bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-27a-3p: An AR-modulatory microRNA with a distinct role in prostate cancer progression and therapy.
Authors: Kalofonou Foteini , Sita-Lumsden Ailsa , Leach Damien , Fletcher Claire , Waxman Jonathan , Bevan Charlotte L.
Published: February 2020

193

Background: Prostate cancer (PCa) is an androgen dependent malignancy. PCa patients initially respond to androgen ablation but eventually the disease becomes castrate resistant. MicroRNAs (miRs) are considered to be master regulators of gene expression and could be potential biomarkers and therapeutic targets for PCa. We previously showed miR-27a-3p to be an androgen receptor (AR)-modulatory oncomiR, with a role in PCa progression. Methods: RNA sequencing was carried out on xenograft tumours treated with an inhibitory antisense oligonucleotide for miR-27a (ASO-27a), or control. Differentially expressed genes were cross-referenced with publicly available patient tissue datasets. ASO-27a was transfected in a panel of PCa cell lines mirroring disease progression, to verify changes in transcriptional and translational levels. Immunohistochemical analysis of encoded proteins was undertaken in a cohort of 46 PCa patients with Gleason 3+4 or 4+3 disease and compared with normal tissue-control. Results: Putative target genes tested included the tumour suppressor HIP2, the oncogenes SRC3, YAP, and PAX3, which can act both as oncogene and tumour suppressor. MRNA or protein levels of the majority of those genes tested were upregulated after ASO-27a treatment of PCa cell lines. In 22Rv1 cells, HIPK2 mRNA levels were significantly upregulated with ASO-27a (p = 0.0137), while protein levels were downregulated . PAX3 mRNA levels were significantly reduced by ASO-27a in 22Rv1 cells (p = 0.0364), while protein levels were significantly increased (p = 0.0112). Immunohistochemically, PAX3 protein was lower in Gleason 7 tumours than in normal tissue, while YAP expression was higher in patients with Gleason 4+3, relative to those with 3+4. SRC3 immunostaining was slightly, but not significantly, higher in patients with 3+4 compared to 4+3. Conclusions: MiR-27a-3p is an AR-modulatory oncomiR in PCa, with potential as a therapeutic target. MiR-27a interaction with its target genes and especially HIPK2, YAP, SRC3 and PAX3 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant disease, through ASO-27a inhibition.
Next-generation sequencing (NGS) of tumor tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC): The PROfound phase III study experience.
Authors: Hussain Maha H. A. , Mateo Joaquin , Sandhu Shahneen Kaur , Fizazi Karim , Saad Fred , Shore Neal D. , Olmos David , Corcoran Claire , Sibilla Caroline , Kohlmann Alexander , Adelman Carrie A. , Elvin Julia Andrea , Goessl Carsten Dietrich , Burgents Joseph , De Bono Johann S.
Published: February 2020

195

Background: The PROfound study (NCT02987543) showed that olaparib provides a statistically significant improvement in radiographic progression-free survival versus physician’s choice of enzalutamide or abiraterone in mCRPC patients (pts) with alterations in genes with a direct or indirect role in the homologous recombination repair (HRR) pathway. This is the largest study to date with central, prospective tumor tissue testing in pts with mCRPC. Here, we report learnings during testing in the PROfound study. Methods: An investigational clinical trial assay, based on the FoundationOne CDx NGS test developed in partnership with Foundation Medicine, Inc (FMI), was used to prospectively identify pts with qualifying alterations in ≥1 of 15 prespecified genes, including BRCA1, BRCA2 or ATM. Tumor testing was conducted centrally using archival or recent biopsy from primary or metastatic tissue. Results: Of 4047 pts who submitted tumor samples, 2792 (69%) were successfully sequenced and yielded a biomarker status. Categories for test failure (n=1255; 31%) were pathology review failure in 277 (6.8%) pts (eg estimated tumor fraction <20% or tumor volume <0.2 mm2), DNA extraction failure in 533 (13.2%) pts, and failure after DNA extraction in 280 (6.9%) pts, with 165 (4.1%) pts in >1 category. Regarding the sample disposition, approximately two-thirds of samples were from core needle biopsies, although higher success rates were observed with larger samples (ie prostatectomy). Samples were mainly from the prostate gland, with <5% from bone. Most samples were from archived tissue of primary tumors; only ~10% were from newly collected tissue. Test turnaround time, as well as representation of sample characteristics and country of origin relative to success rate, will be presented. Conclusions: The PROfound study has demonstrated that tissue testing to identify HRR alterations in men with mCRPC is feasible. Careful selection of high-quality tumor tissue samples is key to ensure success both at pathology review and during downstream steps of the NGS tissue testing process. Clinical trial information: NCT02987543.
Prognostic factors that affect survival outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223.
Authors: Al-Ezzi Esmail Mutahar , Alqaisi Husam , Picardo Sarah , Iafolla Marco , Sridhar Srikala S. , Sacher Adrian G. , Fallah-Rad Nazanin , Catton Charles , Warde Padraig , Hamilton Robert James , Fleshner Neil Eric , Zlotta Alexandre , Hansen Aaron Richard
Published: February 2020

