bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel predictive biomarker of immunotherapy response in metastatic renal cell carcinoma (mRCC): The lymphocyte microRNA expression profile.
Authors: Incorvaia Lorena , Fanale Daniele , Badalamenti Giuseppe , Rinaldi Gaetana , Vincenzi Bruno , De Luca Ida , Galvano Antonio , Corsini Lidia Rita , Gristina Valerio , Guarini Aurelia , Simonato Alchiede , Tonini Giuseppe , Bazan Viviana , Gori Stefania , Porta Camillo , Russo Antonio
Published: May 2019

e16109

Background: Predicting which patient with metastatic renal cell carcinoma (mRCC) will benefit from immune checkpoints inhibitors (ICPIs) still remain an issue. Biological factors particular to certain individuals have a clear effect on variation in response. Emerging evidence suggests that small non-coding RNA, such as microRNAs (miRNAs), are critical modulators of numerous cellular processes, including immune surveillance. The main aim of this study was to analyze the lymphocyte miRNA expression profile in mRCC patients and dynamic changes after the treatment with ICPI, in order to investigate the molecular mechanisms and signaling pathways involved in ICPI response and their potential role as predictive biomarker. Methods: Total RNA and miRNAs were isolated from peripheral lymphocytes of 14 mRCC patients, treated with nivolumab as second line. The blood samples were collected before nivolumab treatment (T0) and at progression disease (T1). The quality and quantity of miRNAs were assessed using the miRNeasy Mini Kit, 2100 Bioanalyzer and spectrophotometer NanoDrop ND-1000. Through a TaqMan Low Density Array A human microRNA microarray analysis, the expression profile of 377 lymphocyte miRNAs was analyzed. A cut off of fold change > 2 was considered for up-regulated miRNAs and < 0.3 for down-regulated. The patients were divided into 2 groups: patients with PD within 6 months of treatment (G1), and patients with stable therapy response (RC, RP or SD) over 12 months (G2). Results: Microarray analysis showed a subset of 59 miRNAs involved in several cancer-related processes, including cell cycle regulation, PI3K/Akt, FOXO and HIF-1 signaling pathways, differentially expressed in peripheral lymphocytes of mRCC of G1 and G2 group of patients. Among all miRNAs analyzed, several were deregulated, such as miR-155, miR-22, miR-24, miR-484, miR-335 and miR-492, some up-regulated and others down-regulated. This deregulation of specific miRNAs was different into G1 and G2 groups, and seem to be related with the duration of response to ICPI. Conclusions: Our data, for the first time, study the expression profile of miRNAs in the peripheral lymphocytes, and show a correlation between deregulation of miRNAs and response to Nivolumab. These knowledge could help to identify potential biomarkers predictive of response to ICPIs for the personalization of treatment.
Comparative analysis of profiles of second-line stage IV renal cell carcinoma patients by first-line to second-line treatment sequencing in the United States.
Authors: DaSilva Corrina , Spindel Julie , Franceschetti Alessandra
Published: May 2019

e16110

Background: Treatment of metastatic renal cell carcinoma (RCC) is evolving. With new agents, 2nd line (2L) therapies becoming frontline (1L) options, and growing research on outcomes, optimal treatment sequencing is increasingly complex. Methods: Real world data from Ipsos Global Oncology Monitor©: geographically representative physicians in US reported on 1,120 stage IV RCC anti-cancer drug-treated patients seen in consultation from 10/2017–9/2018, providing patient demographics, current and historic treatment data. Analysis of 1L to 2L treatment algorithm was conducted for current 2L patients. Patient profiles of 2 most frequent algorithms [TKI-TKI (n = 298) and TKI-CKI (n = 443)] were compared using inferential statistics. Results: Patients treated with 1L TKI and 2L CKI (TKI-CKI) vs. those treated with 1L TKI and 2L TKI (TKI-TKI) are older (mean: 65.8 vs 62.7; p < 0.05), have metastases in ≥ 2 sites (52% vs 36%; p < 0.01) and maintained 1L treatment for longer (mean: 10.0 vs 8.8 months; p < 0.05). 2L CKI patients were more likely to have achieved CR, VGPR or PR from 1L TKI (60% vs. 50%; p < 0.05) and less likely to have distant progression (19% vs. 26%; p < 0.05) or discontinued 1L TKI due to toxicities (9% vs. 16%; p < 0.01). 2L CKIs are more likely prescribed due to new clinical data (20% vs 12%; p < 0.05) and biomarker results (7% vs 2%; p < 0.05); 2L TKIs are prescribed more for convenience (10% vs 4%; p < 0.01). Physicians prescribed 2L CKIs more frequently with intent to extend life (53% vs 40%; p < 0.01) than palliative intent (47% vs 60%; p < 0.05). TKI-CKI patients were more involved in 2L treatment choice (17% vs 8%; p < 0.01) and physicians stated higher satisfaction with their current CKI (36% vs 26%; p < 0.01) relative to TKI-TKI patients.Conclusions: TKI-CKI patients are likely to have a more progressed disease, but also to have had a more positive outcome from 1L TKI, suggesting a therapeutic strategy driven by clinical attributes. New clinical data reinforce prescribing CKIs to extend life rather than for palliative purposes. When prescribing CKIs, patient involvement is higher (possibly due to mode of administration requiring more commitment) and physicians are more satisfied with results (despite these patients being older and with more metastases).
Stereotactic radiotherapy for stage I renal cell carcinoma: Overall survival and treatment trends compared to thermal ablation and surgical resection.
Authors: Uhlig Annemarie , Uhlig Johannes , Trojan Lutz , Kim Hyun S.
Published: May 2019

