bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers of lung damage with possible predictiveness of ARDS within CS in super high-risk patients with germ cell tumors.
Authors: Rejlekova Katarina , Kalavska Katarina , Celec Peter , Makovnik Marek , Chovanec Michal , Hapakova Nikola , De Angelis Valentina , Obertova Jana , Palacka Patrik , Sycova Zuzana , Mardiak Jozef , Mego Michal
Published: February 2020

411

Background: Germ cell tumors (GCTs) represent a highly curable disease; however, a small proportion of patients with super-high-risk characteristics (choriocarcinoma, massive lung metastases, choriogonadotropin > 50 000 mIU/ml) can develop choriocarcinoma syndrome (CS) and consecutive acute respiratory distress syndrome (ARDS) shortly after the chemotherapy start with high mortality rate. This study aimed to evaluate biomarkers of lung damage as predictive biomarkers for ARDS development within CS in poor-risk GCTs patients. Methods: This study included 23 poor-risk GCTs treated from November 2000 to May 2018 in National Cancer Institute in Slovakia for whom plasma samples before chemotherapy initiation were available. Plasma levels of lung damage biomarkers (surfactant protein (D-SPD), receptor of advanced glycation end-products (sRAGE), and club cell secretory protein – (CC16)) were evaluated by ELISA assays. Results: Five (22%) of 23 patients developed CS, and all of them died shortly after the chemotherapy start. with median of 7 days (4 - 35 days). Four of them developed ARDS within CS, while one patient died due to massive abdominal hemorrhage. Pre-treatment levels of s-RAGE and SPD but not CC-16 were significantly associated with CS development ( P = 0.03 and P = 0.04). Level of sRAGE and SPD correlated significantly with dyspnea, weight loss, extent of metastatic lung involvement and need of mechanical ventilation after chemotherapy start, as well as with PFS and OS, while CC-16 did not correlate with any of these factors. Conclusions: In this study we identified new predictive biomarkers for CS development in poor-risk GCTs. Abovementioned factors might help to improve the risk stratification of these patients with GCTs as well as discover new treatment approaches preventing ARDS development within CS which may result in enhanced treatment outcome.
Response to olaparib or carboplatin in a real-world cohort of men with DNA damage repair (DDR) deficient metastatic castration-resistant prostate cancer (mCRPC).
Authors: Berchuck Jacob E , Silver Rebecca , Bakouny Ziad , Abou Alaiwi Sarah , Hamid Anis , Sweeney Christopher , Freedman Matthew L. , Pomerantz Mark , Taplin Mary-Ellen
Published: February 2020

43

Background: PARP inhibitors (PARPi) and platinum chemotherapy cause synthetic lethality and result in clinical benefit in men with mCRPC whose tumors harbor deleterious alterations in DDR genes. BRCA2 is the strongest predictor, but data supports a role for BRCA1, ATM, and other genes. PARPi are more expensive than platinum chemotherapy; whether they are more effective is not known. We evaluated outcomes in men with DDR-deficient mCRPC treated with PARPi or platinum chemotherapy. Methods: We identified men treated at Dana-Farber Cancer Institute who received olaparib or carboplatin for mCRPC and underwent tumor mutation profiling. Progression-free survival (PFS) was determined using Prostate Cancer Working Group 3 guidelines. Pathogenic germline or somatic single-nucleotide variants, insertions/deletions, and copy number loss in BRCA2, BRCA1, and ATM, were identified. Log-rank test was utilized to compare differences in PFS. Results: We identified 27 men who received olaparib: 19/27 (70.4%) received prior taxane chemotherapy and 3/27 (11.1%) prior carboplatin; 16 had mono- or bi-allelic alterations in BRCA2 and 2 had alterations in BRCA1 or ATM. We identified 41 men treated with carboplatin: 39/41 (95.1%) received carboplatin in combination with a taxane; 36/41 (87.8%) received prior taxane chemotherapy and 7/41 (17.1%) prior PARPi; 16 had BRCA2 alterations and 5 had alterations in BRCA1 or ATM. Among men with BRCA2 alterations, there was no significant difference in PFS (HR 0.71, 95% CI 0.45-1.11; p = 0.13) between those treated with olaparib (4.9 months [m]) versus carboplatin (5.4 m). Similarly, no difference in PFS (HR 0.80, 95% CI 0.54-1.16; p = 0.24) was observed among men with BRCA2, BRCA1, or ATM alterations treated with olaparib (3.8 m) versus carboplatin (3.6 m). Conclusions: In a small real-world cohort of men with mCRPC harboring deleterious alterations in BRCA2, BRCA1, and ATM, there was no difference in PFS between those treated with olaparib versus carboplatin. These findings support further investigation into the comparative effectiveness and cost-effectiveness of PARPi and platinum chemotherapy in men with DDR-deficient mCRPC.
Patient-reported outcomes (PRO) from a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vlachostergios Panagiotis J. , Goswami Sukanya , Niaz Muhammad Junaid , Thomas Charlene , Christos Paul J. , Osborne Joseph , Vallabhajosula Shankar , Molina Ana M. , Sternberg Cora N. , Singh Sharon , Tan Angela , Patel Amie , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: February 2020