225

Background: Radium-223 (Ra-223) improved overall survival (OS) in men with mCRPC with predominantly bone metastases. We analyzed their survival outcomes to identify factors associated with prognosis for men treated with Ra-223. Methods: This was a retrospective study of men with mCRPC at Princess Margaret Cancer Centre treated with Ra-223. Demographics, disease characteristics, number of bone metastasis [ < 6, 6-20, > 20], laboratory results, number of Ra-223 doses, systemic treatment lines after radium-223, use of bone protecting agents (BPA) and survival outcomes were collected. OS and progression-free survival (PFS) were estimated by Kaplan-Meier (log-rank) analysis. Uni- (UVA) and multi-variate (MVA) analysis (Cox-regression) were used to evaluate patient and disease characteristics, number of Ra-223 doses and overall survival. Results: 114 men received Ra-223 between May 2015 and May 2018 with median age 75 years (range 53-93). Median radium doses was 5 (68 [59.6%] received > 4 doses, 46 [40.4%] received ≤4 doses). Median baseline ALP 113.5 U/L (31-1121), median baseline Hb 118 g/L (69-153), median baseline PSA 70.2 ug/L (0.15-5275), median LDH 242 UL (82-1426). 58% had 6-20 bone metastases and 28% had > 20 bone metastases. The median OS and PFS for men who received ≤4 doses vs > 4 doses was 4.56 vs 19.8 months (HR = 8.4; 95%CI: 4.861-14.62; p≤ 0.0001) and 2.9 vs 7.45 months (HR = 4.6; 95%CI: 2.837 to 7.537; p≤ 0.0001) respectively. The baseline median ALP was (154 vs 98; p = 0.03) for men who received ≤4 doses vs > 4 doses Ra-223. On UVA, ECOG 0-1 (HR = 0.33; p = 0.0003), baseline PSA < 70 ug/L (HR = 0.51; p = 0.0023), LDH < 250 U/L (HR 0.55; p = 0.0082), Hb > 120 g/L(HR 0.46; p = 0.0004), ALP < 150 U/l(HR 0.38; p ≤ 0.0001) and receipt of subsequent treatment after Ra-223 (HR = 0.33; p < 0.0001) were associated with improved OS. On MVA, receipt of subsequent treatment, administration > 4 cycles of Ra-223 and baseline ALP < 150 U/L were associated with improved OS. Conclusions: Men who receive > 4 cycles of Ra-223 have significantly better OS than those who receive ≤4 doses. Baseline ALP was independently associated with better OS and could be used to identify patients most likely to benefit from Ra-223.
Review of the real-world prevalence of mHSPC, nmCRPC, mCRPC, and gene alterations associated with HRR in prostate cancer (PC).
Authors: Shore Neal D. , Oliver Louisa , Shui Irene , Gayle Alicia , Wong On Yee , Kim Jeri , Payne Sarah , Ghate Sameer R.
Published: February 2020

229

Background: The clinical journey of PC is evolving rapidly. New hormonal agents (NHA) have demonstrated clinical efficacy in metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castrate-resistant prostate cancer (nmCRPC) and metastatic castrate-resistant prostate cancer (mCRPC). A shift in the treatment landscape considering precision medicine, recently supported by the phase III PROFOUND study, suggests updates to the currently limited clinical guideline recommendations for genomic testing. Better understanding of the patient pathway and respective proportion of patients to support patient care is needed. The objective of this SLR was to summarize published literature on the prevalence of mHSPC, nmCRPC, mCRPC and HRR gene alterations. Methods: An SLR was conducted across nine databases in OVID to capture English language studies published 01/2009–05/2019 on global epidemiology and clinical practice trends for mHSPC, nmCRPC, mCRPC and HRRm. 4,732 papers were identified which were systematically screened for inclusion. Grey literature searches included 10 conference proceedings from 2014–2019. Results: In total, 244 observational publications met the inclusion criteria - 4 studies reported the prevalence of mCRPC, 3 on nmCRPC and 0 on mHSPC. From these, the estimated prevalence of mCRPC and nmCRPC is 1.6–2.1 and 1.1–2.1 per 100 PC cases, respectively. HRRm were investigated in 13 publications with next generation sequencing of tissue and blood samples being reported as the most frequent method. Of the HRR gene alterations examined, BRCA2 were found to have the highest prevalence with a range of 4.5–9.3 and 1.1–15.1 per 100 overall PC cases for germline and somatic gene alterations, respectively. Other prevalent HRR gene alterations included germline ATM, BRCA1 and CHEK2. Conclusions: Limited data are available evaluating the prevalence of mHSPC, nmCRPC and mCRPC required to quantify the burden of these populations suggesting a lag in the published literature following updates to US treatment guidelines. Our review also shows that HRR gene alterations, specifically BRCA2, are prevalent in PC consistent with recently published data on PROFOUND population.
Late dosing of luteinizing hormone-releasing hormone agonists (LHRH) and testosterone (T) levels >20 ng/dL in prostate cancer (PCa).
Authors: Twardowski Przemyslaw , Atkinson Stuart , Boldt-Houle Deborah , Sartor A. Oliver
Published: February 2020

31

Background: LHRH agonists are the most frequently used drugs for the delivery of androgen deprivation therapy (ADT) for PCa. Evidence suggests achieving and sustaining T levels ≤20 ng/dL with ADT is desirable and correlates with improved disease-specific survival in advanced PCa patients. However, T levels may rise above castration level (50 ng/dL) between injections, especially if a subsequent dose is delayed. Increase in prostate-specific antigen (PSA) level on ADT may represent true disease progression to castration resistant PCa, or may be a result of late ADT dosing and inadequate T suppression. Current study evaluated timeliness of LHRH agonist dosing, subsequent rate of T breakthroughs and frequency of T/PSA testing prior to dosing in PCa patients. Methods: A retrospective review of electronic medical records and associated claims data (1/1/07-6/30/16) of LHRH agonist injections (n=85,030) evaluated the frequency of late dosing (defined as occurring after day 32, 97, 128, 194 for 1-, 3-, 4-, 6-month formulations, respectively), T tests >20 ng/dL and frequency of T/PSA tests prior to dosing. Results: 26.9% of injections were late: 14.4% were ≤1 week late, 3.1% were between 1-2 weeks late and 9.4% were >2 weeks late. 43% of T values exceeded 20 ng/dL for late injections; while only 21% exceeded this level for early/on-time injections. 83% of LHRH injections had a PSA value drawn prior to dosing; however, only 13% had a similarly timed T assessment. Conclusions: Overall, >25% of injections were late. For late injections, the proportion of T tests with T >20 ng/dL was higher compared to when the dosing was early/on-time. Late injections correlated with ineffective T suppression (>20 ng/dL) over 40% of the time. For all injections, T levels were not monitored as frequently as PSA levels. Considering the potential clinical benefits of maintaining effective T suppression throughout the course of ADT, clinicians should ensure treatments are delivered within approved dosing instructions, routinely monitor T levels and consider prescribing treatments with proven efficacy through the dosing interval to maintain T ≤20 ng/dL.
Transperineal prostate biopsies without antibiotic prophylaxis: Safety evaluation of the first 65 patients.
Authors: Kohl Tobias , Schuster Kai-Peter , Lang Konrad , Blanckenberg Alexandra , Kuru Timur H. , Zumbé Jürgen , Porres Daniel
Published: February 2020