e16111

Background: Stereotactic radiotherapy (SRT) is a non-invasive treatment modality that is currently evaluated for use in renal cell cancer (RCC). We aimed to evaluate current utilization of SRT for stage I RCC and compare associated overall survival with thermal ablation (TA) and partial nephrectomy (PN). Methods: The 2004-2015 United States National Cancer Database was searched for histopathologically approved stage I RCC treated with PN, cryoablation (CRA), radiofrequency- or microwave-ablation (RFA/MWA) or SRT. Patients were propensity score matched to account for potential confounders. Overall survival (OS) was evaluated with Kaplan-Meier plots, log-rank tests and Cox proportional hazards models. Results: A total of 91,965 patients were included (SRT n = 174; PN n = 82,913; CRA n = 5,446; RFA/MWA n = 3,432).Stage I SRT patients tended to be older females with fewer comorbidities and treated at non-academic centers in New England states. After propensity score matching, a cohort of n = 660 patients was obtained with well-balanced distribution of confounders between the different treatment strategies. In the matched cohort, OS following SRT was inferior to PN and thermal ablation (PN vs. SRT HR = 0.33, 95% CI: 0.22-0.50, p < 0.001; CRA vs. SRT HR = 0.44, 95% CI: 0.30 – 0.66, p < 0.001; RFA/MWA vs. SRT HR = 0.53, 95% CI: 0.36-0.77, p < 0.001). OS following CRA was comparable to PN (HR = 1.35, 95% CI: 0.84-2.18, p = 0.216), while OS following RFA/MWA was inferior to PN (HR = 1.61, 95% CI: 1.01-2.56, p = 0.046). OS rates are summarized in table 1. Conclusions: Only a minority of RCC patients receive SRT. In stage I RCC, current renal SRT protocols yield lower overall survival compared to thermal ablation and resection, while CRA and PN show comparable outcomes. Based on the current body of evidence, SRT for RCC should be reserved for clinical trials or exceptional clinical circumstances.[Table: see text]
Hypoxia signaling and immune infiltration in a presurgical trial of sunitinib in patients with clear cell renal cell carcinoma (RCC).
Authors: Hasanov Elshad , Peterson Christine B , Matin Surena F. , Wood Christopher G. , Sircar Kanishka , Tannir Nizar M. , Jonasch Eric
Published: May 2019

e16115

Background: Presurgical clinical trial design allow for pharmacodynamically relevant tissue collection that can inform regarding drivers of tumor biology. An unmet need is the ability to identify tumors that may respond to immunotherapy and the underlying mechanism of immune infiltration. Methods: This single arm phase II study was designed to test efficacy and safety of presurgical sunitinib treatment in metastatic RCC, and to identify drivers of tumor biology. Patients (pts) with metastatic RCC and a resectable primary received sunitinib 50mg PO daily for four weeks, and underwent restaging. If deemed a candidate, pts underwent cytoreductive nephrectomy (CN) during their second cycle of sunitinib, with last dose administered the day before surgery. Pts were restaged postoperatively and continued on sunitinib if no progressive disease was seen. Genomic and histological characteristics of RCC were evaluated for correlations between response and biological features. Results: Between June 2008 and October 2011, 50 pts were enrolled. 41 underwent CN. Seven pts showed refractory disease and were not considered surgical candidates. No sunitinib related perioperative toxicities were observed. Six pts progressed on first postoperative imaging studies, with three patients developing new brain metastases. Median progression free survival (PFS) was 8.6 months, and overall survival was 38 months. Objective response rate was 30 percent with 2 pts demonstrating a complete response. Analysis on 39 pts showed HIF1a staining was significantly associated with PFS (p = 0.023*, univariate Cox model), with a hazard ratio (HR) of 1.028 (95% CI, 1.004-1.053). This association remained significant in a multivariate Cox model adjusting for age and gender (p = 0.019*). In addition, HIF1a correlated with multiple immune markers (CD8, CD45RO, PD1, Treg, CD68, and LAG3). Analysis of genomic correlates is ongoing. Conclusions: Presurgical sunitinib therapy in RCC is safe and efficacious. HIF1a staining is associated with shorter PFS, and with increased immune infiltration. Tissue HIF1a should be explored as a marker, and studied mechanistically as a driver of the immune microenvironment in RCC. Clinical trial information: NCT00715442.
A study of tobacco abuse as a risk factor for adrenal cortical carcinoma.
Authors: Kolodney Joanna Amy , Kolodney Michael , Patterson Jessica , Hagen Rachael , Smolkin Matthew , Hobbs Gerald , Hogan Thomas F. , Hafez Maria , Albandar Heidar
Published: May 2019