45

Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with 177Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with improvement in PRO. Methods: Inclusion: progressive mCRPC following potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2, without preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 (7.4 to 22 GBq in phase 1; 22.2 GBq in phase 2). PRO tools included FACT-P and BPI-SF at baseline and follow up. Results: 44 men with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >2 prior ARPI, 27% with Ra223, 30% sip-T, 5% 177Lu-J591. 59.1% with >50% PSA decline (66.7% at 22.2 GBq, n=21), median overall survival 16 months (95% CI 11-NR). High grade (Gr) toxicity was rare with 6.8% Gr 3 anemia and 2.3% Gr 3 platelets. Gr 1/2 treatment-emergent AE’s include 81.8% with pain flare, 61.4% xerostomia, 29.5% fatigue, 25% platelets, 25% anemia, 25% pain, 15.5% nausea. FACT-P scores tended to improve in all categories by D22 (1 week later), with overall FACT-P scores improving by mean of 8.9 points (p=0.07) at D22 and remaining improved at 12 wks. All BPI scores also improved, with BPI overall severity score improving by mean of 3.0 at D22 (p=0.008) and remained better than baseline at 12 wks. There was no clear association with any AE and PRO changes, but those with PSA decline tended to have improved pain scores (p=0.1). Conclusions: A single cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe with fractionated (D1 & D15) dosing, with encouraging early efficacy signals in a population unselected for PSMA expression and improved quality of life and pain scores by validated PRO instruments. Clinical trial information: NCT03042468.
A risk scoring system for African-American (AA) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line abiraterone (ABA) or enzalutamide (ENZ).
Authors: Brown Jacqueline T , Liu Yuan , LaFollette Jennifer Ann , Kucuk Omer , Moore Melvin R. , Bilen Mehmet Asim
Published: February 2020

51

Background: AA pts represented < 3% of the COU-AA-302 and PREVAIL trial cohorts that led to the approval of ABA and ENZ in the 1st line treatment of mCRPC. We characterized the clinical outcomes (CO) and developed a risk score for AA pts with mCRPC on these agents. Methods: We retrospectively reviewed 77 AA pts with mCRPC treated with 1st line ABA or ENZ at Grady Memorial Hospital from 2015-2018. The CO included median overall survival (mOS), progression-free survival (mPFS) and PSA response (PSAr) as defined by a ≥ 50% drop in PSA over the 1st 12 weeks of treatment. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS and logistic regression model for PSAr. The risk score was built by regression coefficient-based scoring system using OS as the 1° outcome. Covariates included grade group (GG), baseline (bl) PSA, albumin, and BMI, ECOG status, and age. Results: Median age was 60 years with median follow-up of 11.5 months (mos). 50 pts received ABA; 27 received ENZ. The overall mOS was 45.7 mos, mPFS was 12.9 mos, and PSAr was 84.4%. CO did not differ significantly for ABA vs. ENZ with a 24-month OS of 66.6% vs. 57.7% and PFS of 34.3% vs. 45%. 1 point was assigned for each of the following: GG > 3, bl PSA ≥ 108, or bl albumin ≤ 4.2. The total was classified into low (0-1), intermediate (2), and high (3) risk and associated with CO via univariate (UVA) and multivariate (MVA) analyses (Table). Conclusions: We present the efficacy of ABA and ENZ in a cohort of AA pts with mCRPC. Risk grouping using bl PSA, bl albumin and GG may predict CO in this population. These results should be validated in a larger, prospective study.[Table: see text]
Characterization of the urinary microbiota in bladder cancer patients.
Authors: Oresta Bianca , Hurle Rodolfo , Lazzeri Massimo , Frego Nicola , Saita Alberto , Faccani Cristina , Fasulo Vittorio , Casale Paolo , Pozzi Chiara , Guazzoni Giorgio Ferruccio , Rescigno Maria
Published: February 2020