355

Background: There is an ongoing trend towards perineal prostate biopsies for the detection of prostate cancer. For many reasons the issue of antibiotic prophylaxis in prostate biopsies is becoming more important, especially with quinolone antibiotics being excluded from this indication and an increasing antibiotic resistance. Considering that the perineal biopsy is a sterile procedure, not giving antibiotics for prophylaxis seems to be an alluring approach. Methods: At the General Hospital Leverkusen, transperineal (TP) MRI TRUS fusion biopsies are performed using the Ginsburg Protocol with a template and software-guided approach in general anesthesia. Patients received single dose antibiotics (Ciprofloxacine 500 mg) two hours prior to surgery from Jan 2019 to Aug 2019 (group 1). Starting in Sep 2019, no antibiotics were used for prophylaxis (group 2). Surgical disinfection using Povidone-iodine was performed ahead of every procedure. In this study, postoperative infection rates were assessed. Patients were followed up by telephone interview at least two weeks after biopsy and were asked about the need for postoperative antibiotics to treat regular UTI, fever, prostatitis or for readmission to other hospitals. Results: A total of 180 TP biopsies were performed with a median of 22 cores (min 18, max 28). Out of 115 cases with antibiotic prophylaxis, no patient was readmitted to the hospital due to infection or fever. Group 2 included 65 patients. No one was readmitted with fever or prostatitis. At the time of abstract admission 45 out of 65 patients in this group were followed up by telephone interview. None needed antibiotics and none was readmitted to a hospital elsewhere. Conclusions: The study shows an infection rate of 0 % for perineal prostate biopsies with or without antibiotic prophylaxis. The results argue in favor of perineal prostate biopsies and challenge the dogma of prostate biopsies needing an antibiotic prophylaxis irrespective of the approach. However, a larger prospective multicenter study should be initiated to ensure patient safety.
WATChmAN: A randomized trial of virtual surveillance versus standard in-person care for clinical stage I testicular cancer.
Authors: Hamilton Robert James , Landoni Lauren , Kuhathaas Kopika , Chung Peter W. M. , Bedard Philippe L. , Warde Padraig Richard , Hansen Aaron Richard , Truong Tran , Hahn Ezra , Jewett Michael A.S.
Published: February 2020

396

Background: Most guidelines recommend active surveillance (AS) as initial management for stage I testis cancer (TC). AS entails blood work and imaging at regular intervals requiring multiple clinic visits spanning 5 years. This can be time-consuming, difficult to adhere to, dissatisfying and costly for patients and health care systems. We innovated a secure online platform, WATChmAN (Web-based virtuAl Testicular CANcer clinic) allowing asynchronous communication between patients, results, and physician team. Methods: We are conducting an RCT (NCT03360994) where patients with stage I TC on AS are randomized to virtual care (WATChmAN), or standard in-person care. Primary endpoint is safety: examining loss-to-follow-up and compliance with AS schedules, incidence of relapse, delays in detection of relapse, and burden of relapse. Non-compliance represents a) patient-derived delay in visit; or b) follow-up visit with incomplete testing. Secondary endpoints include: patient/physician satisfaction and cost savings. Results: At present, 102 of a planned 144 patients are enrolled: 51 to virtual care, and 51 to standard in-person care. More patients in the virtual arm have been compliant with AS schedules (89% vs 73%) with shorter median compliance delays (12 vs. 14 days). To date, 10 patients have relapsed: 6 virtual (11.8%) and 4 standard (7.8%). Median time to relapse was shorter for the virtual arm (8 vs. 9.5 months), with no difference in burden of disease at relapse. Response rates to 6-month surveys were 90% and 59% for virtual and standard arms respectively. When asked if satisfied with their care, on the virtual arm 67% reported “extremely satisfied”, and 33% “satisfied” compared to 50% and 45% for the standard arm. When WATChmAN patients were asked if the application is able to provide the same excellence of care as in-person appointments, 82% reported “strongly agree” or “agree”. Conclusions: Interim results suggest virtual care in stage I TC is feasible and safe with improvements in patient satisfaction. Through semi-structured interviews and cost-effectiveness analyses, we anticipate more insight into virtual care. This may serve as a potential model for virtual care for other cancers. Clinical trial information: NCT03360994.
Prevalence and clinical impact of BRCA1/2 mutations in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Martinez Chanza Nieves , Tkint De Roodenbeke Marie , Desmyter Laurence , Wilkin Francoise , Badoer Cindy , Vandernoot Isabelle , Smits Guillaume , Accarain Anna Ayako , Sideris Spyridon , Gil Thierry , Awada Ahmad , Roumeguere Thierry Andre , Hamid Anis
Published: February 2020

