primary progressive (16.97 and 28.2 ng/ml, respectively), the difference was not statistically significant (p=.15). There was also non-significant trends for the de novo group to be more likely to have a lymph node metastasis (70%, p=.40) and Caucasian (62%, p=.16) compared to the primary progressive group (46% lymph node metastasis, 23% Caucasian). Conclusions: While the reported samples are small, our data reveals a potential difference in disease aggressiveness in those presenting with de novo metastatic cancer with higher-risk disease and shorter time to castration resistance. Further data collection is underway and a prospective trial assessing the difference molecularly between both groups is planned to confirm these findings.
Health-related quality of life in patients with advanced prostate cancer undergoing treatment with TRIPTOrelin Pamoate SIX month formulation: Results of the non-interventional TRIPTOSIX study.
Authors: Eisenhardt Andreas , Schneider Tim , Scheithe Karl , Colling Christiane , Heidenreich Axel
Published: February 2017

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Background: Preserving quality of life (QoL) is an important therapeutic aim in advanced prostate cancer (PCa). The effects of treatment on QoL were studied in a non-interventional study performed from 2010 until 2012 evaluating 1 year of treatment with a LHRH agonist, triptorelin pamoate 6-month depot (TP 6M). Methods: Data of 564 patients with advanced PCa treates in 129 German urology outpatient clinics were analysed. Data on QoL were collected by EORTC questionnaires (QLQ-C30 and -PR25) at baseline, 6 months and 12 months. The QLQ-C30 assesses functional QoL, global health and symptoms of disease, the QLQ-PR25 covers PCa specific symptoms and sexual activity. A clinically relevant improvement, i.e. increase of ≥10 points in the QLQ-C30 global health status/QoL scale, defined treatment responders. Response at month 6 compared to baseline was the primary study endpoint. Results: GlobalHealth Related (HR) QoL was similar over the 1 year follow-up period with a mean (± SD) score of 60.9 (±21.8) at baseline and 61.7 (±22.2) at 12 months. Within the first 6 months, 24.0% of patients were identified as responders (i.e. a clinically relevant improvement in this parameter of ≥10 points). The responder rate was maintained at 12 months of treatment (25.5%). This trend in QoL was also seen in the QLQ-C30 subscales, which were generally similar over the study period. QLQ-PR25 scores were also found to be similar over 1 year, although some deterioration was reported by sexually active patients, as expected. Subgroup analyses on response rates identified age, risk group, pretreatment for PCa and baseline QoL scores as predictors of change in QoL. Conclusions: Treatment with TP 6M over 12 months is associated with few changes in HRQoL and might lead in some patients to clinically meaningful improvements of HRQoL.
Comparison of genetic alterations from the bladder cancer genome atlas (TCGA) and a prospective set of high-grade urothelial carcinoma tumors using a CLIA laboratory next generation sequencing assay.
Authors: Iyer Gopa , Bagrodia Aditya , Cha Eugene K. , Boyd Mariel Elena , Zehir Ahmet , Cheng Donavan T , Hyman David Michael , Bambury Richard Martin , Arcila Maria E. , Ladanyi Marc , Viale Agnes , Al-Ahmadie Hikmat , Berger Michael F. , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B.
Published: February 2017