535

Background: Mounting evidence indicates that the microbiota plays an important role in carcinogenesis and response to treatments. The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiota has been linked to urological disorders. We tested the hypothesis that alteration in urinary microbial community composition may be associated to bladder cancer development and progression. Therefore, we performed a study to characterize the urinary microbiota associated with non-muscle invasive and muscle invasive bladder cancer (NMIBC, MIBC). Methods: Urines were collected with a catheter from BC patients before transurethral resection or cystectomy, and age-matched non-neoplastic subjects. Subjects with prior history of sexually transmitted infection, chronic intestinal inflammation, urinary tract infection and recent usage of antibiotic or immunomodulatory agents were excluded. Bacterial DNA was extracted and amplified for 16S rDNA sequencing. Results: We isolated bacterial DNA from urine samples of 12 non-neoplastic control subjects and 27 BC patients. The most abundant phyla in both groups were Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria, with Bacteroidetes being slightly more abundant in bladder cancer at the expense of Proteobacteria. Interestingly, we found that NMIBC displayed a reduction in the abundance of Sphingobacteriaceae, Bifidobacteriaceae and Enterobacteriaceae. High grade NMIBC and MIBC showed decreased Bifidobacterium and Ruminococcus, which are known to protect from inflammation, and increased Corynebacterium, a potential opportunistic bacteria. No correlation with environmental risk factors (i.e. smoking) was investigated. Conclusions: The urinary microbiota of BC patients displayed a significantly different pattern relative to control group, suggesting that the tumor microenvironment can influence dysbiosis. In particular, we found specific bacteria to associate with aggressive tumors. A better understanding of the urinary microbiota could pave the way for exploring new therapeutic options based on the manipulation of the microbial community. Analysis of additional samples is ongoing.
Intravesical anti-PD-1 immune checkpoint inhibition in urothelial bladder cancer in a mouse model.
Authors: Rajkumar Anne , Wang Jian , Neuzil Kevin E. , Kirschner Austin Noah , Chang Sam S.
Published: February 2020

537

Background: Non-muscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with BCG or chemotherapy, but the majority of intermediate- and high-risk cases subsequently recur. Systemic administration of anti-PD-1 immune checkpoint inhibitors (anti-PD-1) are approved treatments for metastatic urothelial bladder cancer. We hypothesized that intravesical instillment with an anti-PD-1 inhibitor would treat localized bladder cancer. Methods: We investigated a syngeneic wild-type mouse model of orthotopic urothelial bladder cancer. We instilled MBT2 cells into wild-type C3H mice to compare treatments, which included weekly intravesical administration of chemotherapy and anti-PD-1 antibody alongside intraperitoneal administration of anti-PD1 antibody. Results: Anti-PD-1 antibody administered by bladder instillment (intravesical route) successfully treats the disease, similarly to anti-PD-1 by systemic route. Anti-PD-1 antibody by either route provides significant survival advantage over isotype control antibody given by bladder instillment. Treatment by immune checkpoint inhibitor increases CD8+ cell infiltration in tumors, particularly when administered intravesically. In addition, antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment, showing initial-anti-PD-1 treated mice did not grow tumors but initial mitomycin-treated mice did grow tumors. Conclusions: Intravesical administration of anti-PD-1 is a promising avenue for treatment of localized bladder cancer, with comparable anti-tumor activity compared to systemic anti-PD-1 in this mouse model.
Comprehensive targeted gene profiling to determine the genomic signature likely to drive progression of high-grade nonmuscle invasive bladder cancer to muscle invasive bladder cancer.
Authors: Alkhateeb Abedalrhman , Atikukke Govindaraja , Porter Lisa , Fifield Bre-Anne , Cavallo-Medved Dora , Facca Julianna , El-Gohary Yasser , Zhang Tianmin , Hamzeh Osamah , Rueda Luis , Kanjeekal Sindu Mary
Published: February 2020