44

Background: Somatic BRCA gene mutations ( sBRCAm) have been identified in a significant proportion of patients (pts) with castration resistant PC (CRPC), with mixed data regarding effect on CRPC therapies. However, the prevalence and clinical significance in mHSPC are not well characterized. Methods: Sequencing of primary tumor for sBRCA1/2 was performed in unselected pts with de novo mHSPC. We assessed the association of sBRCAm on time to CRPC (TTCRPC) and overall survival (OS) from diagnosis using Kaplan-Meier method, as well as PSA response (50% fall from baseline). Associations were evaluated using a Cox regression model with multivariable analyses adjusting for docetaxel use. Results: We identified 69 pts with de novo mHSPC, of whom 7 (10%) harbored a pathogenic sBRCA2m. Median age at diagnosis was 66 years. The majority were classified as high volume disease (n=54; 84%) with Gleason 9-10 grade (n=40; 61%). Therapies in the HSPC setting included ADT alone (n=29, 42%), ADT + Docetaxel (n=35, 51%), and ADT + Docetaxel + Abiraterone (n=5, 7%). Only 1 s BRCA2m case compared to 39 wild-type pts were treated with docetaxel. PSA response was achieved in 65 (96%) and PSA £ 0.2 ng/ml at 7 mos in 20 (31%) pts, without significant association with BRCA status ( p=0.13 and p=0.66, respectively). At a median FU of 29 mos, CRPC occurred in 44 (64%) pts with a median TTCRPC of 24 mos. TTCRP was numerically shorter for non-mutated pts compared to sBRCAm (22 vs. 40 mos, HR 0.5, p=0.23); there was no significant association with docetaxel use. In multivariate analyses, there was no significant association between sBRCAm and TTCRPC (HR 0.43, p=0.175). Median OS was 74 mos without any difference according to BRCA status ( p=0.30) nor docetaxel use ( p=0.14). Conclusions: In this real-world study of routine s BRCA1/2 assessment, we found a 10% prevalence in de novo mHSPC. Time to CRPC trended longer in the sBRCAm population despite less use of docetaxel, indicating that pts with sBRCAm appear to have at least similar outcomes with standard mHSPC therapies. Larger datasets correlating genomics with outcomes in this subset of pts are warranted.
Secondary analysis of PURE-01: Role of FDG-PET/CT in evaluating lymph node involvement of patients with muscle invasive bladder cancer (MIBC) receiving neoadjuvant pembrolizumab and radical cystectomy (RC).
Authors: Marandino Laura , Capozza Antonella , Briganti Alberto , Raggi Daniele , Farè Elena , Pederzoli Filippo , Gallina Andrea , Bandini Marco , Capitanio Umberto , Bianchi Marco , Gandaglia Giorgio , Fossati Nicola , Giannatempo Patrizia , Seregni Ettore , Salonia Andrea , Montorsi Francesco , Alessi Alessandra , Necchi Andrea
Published: February 2020

445

Background: FDG-PET/CT has limited utility in clinical N0 (cN0) patients (pts) with MIBC who receive neoadjuvant chemotherapy and RC or RC alone (Dason, AUA19). Methods: In PURE-01 (NCT02736266), 3 courses of 200 mg pembrolizumab, q3 weeks, were administered prior to RC. Pts were assessed with thorax-abdomen CT scan and with PET/CT scan during screening and before RC. Imaging review and analysis was internally performed. For each pt with lymph node (LN) increased uptake in abdomino-pelvic area, the SUVmax and the short-axis size of the most intense LN were recorded. All pts underwent extended pelvic LN dissection (LND) with packeted node submission. Results: From 02/17 to 06/2019, 103 total evaluable pts (206 PET/TC scans) were enrolled ad treated. Six pts (5.8%) had LN uptake at baseline PET/CT: mean SUVmax=2.75; mean short axis: 6.2 mm. Eight pts (7.8%) had LN uptake at PET/CT post-pembrolizumab: mean SUVmax=4.21; mean short axis: 7.2mm. The rate of pathologic LN positive (pN+) disease was 15.5% (16 pts). The performance of post-pembrolizumab PET/CT in predicting pN+ disease is indicated in the Table. In total, 4/6 pts (66.7%) with baseline FDG uptake revealed as pN+ vs 12/97 (12.4%) with no baseline FDG uptakes (p=0.005). A total of 39 pts (37.9%) developed inflammatory FDG-uptakes post-pembrolizumab in several target organs/regions: top 5 sites were thyroid (N=21, 61.8%), stomach and mediastinum (13 pts each, 12.6%), lung (N=10, 9.7%), other lymph nodes (N=4, 3.9%). These changes were clinically evident (signs/symptoms or laboratory changes) in 15 pts (38.5%). Conclusions: Criteria for eligibility of cN0 pts to single-agent neoadjuvant pembrolizumab trials may be enhanced with PET/CT use. Three cycles of pembrolizumab determined profound inflammatory changes, whose long-term impact on safety is still to be determined. Clinical trial information: NCT02736266 . [Table: see text]
Vefora, GETUG-AFU V06 study: Randomized multicenter phase II/III trial of fractionated cisplatin (CI)/gemcitabine (G) or carboplatin (CA)/g in patients (pts) with advanced urothelial cancer (UC) with impaired renal function (IRF)—Results of a planned interim analysis.
Authors: Mourey Loic , Flechon Aude , Tosi Diego , Abadie Lacourtoisie Sophie , Joly Florence , Guillot Aline , Loriot Yohann , Dauba Jerome , Roubaud Guilhem , Rolland Frederic , Abraham Christine , Gauthier Hélène , Barthelemy Philippe , Gravis Gwenaelle , Nénan-Le Ficher Soazig , Cabarrou Bastien , Filleron Thomas
Published: February 2020

461

Background: Standard treatment for advanced UC is chemotherapy (CT) combining CI and G. 70% of pts with UC are over 65 and 40% of them are unfit for CI because of IRF or comorbidities. CA replaces frequently CI, when creatinine clearance (Cr Cl) is < 60 ml/min according to Cockroft and Gault formula (CGF). However, CA tends to show a lower efficacy than CI, due to decreased dose intensity of CT. Methods: We performed a multicentre randomized phase II/III study in order to compare the activity and safety of a CT regimen with fractionated CI or CA for advanced UC in 1st line setting among pts unfit for standard CT because of IRF (40 ≤ Cr Cl ≤ 60ml/min) according to CGF. We report here the results of the interim analysis of phase II. Treatment: Arm A: CA AUC4,5 D1+ G 1000 mg/m² D1, [D1 = D21]; Arm B: fractionated CI 35 mg/m² D1D8 + G 1000 mg/m² D1D8, [D1 = D21] The co-primary objectives of the phase II were to evaluate activity (non-progression (RECIST V1.1) at (D21 C6)) and safety defined by the absence during treatment of: IRF: Cr Cl <35 mL/min or deterioration of Cr Cl >20%; delayed CT (≥ 2 weeks); decrease twice G dose on day 1 for: NCI CTC grade III or IV non-hematologic toxicity; hematologic toxicity; A two-stage Bryant and Day design was used. Results: A planned first step analysis was performed after randomization of 25 and 21 pts from April 2015 to January 2018. 23 and 19 of them were evaluable (resp. Arm A/B). 8 failures were reported for safety reason in experimental arm B, 7 for renal toxicity. Conclusions: According to our pre planned first step analysis, the trial met criteria for excessive toxicity in experimental arm (fractionated CI), predominantly renal toxicity. The study was therefore definitely stopped. Survival results will be available at the meeting. Clinical trial information: NCT02240017 . [Table: see text]
Sarcomatoid urothelial carcinoma (SUC): A single-institution experience of oncologic outcomes and recurrence patterns.
Authors: Diamantopoulos Leonidas Nikolaos , Sekar Rishi Robert , Khaki Ali Raza , Winters Brian , Vakar-Lopez Funda , Tretiakova Maria S. , Gore John L. , Schade George R. , Psutka Sarah P. , Hsieh Andrew Caleb , Lee John Kyung , Yezefski Todd , Schweizer Michael Thomas , Cheng Heather H. , Yu Evan Y. , Lin Daniel W. , Montgomery Robert B. , Grivas Petros , Wright Jonathan L.
Published: February 2020