e16119

Background: Smoking has been suggested as a risk factor for adrenal cortical carcinoma (ACC), but, due to the rarity of this tumor, this hypothesis has only been inferred from single study using a mixed population of adrenal tumors that included pheochromocytoma and neuroblastoma as well as ACC. Methods: De-identified IRB exempted records were analyzed for age, gender, and smoking history in adult patients diagnosed with ACC in both the West Virginia University database containing 2,699,193 patients and, in the larger TriNetX database of 21,426,477 patients from 2008-2018. In addition, the statewide ratio of smoking to ACC prevalence was computed in all 50 states using data from SEER and the CDC. Results: Given the high rate of both tobacco use and ACC in the West Virginia Health System, we hypothesized that smoking contributed to increased prevalence of ACC in our state. We compared the rates of ACC and smoking in all 50 states using data from SEER. Among the 50 states, West Virginia had the highest smoking rate and the second highest rate of ACC. Utah had the lowest rate of smoking and the third lowest rate of ACC. The sample correlation between statewide smoking and ACC is .4177 indicating a significant association between the two (p = .0035). From 2008 to 2018, 20 patients with ICD10 code c74.0 (ACC) were abstracted from our EMR system. Examination of the individual charts determined 15 of the 20 patients had confirmed ACC diagnosis. This cohort was compared with matched age and gender matched controls. In the control group, there 13.3% were smokers while in the ACC group, 60% were smokers. The difference is significant (p = .0005) (OR) = 9.75 (95% CI; (2.54, 37.38). We next reviewed the larger TriNetX database and found that the prevalence of smoking in the ACC group to be 35.2% as compared to 9.0% in the TriNetX group(p-value < .0001). Conclusions: Our retrospective review strongly supports smoking as a major risk factor ACC. To our knowledge, this is the first study to demonstrate a strong association of smoking in a cohort of biopsy proven ACCs.
Whole genome and transcriptome analysis (WGTA) of metastatic adrenocortical carcinoma (mACC).
Authors: Lavoie Jean-Michel , Csizmok Veronika , Wang Gang , Williamson Laura , Marra Marco A. , Laskin Janessa J. , Jones Steven J. M. , Renouf Daniel John , Kollmannsberger Christian K.
Published: May 2019

e16123

Background: mACC is a rare disease, and no standard treatments exist beyond cytotoxic chemotherapy and mitotane. Recurrent molecular changes have been described, but their clinical significance is still poorly understood, and whether they can guide treatment is unknown. Methods: The genomic and transcriptomic profiles of 6 pts with mACC were analyzed as part of a prospective molecular profiling clinical trial (NCT02155621). Findings were correlated with histopathological and clinical data. Results: Whole genome sequencing of six ACC tumors and matched normal tissues was performed; whole-transcriptome sequencing was performed on five of the six tumors. All cases met Weiss criteria for ACC (including 1 pt with oncocytic ACC). Profiling revealed gain of function variations in CTNBB1 gene in 3 cases (p.S45A, p.S45P and homozygous deletion of exons 2 and 3). A stop-gained mutation (Q167*) and a homozygous copy loss of TP53 gene was observed in 2 cases; mutations of CTNBB1 and TP53 co-occurred in one case. Variations in other DNA repair genes included germline FANCA Q1362* and somatic BRCA2 E790* stop-gained mutations, and a structural variation in RAD52. Copy number amplification was observed for KDM5A (2/6) and RAD52 (2/6), while NF1 (1/6), CDKN2A (1/6), CDKN2B (1/6) and RB1 (2/6) were subjected to homozygous copy losses. Average ploidy models: one diploid, 4 triploid and one tetraploid case; whole chromosome copy losses and gains were seen in all samples. Three cases showed high homologous repair deficiency scores; associated with respectively, an in-frame deletion of V613 in ATM, a TP53 homozygous loss, and a structural variant of RAD52. All six cases exhibit signature 3 or signature 8. At last follow-up, 2 pts remained alive. Treatments included cytotoxic chemotherapy, mitotane, streptozotocin, sunitinib, avelumab with a SMAC mimetic (NCT02022098), a TTK inhibitor (NCT02792465) on the basis of a CTNNB1 mutation and temozolomide with olaparib on the basis of ATM loss. Conclusions: Our findings recapitulate published data on the molecular profile of mACC and support previous findings of large scale chromosomal variation. We identify new potential drivers in chromatin remodelling, cell cycle, and DNA damage repair genes.
Relationship between body composition and hormone sensitivity for androgen deprivation therapy in metastatic prostate cancer patients.
Authors: Kashiwagi Eiji , Shiota Masaki , Imada Kenjiro , Monji Keisuke , Takeuchi Ario , Inokuchi Junichi , Tatsugami Katsunori , Eto Masatoshi
Published: May 2019

e16500

Background: Obesity has been reported to have an influence on prostate cancer incidence and its aggressive phenotype but this remains controversial. Body mass index (BMI) is useful marker of obesity but it does not represent body fat percentage precisely. The relationship between body composition and the efficacy of androgen deprivation therapy (ADT) has not well been studied. Here, we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. Methods: This study enrolled hormone-sensitive metastatic prostate cancer patients who were treated with primary ADT from April 2006 to August 2009 in Kyushu University Hospital, and who underwent a CT scan prior to primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm2), and BMI. Results: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival (PFS) and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio [HR]: 0.448; 95% CI = 0.206–0.922; P= 0.028). Conclusions: This study demonstrated that higher psoas muscle ratio predicts longer OS among non-localized prostate cancer patients treated with primary ADT. [Table: see text]
Radium 223 (Ra-223) experience in twenty-four castration resistant prostate cancer (CRPC) patients treated at West Virginia University (WVU) 2014-2018.
Authors: Ahmad Zeeshan , Arays Ruta , Veselicky Kenneth , Kolodney Joanna Amy , Hogan Thomas F.
Published: May 2019