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Background: The type and frequency of recurrent, targetable alterations in muscle-invasive, treatment-naïve urothelial cancer (UC) have been well-catalogued through the bladder TCGA. We sought to validate these findings within a prospective cohort of patients (pts) with progressive UC treated at our institution. This cohort typifies the UC patient population managed by medical oncologists. Methods: Pts with a diagnosis of UC were enrolled onto an IRB-approved protocol between 1/14/14 and 7/29/14, which allowed for sequencing of all exons in 341 oncogenes and tumor suppressor genes using an exon capture next generation sequencing assay (NGS) platform (MSK-IMPACT) in a CLIA lab from tumor and matched germline DNA. Somatic point mutations, truncations, copy number alterations, and insertions/deletions were detected. Results: 49 UC pts were sequenced, 5 (10%) having upper tract disease. 33 (67%) tumors were pure UC histology with the remainder containing divergent differentiation. 17 samples (24%) were metastatic in origin, and 40 samples were analyzed from pts who had received prior chemotherapy. The most common alteration identified was point mutations within the TERT promoter (71%), a region not sequenced by TCGA. Additional alteration frequencies were similar between both sets. FGFR3 mutations overlapped with both PIK3CA and TSC1 alterations and co-alterations were observed between FGFR3 and CDKN2A as well as PIK3CA and CCND1. Conclusions: TERT promoter mutations were found at high frequency in the MSK-IMPACT tumor cohort. The frequency and type of alterations identified in the bladder TCGA are similar to the MSK-IMPACT cohort, suggesting that TCGA data can be used to guide clinical trials in the metastatic, pre-treated population. Overlap of alterations within and across core signaling pathways underscores the need for functional validation of alterations and for rational combinations of targeted therapies to effectively treat advanced UC. [Table: see text]
Risk group stratification in patients with micropapillary bladder cancer treated with radical cystectomy and/or neoadjuvant chemotherapy.
Authors: Williams Stephen Bentley , Fernandez Mario , Willis Daniel Levi , Slack Rebecca , Siefker-Radtke Arlene O. , Navai Neema , Dickstein Rian J. , Guo Charles , Czerniak Bogdan , McConkey David James , Parikh Sahil , Pisters Louis L. , Shah Jay Bakul , Grossman H. Barton , Dinney Colin P. N. , Kamat Ashish M.
Published: February 2017

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Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carcinoma. We have previously published clinical risk stratification groups for patients with conventional urothelial carcinoma and sought to identify if these were valid in patients with this variant histology. Methods: An IRB approved review of 1910 patients in our radical cystectomy database revealed 106 patients with preoperative diagnosis of ≤cT4aN0M0 MPBC between December 1992 and January 2012 who underwent upfront radical cystectomy (RC, n = 74) or neoadjuvant chemotherapy (NAC) followed by RC (n = 32). To determine whether patients with MPBC can be risk stratified using traditional risk factors, a recursive partitioning analysis (RPA) was performed. Results: In multivariate analyses, hydronephrosis (HR=3.1; p=0.01), and extent of MPBC at transurethral resection (TUR) (HR=1.9; p=0.04) were associated with shortened OS. In the reduced model, clinical stage also achieved significance (HR=2.8; p=0.03). Results were similar for DSS: hydronephrosis (HR=2.4, p=0.03), extent of MPBC (HR=2.1, p=0.03) and clinical stage (HR=4.7, p=0.02). Using the RPA analysis, following risk groups were identified according to OS or DSS: 1) cT1 disease with no hydronephrosis; 2) cT2 or higher with no hydronephrosis; or 3) hydronephrosis (with any cT stage). These groups corresponded to a low, intermediate and high-risk groups with 5-year OS and DSS rates of 85% and 91%, 50% and 57% and 16% and 17%, (p<0.001), respectively. We found these risk groups to hold true in those treated with NAC or upfront RC; those who received NAC trended towards better outcomes. Conclusions: In patients with MPBC, preoperative risk factors can help stratify patients into different risk groups similar to what is seen in patients with conventional UC. Presence of hydronephrosis is an especially ominous sign.
Safety and efficacy of temsirolimus as second-line treatment for patients with recurrent bladder cancer.
Authors: Houede Nadine , Roubaud Guilhem , Mahammedi Hakim , Vedrine Lionel , Joly Florence , Mourey Loic , Pfister Christian , Culine Stephane , Goberna Alejandro , Lortal Barbara , Pulido Marina , Pourquier Philippe , Bellera Carine A.
Published: February 2017