465

Background: SUC is a rare histology with aggressive behavior. We evaluated outcomes and recurrence patterns of patients (pts) with SUC, in comparison with conventional urothelial carcinoma (CUC). Methods: We retrospectively assessed our radical cystectomy (RC) database to identify pts with cT2-4 SUC (any %) or CUC, at RC or transurethral resection specimens. Clinicopathologic/treatment data were captured and compared with t and χ2 tests, as appropriate. Overall survival (OS; diagnosis to death) and recurrence-free survival (RFS; RC to recurrence or death) were estimated (KM method). Significant factors in univariable (UVA) Cox regression for OS were included in multivariable analysis (MVA). Results: We identified 38 consecutive pts with cT2-4 SUC and 287 with CUC (2003-2018); 17 (45%) and 162 (56%) received neoadjuvant chemotherapy (NAC). The primary non-mesenchymal component was urothelial in all SUC cases. SUC had higher rates of pT3/4 (66% vs. 35%, p < .001) but comparable rates of pN+ disease (26% vs. 20%, p = .38). Complete response (ypT0N0) after NAC was lower for SUC (6% vs. 35%, p = .02). Median follow-up was 73.6 months (95%CI 62.6 – 84.7). Median RFS and OS was inferior among pts with SUC (9.4 vs 109.8 months, p < .001, 19.7 vs. 130.4 months, p < .001 respectively). On MVA, SUC was independently associated with worse OS ( Table). Of 17 (45%) pts with SUC who recurred post-RC, 5 presented with abdomino-pelvic cystic masses, with an average time to recurrence < 5 months. Conclusions: SUC was associated with high rates of extravesical spread at RC and worse NAC response, RFS and OS, vs. CUC. Development of abdomino-pelvic fluid collections should raise suspicion of recurrence among pts with this histology. [Table: see text]
An open-label, multicenter, phase IIIb study of patients with urinary tract carcinoma (UTC) (STRONG): Interim safety results for fixed-dose durvalumab (D) monotherapy (module A).
Authors: Sonpavde Guru , Sternberg Cora N. , Lee Jae-Lyun , Palhares de Miranda Paulo Andre , Lima Ana Rita , Sarkeshik Makan , Hotte Sebastien J.
Published: February 2020

484

Background: Patients (pts) with advanced UTC who fail first-line therapy have a poor prognosis and limited treatment options, with only modest benefit from chemotherapy. D (anti-PD-L1 antibody) is approved for the treatment of metastatic urothelial carcinoma after progression on platinum-based chemotherapy. Methods: Module A of the phase IIIb STRONG study (NCT03084471) will determine the short- and long-term safety of a fixed dose of D monotherapy (1500 mg, every 4 weeks) in pts with urothelial and non-urothelial carcinoma of the UT who progressed on or after prior chemotherapy. The primary endpoint is to determine the number of pts with adverse events of special interest (AESIs). This analysis included AEs with onset date on or after the date of first dose and up to 90 days after discontinuation of study treatment. Interim results from module A are reported. Results: A total of 700 pts received D monotherapy. Median age was 68.2 yr and 79.6% were male; 88.6% had an ECOG PS 0 or 1 and 11.3% an ECOG PS 2. Most (88.4%) had urothelial (transitional cell) carcinoma. Tumor PD-L1 expression was high (tumor or immune cell membrane positivity ≥25%) in 183/436 (42%) pts with PD-L1 data. Median treatment duration was 11.7 weeks (range, 1-73). AEs of any grade were reported in 86.9% of pts (Table), and in 89.0%, 86.9%, and 78.5% of pts with ECOG PS 0, 1, or 2, respectively. The most common grade ≥3 AESI was increased lipase (1.4%). Deaths related to study treatment occurred in 10 pts (1.4%). Conclusions: Fixed-dose D monotherapy has an acceptable safety profile as second-line therapy for UTC. Long-term safety data reported here are consistent with published studies of D monotherapy. Clinical trial information: NCT03084471.
Durvalumab as neoadjuvant therapy for muscle-invasive bladder cancer: Preliminary results from the Bladder Cancer Signal Seeking Trial (BLASST)-2.
Authors: Wei Xiao X. , McGregor Bradley Alexander , Lee Richard J. , Gao Xin , Kilbridge Kerry L. , Preston Mark A. , Mossanen Matthew , Ingham Matthew D. , Steele Graeme S. , Klein Alyssa , Van Allen Eliezer Mendel , Severgnini Mariano , Giannakis Marios , Sonpavde Guru
Published: February 2020