e16502

Background: Ra-223 was FDA approved for CRPC with symptomatic bone metastases without visceral metastatic disease. Methods: De-identified IRB exempted records were abstracted for demographic, clinical, and laboratory data from CRPC men treated with Ra-223 at WVU 2014-2018. Results: 24 men had in total 95 Ra-223 infusions; 20 men (83%) were referred from outside institutions. Average ages (yrs; ranges) were 63 (48-87) at initial PC diagnosis; 68 (49-89) at first WVU-visit; and 69 (54-89) at first Ra-223 infusion. At diagnosis, 4 men (17%) had prostatectomy; 12 (50%) were M1/stage 4; PSAs ranged from 7-9,600 ng/mL. In 24 men, there were 73 courses of different androgen deprivation therapies (ADT); all had one, 22 (92%) two, 17 (71%) three, & 10 (42%) four or more; 68 (93%) of the 73 ADT trials preceded Ra-223. In 24 men, 19 (79%) had docetaxel or cabazitaxel chemoRx; 10 of 19 (53%) had 2nd line and 2 of 19 (11%) had 3rd - 4th line; chemoRx preceded Ra-223 in 18 of the 19 men (95%). In 24 men, 19 (79%) received 33 courses of radiation; in 9 of 33 (27%) the prostate was targeted; another 24 (73%) were palliative; 18 of 19 men (95%) had radiation before Ra-223. In 24 men, 24 had a 1st Ra-223 infusion, 21 (88%) a 2nd, 16 (67%) a 3rd, 12 (50%) a 4th, 12 (50%) a 5th, and 10 (42%) a 6th infusion; 14 men (58%) did not complete 6 infusions, most stopping for clinical decline or death. In 24 men, median overall survival (OS) from first Ra-223 infusion to last visit or death was 4.9 months (0-33); OS from last Ra-223 infusion was 1.2 months (0-28); 13 men (54%) remain alive & 3 (13%) continue Ra-223. Conclusions: Our CRPC patients’ best OS of 4.9 months with Ra-223 does not match the 14.9 months first reported (NEJM 2013; 369:213-223). Fourteen of our 24 men (58%) did not complete 6 planned Ra-223 infusions because of clinical decline or death. This may represent a “real world referral bias” of heavily pre-treated patients as documented above. Selecting more appropriate patients for Ra-223 is currently under review (https://www.esmo.org/Oncology-News/EMA-PRAC-Recommends-Restricting-Use-of-Prostate-Cancer-Medicine-Radium-223-Dichloride)
A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa): Tolerability and geriatric asssessment (GA) results.
Authors: Zittel Jason , Fung Chunkit , Babu Dilip Sankar , Guancial Elizabeth A. , Sahasrabudhe Deepak M. , Bylow Kathryn A. , Burfeind John D. , Musto Kaylinn , Wang Bokai , Patil Amita , Messing Edward M. , Mohile Supriya Gupta , Kilari Deepak
Published: May 2019

e16518

Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In this phase II study, we evaluated Enz and Dut/Fin in lieu of ADT for at-risk older patients with HNSPCa. Methods: Eligible patients were ≥65 years (y); at high risk of AEs from ADT by GA or treating physicians; metastatic (M1) or non-metastatic (M0) HNSPCa with a PSA doubling time ≤ 9 months and testosterone > 50ng/dl. They received Enz 160 mg/day and Dut 0.5 mg/day or Fin 5 mg/day until disease progression. GA was performed at baseline and week (wk) 61 and/or at the time of progression. GA included validated tests: Instrumental Activities of Daily Living (IADL), fall history, Short Physical Performance Battery (SPPB), Geriatric Depression Scale (GDS), and Montreal Cognitive Assessment (MOCA). The prevalence of impairment for each assessment was calculated; change in prevalence from baseline to wk 61 was analyzed using paired sample t-test. Results: 43 patients were enrolled in the study. Median age at enrollment was 78 y (range 66-94) and 93% were ECOG 0-1; 37% (n = 16) had M0 and 63% (n = 27) had M1 HNSPCa, with the majority (67%) having Gleason 6 or 7 disease. At baseline, 18.6% met the cutoff for impairment for IADLs, 53.7% for SPPB, 7.9% for GDS and 64.3% for MOCA; 9.8% had a recent fall. Median baseline PSA was 11.38 ng/ml (range: 2-145). At the time of analysis, 29 men (67.4%) remain on study treatment. 95.3%, 74.4% and 46.5% of patients reported at least one Grade 1, 2 or 3 AE respectively. No patient had a Grade 4 AE and one Grade 5 AE was reported but was an unrelated event. The most common Grade 3 AEs were hypertension (27.8%), GI (19.4%), and cardiac (8.3%); all Grade 3 GI AEs reported were deemed unrelated to the study drugs. Only impairment in ≥ 1 IADL showed a statistically significant increase in prevalence at wk 61 of treatment (40.6%) compared to baseline (18.6%, p = 0.036). Conclusions: For older men with HNSPCa, Enz with Dut/Fin demonstrated efficacy with reasonable toxicity profile, and no significant impact on the majority of GA domains. Clinical trial information: NCT02213107.
Does a food intervention makes abiraterone treatment affordable?
Authors: Van Erp Nielka P. , Benoist Guillemette Emma , Gerritsen Winald R. , Mehra Niven , Burger David , Hamberg Paul , van Oort Inge , Lubberman Floor
Published: May 2019