568

Background: Bladder cancer is the fifth most common cancer and eighth leading cause of cancer related-death in North America. It can present as non-muscle invasive bladder cancer (NMIBC) and/or muscle invasive bladder (MIBC). Although genomic profiling studies have established that low-grade NMIBC and MIBC are genetically distinct, high-grade NMIBC can recur and progress to MIBC [ Knowles, M.A. and C.D. Hurst, 2015]. Low grade, non-invasive bladder cancers are characterized by activating mutations in fibroblast growth factor receptor 3 (FGFR3), HRAS or other pathways of receptor kinase activation. High-grade disease, which is often becomes invasive, is characterized by inactivation of TP53 and Rb pathways [Kim, J., et al.]. Finding a subtype of invasive carcinoma with FGFR3 mutation may suggest an alternate pathway by which low grade, non-invasive pathology could transform into invasive disease [Knowles, M.A. and C.D. Hurst, 2015]. Methods: In this study, using a total of 30 bladder cancer (NMIBC and MIBC) patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions / deletions, copy number variants and splice variants in over 500 common tumor genes panel. Results: Preliminary data from our study correlates with previously published mutation landscape for NMIBC and MIBC, and includes mutations in EGFR, FGFR3, FGFR4, PIK3CA, CDK6, ALK, JAK, as well as RET. While mutations in AKT1, BRCA1, CCND1, ERBB2, FGFR1, FGFR2, HRAS, and MET appear to be prevalent in NMIBC, mutations in IDH1 and MAP2K2 appear to be more common in MIBC. Three of the samples used in the study are from patients who progressed from high-grade NMIBC to MIBC. Conclusions: Therefore, have the genomic profiling performed at these two stages, which provides a unique ability to identify the potential “genomic triggers” for the transition.
A novel orthotopic murine model of neuroendocrine bladder cancer: Insights into the phenotypic plasticity of small cell bladder cancer (SCBC).
Authors: Balyimez Aysegul , Ganguly Shinjini , Grivas Petros , Ornstein Moshe Chaim , Gupta Shilpa , Garcia Jorge A. , Lee Byron H , Tendulkar Rahul D. , Stephans Kevin L. , Ciezki Jay P. , McKenney Jesse , Klein Eric A. , Mian Omar Y.
Published: February 2020

571

Background: SCBC is an aggressive subtype of bladder cancer with high metastatic potential and few effective treatment options. We developed an orthotopic mouse model of SCBC to understand the development of this rare bladder cancer variant and identify epigenetic drivers of neuroendocrine differentiation. Methods: Lentiviral particles carrying Cre recombinase were produced using Lenti-sgNeo#2/Cre. The bladders of Rb1fl/fl Trp53fl/fl MycLSL/LSL (RPM) mice was transduced with Cre recombinase expressing lentivirus via transurethral catheterization. Mice were monitored by micro-ultrasound (mUS) and detected tumors were verified by histology. SCBC morphology was confirmed by H&E staining and synaptophysin IHC. Whole transcriptome (RNAseq) analysis was performed to correlate transcriptomic profile of neuroendocrine mouse tumors to a cohort of human SCBC tumors. Results: Transurethral catheterization successfully transduced the bladder urothelium without evidence of exposure of ectopic (non-urothelial) tissues. RPM mice developed SCBC visible on mUS with a latency of 8-10 weeks. As expected in neuroendocrine tumors, mice developed liver and lung metastases. High grade neuroendocrine morphology and NE markers were confirmed on H&E and IHC, respectively, by a GU pathologist. Western blot analysis confirmed cMyc expression and suppression of TP53 and RB1. Synaptophysin expression was confirmed by IHC. Transcriptomic profiling of both mouse and human SCBC demonstrated concordant gene expression. Gene expression profiling of urothelial and non-urothelial neuroendocrine tumors suggested a phenotypic convergence. Conclusions: We developed a novel genetically engineered murine model of SCBC. Ongoing work seeks to identify epigenetic markers playing role in the development of this aggressive variant of bladder cancer. We are assessing the activity of immune checkpoint inhibitors in this immunocompetent background.
Safety and efficacy of immune checkpoint inhibitors (ICI) in metastatic non-clear cell renal cell carcinoma (nccRCC): An institutional experience.
Authors: Schwartzman William , Elias Roy , Patel Viral M. , Bowman Alex Isaac , Chintalapati Suneetha , Kapur Payal , Hammers Hans J. , Brugarolas James
Published: February 2020