507

Background: There is no established neoadjuvant therapy (NAT) for patients (pt) with muscle invasive bladder cancer (MIBC) ineligible for cisplatin-based chemotherapy preceding radical cystectomy. Encouraging prospective data indicate PD-1/PD-L1 inhibitors, including pembrolizumab and atezolizumab, are safe and active as NAT for MIBC. Durvalumab (D), a PD-L1 inhibitor, is FDA approved for treating locally advanced or metastatic urothelial carcinoma following platinum-based chemotherapy. The safety and activity of D as NAT in MIBC have not been reported. Methods: We are conducting a single-center sequential multicohort trial (NCT03773666) of D alone (Cohort 1, N=10) and D plus the CD73 inhibitor oleclumab (Cohort 2, N=10) in cT2-T4aN0M0 MIBC pts who are RC candidates and are ineligible for or declined cisplatin-based chemotherapy. The primary endpoint is feasibility, defined as ≥7 of 10 pts receiving at least 1 dose of D followed by radical cystectomy without dose limiting toxicity (DLT) up to 12 wks post-RC. In Cohort 1, D is administered at 750mg IV Q2W for 3 cycles followed by RC 2-4 weeks after the last dose. Baseline and RC tissue and baseline and on-study blood are collected for correlative studies, including immunohistochemistry, genomics, transcriptomics, and metabolomics. Results: Cohort 1 has completed enrollment; ten pts were enrolled between Feb 2019 to Sept 2019. Median age was 67 (Range: 53-85) and 8 (80%) were men. All 10 pts completed 3 durvalumab doses. Eight pts completed planned RC with at least 12wk follow-up post-op to date. No DLTs were observed. One Grade 3 treatment-related adverse event (trAE) was reported (anemia), with no Grade 4 or higher trAE. Pathologic response (<pT2N0) was seen in 2 of 8 (25%) pts with pathologic complete response (pT0) in 1 (12.5%) pts. Updated safety and efficacy data from Cohort 1 will be presented. Conclusions: D appears to be feasible as NAT in MIBC with preliminary evidence for antitumor activity. Toxicities are consistent with data from other PD-1/PD-L1 inhibitor trials. Future cohorts will examine D-containing combination NAT strategies. Analysis of tissue and blood-based predictive biomarkers are ongoing. Clinical trial information: NCT03773666.
Association of the Lung Immune Prognostic Index with outcome in patients with metastatic urothelial cancer treated with immune checkpoint inhibitor.
Authors: Pauline Parent , Auclin Edouard , Mezquita Laura , Chanza Nieves M. , Dumont Clement , Rodriguez-Vida Alejo , Lozano Rebeca , Vera Beatriz , Ratta Raffaele , Baciarello Giulia , Colomba Emeline , Fuerea Alina , Besse Benjamin , Loriot Yohann , Lavaud Pernelle
Published: February 2020

545

Background: Prognostic factors for survival in metastatic urothelial carcinoma (mUC) have been reported in patients (pts) treated with chemotherapy (Bellmunt and al, JCO 2010). However, no biomarkers have been clearly identified in the setting of immune-checkpoint inhibitors (ICI). The Lung immune prognostic index (LIPI) was associated with clinical outcomes for ICI in lung cancer (Mezquita et al, Jama Oncol 2018) and other tumor types (Varga et al, TAT 2019). In this multicenter retrospective study, we correlated LIPI with outcomes in pts with mUC treated with ICI. Methods: Pts with mUC enrolled from May 2013 to July 2018 in 7 high volume centers were analysed. LIPI score includes: LDH > upper limit of normal and neutrophil/[leukocytes minus neutrophils] ratio (dNLR) > 3. The following LIPI subgroups were defined: good prognosis (0), intermediate prognosis (1) and poor prognosis (2 factors). Median (m) progression-free survival (PFS) and median overall survival (OS) were calculated using Kaplan-Meier method, log rank test was used for statistical comparison. Cox model was used for multivariate analysis. Results: To date, 152 mUC pts have been enrolled and preliminary analysis have been performed in 135 pts. Median age was 67 years, 111 (82%) pts were male, 106 pts (79%) had ECOG PS 0-1, 31 pts (23%) had liver metastasis. Median follow-up was 21.1 months (mo) (95% CI; 16.3-24.5), mPFS was 3.6 mo (95% CI; 2.6-6.0) and mOS was 13.8 mo (95% CI; 11.5-23.2). LIPI classified the population in good (56%), intermediate (35%) and poor (9%) prognosis group. In multivariate analysis, estimated mPFS in good, intermediate and poor prognosis were 5.8 mo (95% CI; 2.6-6.0), 3.6 mo (95% CI; 3.3-16.2) and 1.2 mo (95% CI;0.1-NR), respectively (p = 0.001). Estimated mOS in good, intermediate and poor prognosis were 17.3 mo (95% CI; 13.0-36.8), 16.9 mo (95% CI; 6.9-NR) and 5.4 mo (95% CI;2.5-NR), respectively (p = 0.19). OS data will be validated on larger cohort. Conclusions: The LIPI score is associated with clinical outcome to ICI and may be a useful tool for identifying patients who may not benefit from ICI. Validation in independent prospective cohort is ongoing.
IMvigor130 clinical trial in patients (pts) with metastatic urothelial carcinoma (mUC): Analysis of upper tract (UT) and lower tract (LT) subgroups.
Authors: De Santis Maria , Grande Enrique , Mencinger Marina , Li Jian-Ri , Puente Javier , Izumi Kouji , Lee Jae-Lyun , Kose Fatih , Antonyan Igor , Ding Beiying , Patel Himika , Davis Ian D.
Published: February 2020