e16523

Background: Abiraterone is registered for metastatic prostate cancer. It is used in a fixed oral dose of 1000mg OD in a fasted state in combination with 10mg prednisone daily. Although large differences in the effect of food on abiraterone exposure are reported (ranging from 1-10 fold increase in area under the concentration time curve (AUC)) it is generally accepted that abiraterone is much better absorbed in the presence of food. By administering abiraterone with food a reduced dose can be given while maintaining equivalent abiraterone exposure. Moreover aadministering abiraterone with food is more patient friendly and it could significantly reduce the treatment costs of abiraterone.The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast compared to the standard intake of 1000mg OD in fasted state. Methods: In this phase I cross-over multi-center study abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic prostate cancer who were treated with 1000 mg abiraterone in a fasted state, followed by 500 mg taken with a continental breakfast. After both periods of 14 days, abiraterone plasma exposure was measured. Bioequivalence was assumed when the GMR (fed/fasted) of the AUC0-24h and Cmax and their 90% confidence interval (CI) were within the range of 0.8 and 1.7. Results: 14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. GMR (fed/fasted) AUC0-24h was 0.88 (90% CI 0.73-1.07), GMR Cmax was 1.03 (CI 0.79-1.34) and the GMR of Ctrough was 0.81 (90% CI 0.60-1.10). Conclusions: Ingesting 500mg abiraterone with a continental breakfast was not considered bio-equivalence when compared to 1000mg taken fasted. The criteria for bio-equivalence could not be met due to the large variability in pharmacokinetics of abiraterone within and between patients. Due to this large variability in abiraterone exposure, we believe that dose optimization by food intake is not a feasible strategy for abiraterone. The intake of abiraterone with food could not be advised based on the results presented in our study. Clinical trial information: NCT02883166. [Table: see text]
The National Radium-223 Dichloride Audit group: Data from patients in UK oncology centers with metastatic castration-resistant prostate cancer treated with radium-223 dichloride.
Authors: Randhawa Manreet , Jones Robert J , Stratton Irene ,   National Radium-223 Dichloride Audit Group
Published: May 2019

e16524

Background: Clinicians in 17 UK oncology centres comprise the National Radium-223 Dichloride Audit (NRDA) group which is evaluating treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride (Xofigo). Methods: Patients commencing treatment from 1st September 2017 were included. Clinical and laboratory parameters were collected throughout treatment. Analyses used frequency tables and univariate analysis. Results: As of February 2019, data from 400 patients has been collected. We report the outcomes on the first 150 patients who are evaluable. At first treatment, median age was 72 years (25th to 75th centile: 67-78), 54% of patients had an ECOG performance status (PS) of 1, 32.6% of patients had a WHO pain score of 1, 60% of patients had an ALP level of < 220U/L and 26% of patients received docetaxel for mCRPC. The mean number of cycles completed was 5. Sixty patients (40%) did not complete 6 cycles and 42/60 (70%) discontinued due to disease progression. Changes in variables between treatment 1 and 6 are shown in Table. Adverse events reported were fatigue (76%), diarrhoea (38%), nausea/vomiting (35%), constipation (32%), anaemia (28%), thrombocytopaenia (12%) and neutropaenia (5%). There was no overall change in ECOG PS. In those who completed quality of life (QOL) questionnaires at treatment 1 and 6 (58%), there was no difference. Conclusions: The ongoing NRDA Group records data from mCRPC patients treated across the UK in routine care. To our knowledge, it is the first prospective analysis of such patients and the largest in assessing treatment patterns and outcomes including QOL data as well as standard laboratory parameters. Disclosures: The NRDA Group has been funded by a research grant from Bayer.[Table: see text]
Impact of hormone-therapy used in CRPC patients: Evaluation of abiraterone acetate/prednisone or enzalutamide on activity and cognitive functions in aged castrated mice.
Authors: Castel Hélène , Al Sagheer Tareq , Dubois Martine , Campart Cynthia , Desrues Laurence , Lange Marie , Gandolfo Pierrick , Joly Florence
Published: May 2019

e16526

Background: Prostate cancer (PC) is a major public health problem and represents the most frequent cancer in elderly male patients. Although most patients initially respond to androgen deprivation therapy (ADT) through inhibition of gonadal testosterone biosynthesis, the majority of these patients will progress to metastatic castration-resistant PC (mCRPC). Novel oral agents targeting androgen signaling axis, abiraterone acetate (AA)+prednisone (P) and enzalutamide (ENZ) are available and used in mCRPC patients in addition to ADT, but their impact on cognition is not well understood. Recently, the AQUARiUS study (Thiery-Vuillemin et al., ESMO Open, 2018) showed that after treatment, median Quality of life score improved with AAP. Additionally, results from a phase 2 trial showed that a worsening of depression symptoms were more often detected in ENZ- than in AAP-treated patients (Khalaf et al., Eur Urol, 2018). Methods: Here we developed a preclinical animal model to clarify the potential impact of AAP or ENZ on emotional reactivity and cognitive functions including spontaneous activity, anxiety-like and depression-like behaviors or spatial memory and learning. Results: In aged castrated mice receiving per os vehicle or AAP or ENZ, we showed that, in contrast to AAP, exposure to ENZ reduced spontaneous activity and increased depressive-like behaviors. AAP-treated mice displayed diminished self-grooming suggesting lower arousal in a novel environment. None of the treatments provoked anxiety-like behavior, learning and memory deficits. However, the swimming strategies (Morris-water maze) in AAP and ENZ groups were slightly altered. Analysis of plasma from treated mice revealed a detectable level of corticosterone only in AAP group. Conclusions: These data establish the impact of ENZ on emotional reactivity and of both ENZ and AAP on subtle cognitive functions in castrated aged male subjects. It paves the road for future effective research that could lead to better management of quality of life in mCRPC.
Computer modelling in prostate anticancer therapy (COMPACT).
Authors: Prentice Mark , Man Kenneth , Jani Yogini , Payne Heather Ann , Wong Ian
Published: May 2019