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Background: Bladder cancer is the 7th cause of death from cancer in men and 10th in women. For metastatic patients, prognosis is poor with a median overall survival of 15 months that remained unchanged for the past 15 years. No standard second-line chemotherapy is available for patients who relapse. Acquired mutations leading to a deregulation of the PI3K/AKT/mTOR pathway have been reported in more than 40% of bladder cancers suggesting the use of the mTOR (mammalian target of rapamycin) signalling pathway as an attractive target for the treatment of urothelial tumors. Methods: The main objective of this study was to assess the efficacy of temsirolimus, an mTOR inhibitor that is already used for the treatment of renal cancers, in patients with recurrent or metastatic bladder cancer who already received a first line chemotherapy. Efficacy was measured in terms of non-progression of the disease at two months of treatment following the RECIST v1.1 criteria. Based on a two-stage optimal Simon’s design, a total of 15 non-progressions out of 51 eligible and assessable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg until progression, unacceptable toxicities or withdrawal. Results: Fifty-four patients were enrolled in the study between November 2009 and July 2014 in seven French centres. At the end of the first stage, six patients out of 17 were progression-free at 2 months leading to the inclusion of additional 37 patients in the second stage of the study. Thirty-six patients were eligible and assessable for the primary efficacy endpoint. A total of 18 (50%) non-progressions were observed at 2 months. Among them, partial response was documented for two patients and stable disease for 16. Twenty-five related adverse events were observed in 19 (35.2%) of the patients. Conclusions: Our study is providing the first clinical evidence of a potential benefit of temsirolimus for the treatment of relapsed bladder cancers. Ancillary study is ongoing to investigate the mutational status of genes which are involved in the PI3K/AKT/mTOR signalling pathway in order to identify a predictive signature of response to temsirolimus in bladder cancer. Clinical trial information: NCT0187943NCT0187943.
Second-line chemotherapy for metastatic urothelial cell carcinoma: Pooled analysis and construction of a prognostic model.
Authors: Salah Samer , Lee Jae-Lyun , Rozzi Antonio , Kitamura Hiroshi , Matsumoto Kazumasa , Srinivas Sandy , Morales Rafael , Carles Joan , Al-Wardat Rami , Maakoseh Mohammad
Published: February 2017

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Background: A prognostic model for patients with metastatic urothelial cell carcinoma (UCC) progressing following platinum-based therapy was constructed based on data from the phase 3 vinflunine trial. However, prognostic information for patients treated outside the setting of clinical trials and with variety of second-line regimens are limited. Methods: We gathered individual patient’s data from studies assessing second-line chemotherapy for metastatic UCC and analyzed the influence of factors of interest on overall survival (OS) through univariate and multivariate Cox-regression analysis. A prognostic model was constructed, and data of an independent series from a single institution was utilized for validation. Results: Data for 182 patients from seven studies were pooled. The second-line treatment was single agent in 22 (12%), platinum-based combination (nedaplatin or oxaliplatin) in 59 (33%), and non-platinum combination in 101 (55%). In multivariate analysis, Eastern Cooperative Oncology Group performance status ≥1, Hb<10, and metastatic patterns other than LN only metastasis emerged as independent adverse factors. Patients with all three factors (poor risk), 1-2 factors (intermediate risk), and 0 factors (Good risk) had median OS of 3.1, 8.8, and 16.5 months respectively, p< 0.0001. The corresponding median OS for the validation series (n = 44) were 3.3, 8.1, and 13.3 months, p = 0.023. Platinum – based regimens were associated with OS benefit compared to other combination regimens and to single agents, such benefit was retained when this factor was included in multivariate analysis (HR: 3.1, 95% CI: 1.82- 4.98, p< 0.0001). In addition, freedom of progression at 6 months from initiation of second- line therapy correlated with improved survival compared to progression within 6 months; median OS 13.9 and 6.6 months respectively, p< 0.0001. Conclusions: We proposed and validated a prognostic model for patients with metastatic UCC who are eligible for second-line therapy. The proposed model may prove helpful for risk-stratification. Furthermore, our data suggest that testing second- line platinum-based regimens in randomized trials is warranted.