551

Background: IMvigor130 demonstrated a statistically significant improvement in PFS in pts receiving atezolizumab (atezo; anti–PD-L1) + platinum-based chemotherapy (plt/gemcitabine [gem]; Arm A) vs placebo + plt/gem (Arm C) as first-line treatment for mUC (Grande et al. 2019). Exploratory analyses examined efficacy outcomes in UT and LT mUC subgroups. Methods: Pts with UT and LT mUC from Arm A and Arm C were included. Chemotherapy was gem + investigator choice of plt (cisplatin or carboplatin). Tumors were assessed at baseline and every 9 wk until investigator-assessed PD per RECIST 1.1 or other events. PFS, OS and ORR in UT and LT subgroups are shown. Results: Baseline characteristics were comparable between Arm A and Arm C in the UT and LT subgroups; however, slight imbalances were noted, such as higher PD-L1–positive status (IC2/3) and lower Bajorin risk score in UT Arm A pts. With a median follow-up of 11.8 mo, median PFS was8.2 vs 6.2 mo in Arm A vs Arm C in UT pts (HR, 0.69 [95% CI: 0.51, 0.94]) and 8.1 vs 6.5 mo, respectively, in LT pts (HR, 0.85 [95% CI: 0.70, 1.02]). Interim median OS was 16.9 vs 13.5 mo in Arm A vs Arm C in UT pts (HR, 0.78 [95% CI: 0.54, 1.12]) and 15.8 vs 13.4 mo, respectively, in LT pts (HR, 0.87 [95% CI: 0.70, 1.08]). See table for additional efficacy results. Conclusions: Exploratorysubgroup analyses suggest activity of atezo + plt/gem in both UT and LT mUC, with outcomes in UT pts comparable to those seen in the LT and ITT populations. Clinical trial information: NCT02807636. [Table: see text]
Impact of early identification of brain metastases in metastatic renal cell carcinoma (mRCC).
Authors: Parmar Ambika , Ghosh Sunita , Lalani Aly-Khan A. , Hansen Aaron Richard , Reaume M. Neil , Wood Lori , Basappa Naveen S. , Heng Daniel Yick Chin , Graham Jeffrey , Kollmannsberger Christian K. , Soulieres Denis , Breau Rodney H. , Tanguay Simon , Kapoor Anil , Pouliot Frederic , Bjarnason Georg A.
Published: February 2020

620

Background: Up to one-third of patients with mRCC can present with asymptomatic brain metastases (BM). Timely identification of BM allows for the delivery of early local interventions, which may lead to improved patient outcomes. To investigate the potential utility of routine intra-cranial imaging, we compared the outcomes of mRCC patients with asymptomatic versus symptomatic BM. Methods: Using the Canadian Kidney Cancer information system (CKCis) database, we identified mRCC patients diagnosed with BM between 2011 and 2018. This cohort was divided into two groups dependent on the presence or absence of neurological symptoms. Baseline patient demographics, clinico-pathological disease characteristics and survival data were extracted. Statistical analysis was through chi-square tests, analysis of variance and Kaplan-Meier method to characterize survival outcomes. Results: 269 mRCC patients with BM were identified with the majority presenting with symptomatic disease (n=163; 61%). No significant differences in clinico-pathological disease characteristics were identified. Median overall survival (OS) from mRCC diagnosis for asymptomatic patients was 33.4 months (interquartile range, IQR 27.8-64.4) versus 34.5 months (20.4-43.4) for symptomatic patients (p=0.35). Median OS from time of BM diagnosis revealed a trend favoring asymptomatic, as compared to symptomatic, patients [24.5 (17.6-24.9) vs. 13.1 months (9.0-20.6), p=0.06]. Factors associated with worse OS from time of BM diagnosis included presentation with symptomatic BM [hazard ratio, HR (95% CI): 1.40 (1.03-1.90), p=0.034] and International Metastatic Renal Cell Carcinoma Consortium Database (IMDC)-characterized intermediate/poor risk disease [HR (95% CI): 1.47 (1.01-2.13), p=0.045]. Conclusions: Routine intra-cranial imaging may lead to earlier identification of BM in mRCC. However, further investigation as to whether this practice improves survival is warranted.
Outcomes of patients with pancreatic-only oligometastatic renal cell carcinoma (RCC).
Authors: Duarte Cassandra , Martinez Chanza Nieves , Collier Katharine , Dizman Nazli , Rathi Nityam , McKay Rana R. , Panian Justine , Narayan Vivek , Carneiro Benedito A. , Mega Anthony E. , Hu Junxiao , Meguid Cheryl , Agarwal Neeraj , Pal Sumanta K. , Mortazavi Amir , Harshman Lauren Christine , Lam Elaine Tat
Published: February 2020

681

Background: Patients (pts) with RCC and oligometastatic pancreas metastases are treated with pancreatectomy, stereotactic body radiation therapy (SBRT), or systemic therapy. The optimal approach is not clear. We aimed to evaluate the comparative efficacy of the modalities in terms of progression-free survival (PFS) and overall survival (OS). Methods: This IRB-approved, multi-institutional, retrospective study evaluated pts with pancreatic-only RCC metastasis without concurrent metastases elsewhere. Data on pt demographics, tumor characteristics, treatment, and outcomes were collected. PFS and OS in pts treated with pancreatectomy vs. systemic therapy were compared by log rank tests. Results: Fifty-one pts from 9 institutions were included. All had clear cell RCC; 50 pts had nephrectomy; 30 pts (58.8%) and 18 pts (35.3%) had IMDC favorable and intermediate risk, respectively. Median time from RCC diagnosis to oligometastatic disease was 120 months (mo) (range: 0, 175). As initial treatment, 23 (45%) pts had pancreatectomy (mostly partial); 25 (49%) had systemic therapy (VEGFR TKI and/or immunotherapy); 1 had SBRT; 2 had other treatments. Too few pts had SBRT for comparison. With a median follow-up of 25 mo (2, 68), median PFS for the population was 25 mo (17, 42 95% CI). Median PFS was 36 mo (8, 43 95% CI) for surgery pts and 22 mo (17, NR 95% CI) for systemic therapy pts; this was not statistically significant (NS), p = 0.3. Median OS for the population was 121 mo (100, NR 95% CI). With a median follow-up of 51 mo (2, 217), OS was 121 mo (100, NR 95% CI) for surgery pts and not reached (64, NR 95% CI) for systemic therapy pts; NS, p = 0.52. Conclusions: In this retrospective series, RCC pts with oligometastatic pancreatic-only disease had similar PFS and OS outcomes from initial pancreatectomy or systemic therapy. RCC pts with pancreas-only metastases represent a unique patient population and studies informing the underlying biology are needed to optimize clinical management.
A comparison of combined immune checkpoint inhibitors (IO) versus vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) in the treatment of advanced clear cell renal cell carcinoma.
Authors: Chan Abigail Sy , Pond Gregory Russell , Sonpavde Guru , Alva Ajjai Shivaram
Published: February 2020