e16528

Background: Prostate cancer is the most common solid malignancy in men and despite improving radical therapies a proportion of patients will develop castrate resistant metastatic disease (mCRPC). Therapeutic options in mCRPC include abiraterone acetate and prednisolone (AA+P), enzalutamide (E) and docetaxel (D) with limited evidence to guide clinical choice between agents. COMPACT aims to collate data from multiple data sets within one hospital to assess clinical or biochemical factors that may guide therapeutic strategy. Methods: Data was collated on all patients recorded as receiving therapy with AA+P, E or D in the metastatic castrate resistant setting from the chemotherapy prescribing and dispensing systems and the pathology system at University College Hospital, London. Individual clinical notes were reviewed to determine the reason for stopping therapies. Data was collated in one dataset and analysed to present baseline demographic data. The log-rank test was used to analyse differences in the retention rate among AA+P, E and D. Results: 598 individual treatments were identified in 441 patients. 172 patients received AA+P, 119 E and 307 D with a mean age at treatment initiation of 74.1, 76.8 and 69.5 years respectively. Of the 144 patients receiving two or more treatment lines, 62% (n = 89) received D prior to either AA+P or E. E was first line therapy in 18% (n = 26) and AA+P in 20% (n = 29). 5 (3.5%) patients transferred directly from AA+P to E and 12 (8%) from E to AA+P. Kaplan Meir estimates for time to retention show no statistically significant differences when directly comparing AA+P, E and D on univariate analysis with chi squared test (AA+P vs E = 0.3609, p = 0.558 D vs E = 0.365, p = 0.5457, D vs AA+P = 0.0136 p = 0.9072). Conclusions: The COMPACT study has confirmed that it is feasible for single institutions to retrospectively review real world data from different sources, combining it into a workable database. Patient numbers were sufficient to statistically analyse the data for specific clinical factors that may correlate to a prolonged biochemical response to AA+P, E or D therapy. The failure to detect a statistically significant difference between therapies on univariate analysis may confirm that all three are acceptable treatments in mCRPC.
Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.
Authors: Butler Lisa , Irani Swati , Centenera Margaret , Ryan Natalie , Pegg Neil , Brooks Anthony Nigel
Published: May 2019

e16534

Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.
Family history in primary hormone therapy for prostate cancer from a community-based multi-institutional Japan-wide database.
Authors: Shiota Masaki , Onozawa Mizuki , Hinotsu Shiro , Eto Masatoshi , Naito Seiji , Akaza Hideyuki
Published: May 2019

e16549

Background: Although a positive family history is known to increase the risk of morbidity of prostate cancer, little is known about the prognoses with hormone therapy of individuals with familial prostate cancer. Thus, in this study we aimed to determine the associations between hormone therapy and outcomes of a cohort of men with familial prostate cancer from a large community-based multi-institutional Japan-wide registry. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 15,873 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival, and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 247 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a significant favorable prognostic factor for progression-free survival among patients treated by castration, as was overall survival among patients with PSA level at diagnosis less than 100 ng/mL and those with low or intermediate J-CAPRA risk. Conclusions: Our findings indicate that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, with hormone therapy the prognoses of individuals with familial prostate cancer are comparable to those of individuals with sporadic prostate cancer.
Correlation between innate cytokine levels and progression in men with biochemically recurrent prostate cancer treated with intermittent hormonal therapy.
Authors: Hawley Jessica , Pan Samuel , Figg William Douglas , Lopez Bujanda Zoila , Strope Jonathan , Fojo Antonio Tito , Dallos Matthew , Aggen David Henry , Lim Emerson A. , Stein Mark N. , Hu Jianhua , Drake Charles G.
Published: May 2019

e16554

Background: Suppressive cytokines have the potential to drive prostate cancer progression with consequent decreased survival. Assessing longitudinal cytokine changes may shed light on mechanisms of disease progression, resistance to therapy, and suggest new therapeutic targets. Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time of PSA progression (TTPP) were identified from a previously conducted phase III trial (NCT00020085). Serum samples were archived at baseline, three months after administration of ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay (MesoScale Discovery). Wilcoxon signed rank sum test was used to compare paired observations between time points. Kaplan-Meier analysis was used to calculate progression function (TTPP) dichotomized by above or below the median value of cytokines with Bonferroni adjustment. Pearson’s rank correlation coefficient was used to compare continuous variables. Results: Median TTPP was 399 days (range, 114 - 1641). Median PSA at baseline and progression were 8.5 ng/ml, (range, 1.0 - 76.6) and 5.3 ng/mL (range, 1.2 - 19.4), respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. TNF-α (P = 0.002), IL-23 (P = 0.002), and IP-10 (P = 0.001) significantly increased from baseline to post ADT. Patients with a detectable PSA after ADT had moderately elevated levels of IL-6 (P = 0.049) and IL-8 (P = 0.013) at PSA progression as compared to those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = 0.042). TNF-α was strongly correlated with IL-23 (r = 0.72, P < 0.001) and IL-8 (r = 0.59, P < 0.001) from baseline to after ADT and to PSA progression. NLR correlated strongly with IL-27 (r = 0.57, P < 0.001) and MIP-3α (r = 0.56, P < 0.001). Conclusions: Cytokines associated with the innate immune response were associated with an unfavorable clinical outcome in early prostate cancer. These data suggest cytokine blockade combined with ADT may warrant future investigation.
Deep learning algorithm improves identification of men with low-risk prostate cancer using PSMA-targeted 99mTc-MIP-1404 SPECT/CT.
Authors: Meyer Alexa , Stambler Nancy , Sjöstrand Karl , Richter Jens , Allaf Mohamad , Rowe Steven P. , Wong Vivien , Anand Aseem , Gorin Michael A.
Published: May 2019

e16572

Background: Previous work has shown that the degree of expression of prostate-specific membrane antigen (PSMA) correlates with prostate cancer (PCa) grade and stage. We evaluated the additive value of a deep learning algorithm (PSMA-AI) of a PSMA-targeted small molecule SPECT/CT imaging agent (99mTc-MIP-1404) to identify men with low risk PCa who are potential active surveillance candidates. Methods: A secondary analysis of a phase III trial (NCT02615067) of men with PCa who underwent 99mTc-MIP-1404 SPECT/CT was conducted. Patients with a biopsy Gleason score (GS) of ≤6, clinical stage ≤T2, and prostate specific antigen (PSA) < 10 ng/mL who underwent radical prostatectomy (RP) following SPECT/CT were included in the present analysis. SPECT/CT images were retrospectively analyzed by PSMA-AI, which was developed and locked prior to analysis. PSMA-AI calculated the uptake of 99mTc-MIP-1404 against the background reference (TBR). The automated TBR of 14 was used as a threshold for PSMA-AI calls of positive disease. Multivariable logistic regression analysis was used to develop a base model for identifying men with occult GS ≥7 PCa in the RP specimen. This model included PSA density, % positive biopsy cores, and clinical stage. The diagnostic performance of this model was then compared to a second model that incorporated PSMA-AI calls. Results: In total, 87 patients enrolled in the original trial contributed to the analysis. The base model indicated that PSA density and % positive cores were significantly associated with occult GS ≥7 PCa (p < 0.05), but clinical stage was not (p = 0.23). The predictive ability of the model resulted in an area under the curve (AUC) of 0.73. Upon adding PSMA-AI calls, the AUC increased to 0.77. PSMA-AI calls (p = 0.045), pre-surgery PSA density (0.019) and % positive core (p < 0.004) remained statistically significant. PSMA-AI calls increased the positive predictive value from 70% to 77% and the negative predictive value from 57% to 74%. Conclusions: The addition of PSMA-AI calls demonstrated a significant improvement over known predictors for identifying men with occult GS ≥7 PCa, who are inappropriate candidates for active surveillance. Clinical trial information: NCT02615067.
PMEPA1 gene isoforms to indicate disease progression in solid tumors.
Authors: Sharad Shashwat , Sztupinszki ZsÃ£Â³fia , Szallasi Zoltan , Rosner Inger L. , Srivastava Shiv , Dobi Albert , Cullen Jennifer , Li Hua
Published: May 2019

e16580

Background: Dysfuncitons of androgen and TGF-β signaling play important roles in prostate tumorigenesis. PMEPA1 gene has been defined as an androgen and TGF-β responsive gene which inhibits androgen and TGF-β signaling via negative feed-back loops. Our previous data has established that PMEPA1 distinct isoforms ( PMEPA1-a and PMEPA1-b) with disparities within N-terminus protein sequences navigate different androgen/TGF-β signaling regulations. In this study, the roles of PMEPA1 isoforms in disease progressions were investigated in solid tumors of prostate (CaP), breast, lung and colon. Methods: RNA seq data from total 2479 solid tumor samples in the TCGA dataset were used to study the correlation between expressions of PMEPA1 isoforms and disease progression including Gleason score, pathology stages, progression free survival rate (PFS) and overall survival rate (OS). The cohort is composed of 482 prostate, 1049 breast, 499 lung and 449 colon cancer patients. Results: In CaP, the TCGA data analysis showed that lower transcript level of PMEPA1-b isoform associated with higher Gleason scores and lower progression free survival rate (PFS) (P = 0.014) and worse overall survival rate (OS) (P < 0.01). The ratio of mRNA levels of PMEPA1-a versus PMEPA-b indicated higher Gleason score, lower PFS rate (P = 0.0063) and worse OS rate (P = 0.0042). In contrast, higher expression of both PMEPA1-a and PMEPA- b associated with lower PFS (P = 0.023 and 0.028, respectively) in breast cancer. And the enhanced ratio of PMEPA1-a/ b was also found to indicate lower PFS (P = 0.016) and worse OS (P = 0.016) in breast cancer. Similarly, the increased transcript levels of PMEPA1-a and PMEPA1-b isoforms significantly associated with lower PFS and worse OS rates in lung and colon cancer. The expression of PMEPA1 isoforms was not found to associate with pathology stages of diseases. Conclusions: Our data establish the biomarker potential of PMEPA1 gene isoforms ( a and b) indicating more aggressive disease progressions in 4 solid tumors, further underscoring the PMEPA1 isoform specific biological functions to differentiate regulation of androgen and TGF-β signaling in cancer cells.
Next-generation sequencing of primary prostate cancer tumors to reveal actionable opportunities for clinical management.
Authors: Crona Daniel James , Drier Anthony , Zhu Jing Daisy , Bell Emily Fox , Sketch Margaret Rose , Boland Alexandra , Garrett Amy , Wang Lin , Mitchell Khalis , Tomlins Scott A. , Dees Elizabeth Claire , Godley Paul Alphonso , Dunn Mary , Rose Tracy L , Basch Ethan M. , Milowsky Matthew I. , Whang Young E.
Published: May 2019