692

Background: IO and VEGFR/TKI are approved treatment options, either alone or combination, in advanced clear cell RCC. Currently, there is a lack of evidence comparing efficacy and safety outcomes amongst these therapies. We sought to compare the published data for the various options with respect to efficacy and safety. Methods: A literature search using PubMed, clinicaltrials.gov, ASCO and ESMO meeting abstract databases from January 1, 2015 to June 30, 2019 to identify eligible clinical trials in advanced clear cell RCC involving at least one immunotherapy agent was performed. Due to small sample sizes in the various cohorts, descriptive statistics were provided. Weighting of estimates was based on sample size of the intervention arms. Results: 14 studies involving 6,197 pts were identified. The median age was 62 years (54.8, 64), men constituting median of 75%, and prior TKI receipt in 63%. There were 7 studies in each treatment arm. The efficacy outcomes did not demonstrate statistical differences. In the safety analyses, IO + VEGFR/TKI demonstrated the highest serious adverse event rate, correlating with treatment discontinuation rates. Conclusions: IO + IO and IO + VEGFR/TKI showed comparable efficacy and toxicity outcomes in the treatment of advanced clear cell RCC. There is a non-significant trend towards increased efficacy in some outcomes with IO + VEGFR/TKI, with possibly increased adverse events. Further studies with patient level data, cross-comparative trials, and predictive biomarkers are needed to establish a therapeutic matrix for RCC pts.[Table: see text]
Molecular characteristics of renal cell carcinoma (RCC) risk groups from JAVELIN Renal 101.
Authors: Choueiri Toni K. , Haanen John B. A. G. , Larkin James M. G. , Rini Brian I. , Albiges Laurence , Motzer Robert J. , di Pietro Alessandra , Mu Xinmeng Jasmine , Ching Keith A. , Hariharan Subramanian , Robbins Paul B.
Published: February 2020

744

Background: The phase 3 JAVELIN Renal 101 trial in patients (pts) with advanced RCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate (ORR) with avelumab + axitinib (A+Ax) vs sunitinib (S) (Motzer NEJM 2019). PFS and ORR favored A+Ax in all MSKCC risk groups, but median PFS varied. Here, we report results from analyses of baseline tumor samples to define molecular characteristics underlying risk group classifications. Methods: Nephrectomy or tumor samples from pts enrolled in the study were characterized by immunohistochemistry (CD8 and PD-L1), whole exome sequencing, or gene expression profiling (n = 705–850). Gene expression signatures (GES), pathway activation status, and mutational profiles were examined in relation to MSKCC risk groups. Results: Of the 886 total pts enrolled, 23%, 66%, and 11% had favorable (F), intermediate (I), or poor (P) MSKCC risk factors at baseline. In the F, I, and P groups, the ORR was 66%/38%, 50%/24%, and 31%/9%; median PFS was NR/16.7 mo, 13.3 mo/7.9 mo, and 5.6 mo/2.8 mo for the A+Ax/S arms, respectively. Neither the presence of PD-L1+ immune cells nor CD8+ cells differentiated the subgroups; however, the presence of PD-L1+ tumor cells was highest in the P group (p=0.0159). When compared to the I and P groups, the F group was enriched for NOTCH2 mutations (p=0.0002), displayed high FLT1 expression (p=0.007), and showed a trend favoring angiogenesis GES (JAVELIN Renal 101 and IMmotion150). The I group displayed few distinguishing characteristics (low neutrophil GES [p=0.02] and elevated homeobox gene expression [p=0.00052]). Relative to the F group, the P group showed higher cell cycle gene expression (p=0.0057) and PTEN mutation frequency, wild-type NOTCH2 genotype, elevated IMmotion150 Myeloid inflamed GES (p=0.0024), and macrophage-specific GES (p=0.0327), as well as GES for TH2 (p=0.0002), hypoxia (p=0.0199), glycolysis (p=0.0066), and the lowest expression of a dendritic cell GES (p=0.0209). Conclusions: In advanced RCC patients, biological differences within each MSKCC risk category may impact response to treatment and may help explain why these groups perform differently. Clinical trial information: NCT02684006.
Oligopelvis-GETUG P07: A multicenter phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer.
Authors: Supiot Stephane , Pasquier David , Buthaud Xavier , Magné Nicolas , Beckendorf Veronique , Sargos Paul , Crehange Gilles , Pommier Pascal , Loos Genevieve , Hasbini Ali , Latorzeff Igor , Silva Marlon , Denis Fabrice , Lagrange Jean-Leon , Campion Loic , Vaugier Loig , Blanc-Lapierre Audrey
Published: February 2020

93

Background: Oligorecurrent pelvic nodal relapse of prostatic cancer is a challenge for regional salvage treatments. We conducted OLIGOPELVIS – GETUG P07, a phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer (NCT02274779). Methods: OLIGOPELVIS–GETUG P07 was a prospective multi-center phase II trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron-emission-tomography (FCH- PET)-positive pelvic lymph nodes (PLN), combined with six-month androgen blockade (LH-RH agonist or antagonist injections). The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathological PLN. Toxicity (CTCAE v4) and complete response rates (PSA < 0.20 ng/ml) were analyzed. The main objective was to assess biochemical-clinical failure defined by a cluster of events including PSA progression (≥25 % and ≥ 2 ng/ml above the nadir) or clinical evidence of local or metastatic progression or post- treatment initiation of hormonal therapy or prostate cancer-related death. We hypothesized that salvage treatment would achieve a 2-year relapse-free survival of 70 %. Results: Seventy-four patients were recruited in fifteen French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included sixty-seven patients. Half of them had received prior prostatic/prostate bed irradiation. Median age was 67.7. Grade 2+ two-year urinary and intestinal toxicity were 10% and 2% respectively. At 2 and 3 years, 73.1 and 45.9% of patients achieved a persisting complete response respectively. After a median follow-up of 34 months, the 2-year progression-free survival rate was 77.6%. Median progression-free survival was 40.1 months. Conclusions: Combined pelvic salvage radiotherapy and hormone therapy allowed for prolonged tumor control in oligorecurrent pelvic node relapses of prostate cancer with limited toxicity. Clinical trial information: NCT02274779.