e16582

Background: The Strata Trial (NCT03061305) is a multi-institutional precision oncology collaboration structured as an observational protocol that aims to match patients to genomically guided therapies. Methods: Selected University of North Carolina (UNC) metastatic prostate cancer (mPC) patients were enrolled on this IRB-approved study. Formalin fixed paraffin-embedded primary tumor specimens, without matched germline controls, were sent for targeted next generation sequencing (NGS) to detect actionable variants, including: mutations in 87 genes, copy number variations in 31 genes, gene fusions in 46 gene drivers, and microsatellite instability (MSI) status. mPC-related genes of specific interest included: AR, ATM, BRCA1/2, ERG, MSH2, MSH6, PTEN, RB1, and TP53. Results: Of the 108 cases sequenced, 6 (6%) failed testing. Of the 102 mPC patients with sequence data, the median age was 69 (47-86), 60 (59%) were white, 35 (34%) were black, 1 (1%) was Asian, and 6 (6%) declined to identify race. NGS data revealed 122 variants in 27 genes: 73 patients (71%) had at least one variant. Among those 73 patients, 38 (52%) had only 1 variant, 24 (33%) had 2 variants, 8 (11%) had 3 variants, and 3 (4%) had 4 variants. TMPRSS2-ERG fusions occurred most frequently (51%), followed by TP53 variants (38%), and PTEN variants (16%). Only 8% of patients had variants in DNA damage repair genes, including ATM (3%), BRCA2 (3%) and MSH2 (2%). Two patients with MSI high tumors were treated with pembrolizumab, while 4 patients with deep BRCA2 or ATM deletions were eligible for trials of PARP inhibition. Conclusions: Our UNC experience shows that a high proportion of primary prostate cancer tumors from mPC patients have genomic variants, and two patients were treated based on these data. Limited actionability may reflect the landscape of currently FDA approved mPC treatments available clinical trials, or due to short duration of follow-up after enrollment on the Strata Trial.
27-year patterns in high-risk prostate cancer treatment in a racially diverse, equal-access health care setting.
Authors: Rocco Nicholas R , Santomauro Michael G , Robertson Audry H , Kuo Huai-Ching , Brand Timothy C. , Chen Yongmei , Musser John E , Porter Christopher R. , Rosner Inger L. , Gable Preston , Cullen Jennifer , Stroup Sean P
Published: May 2019

e16583

Background: Despite the significant stage migration of prostate cancer (CaP), a large proportion of patients harbor high-risk disease. Few CaP series provide long term outcomes with the ability to assess disparities in diverse populations. We examined 27-year outcomes among men treated for high risk CaP in a large, racially diverse, equal access system. Methods: A retrospective cohort study was conducted of patients enrolled into the Center for Prostate Disease Research (CPDR) Multi-Center National Database from 1990-2017. There were 2,241 CaP patients who were NCCN-defined high risk, had a self-reported race of Caucasian (CA) or African American (AA), and had a primary treatment of hormonal therapy (HT), radical prostatectomy (RP), radiation therapy (RT) or no treatment (NoTX). Demographic and clinico-pathological variables were evaluated and stratified by race and treatment. Primary study outcomes included temporal patterns in race-specific treatment intensity and type(s). Secondary outcomes included biochemical recurrence (BCR)-free survival (BRFS) and distant metastasis-free survival (DMFS). Unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis were used. Results: Mean patient age at CaP diagnosis and follow-up time were 68.1 years and 7.8 years, respectively. AAs made up 26.9% of the study cohort. Median prostate specific antigen level was 20.9 ng/mL (IQR: 7.8 - 35.0). 52% of patients had a biopsy Gleason score of 8 or greater. 714 (31.9%) underwent RP, 966 (43.1%) underwent RT, 288 (12.9%) received primary HT, and 273 (12.2%) had NoTX. A decreasing trend of HT, with stable rates of RP and RT, was observed. Median time to BCR after RP and RT was 1.3 and 3.1 years, respectively. After RP and RT, 51.2% and 39.3% experienced BCR while 10.9% and 12.7% experienced distant metastasis, respectively. There were no significant racial differences in treatment intensity, treatment type, BRFS or DMFS. Conclusions: In this longitudinal series, there was racial comparability for all study outcomes. Moreover, in this high-risk patient series with long-term follow up (median = 6.9 years), nearly 50% did not experience BCR, and only 1 in 10 men developed metastasis.