640

Background: ICIs have improved outcomes in clear cell RCC patients (pts), and emerging data suggest that they may be effective against nccRCC. nccRCC comprises ~25% of renal tumors and consist of a diverse group of diseases. Despite recent evidence, data regarding the efficacy of ICIs in nccRCC remain limited, especially among rarer nccRCC subtypes. Methods: We identified all cases of metastatic nccRCC that received at least one dose of ICI therapy at UT Southwestern Medical Center from 2014 – 2018. Baseline characteristics and IMDC criteria were evaluated at the time of ICI initiation. Outcomes included objective response rate (ORR) per RECIST v1.1 criteria, time to next treatment (TNT), and overall survival (OS). Immune-related adverse events (irAE) were graded per CTCAE 4.0 criteria. Survival estimates were evaluated using Kaplan Meier methods. Results: We identified 28 pts with metastatic nccRCC; 12 (42.9%) unclassified RCC (uRCC), 8 (28.6%) papillary RCC (pRCC), 3 (10.7%) chromophobe RCC (chRCC), 3 (10.7%) hereditary leiomyomatosis and renal cell cancer (HLRCC), 1 (3.6%) translocation RCC (tRCC) and 1 (3.6%) acquired cystic disease-associated RCC (ACD-RCC). 23 (82.1%) pts were intermediate or poor risk by IMDC criteria. In total, 13 (46.4%) pts received nivolumab monotherapy, and 15 (53.6%) in combination with ipilimumab. 12 (42.9%) pts received ICI in the first line. The median TNT and OS amongst all nccRCC subtypes was 4.9 (95% CI: 1.7-8.1) and 15.9 (95% CI: 5.9 – 25.9) months respectively. The ORR was 3/28 (10.7%), with 2 complete responses. All responses were restricted to the pRCC and uRCC subtypes. 11 (39.3%) pts experienced any irAE and 5 (17.9%) had a grade 3/4 irAE, including one case of grade 4 myocarditis. The median time to onset of an irAE was 1.9 months (Range: 0.1 to 12.0). At a median follow up of 10.8 months (95% CI: 10.2 – 17.9), 4 pts remain on therapy and 13 pts have died. Conclusions: ICI therapy demonstrated modest efficacy in this cohort with comparable irAE profiles to ccRCC. Objective responses were not seen in pts with HLRCC, ACD-RCC, tRCC, or chRCC in this study.
Surgical learning curve for robotic multiplex partial nephrectomy: The National Cancer Institute Experience.
Authors: Telfer Siobhan , Gurram Sandeep , Gomella Patrick H. , Li Winston , Bratslavsky Gennady , Metwalli Adam R. , Linehan W. Marston , Ball Mark Wayne
Published: February 2020

660

Background: Multiplex partial nephrectomy (MPN) remains the standard of care for hereditary and bilateral kidney tumors. Our institution is an international referral center for the management of hereditary renal cell carcinoma, and therefore has considerable experience with MPN. The objective of this study was to evaluate surgical learning curve for MPN among multiple surgeons at a single institution over an 11-year period. Methods: Retrospective review of a prospectively maintained registry of patients who underwent MPN from 2007-present. The first 100 consecutive surgeries of 3 NIH fellowship trained Urologic Oncologists were identified and evaluated in quartiles. Surgical outcome measures including operative duration (OD), estimated blood loss (EBL), number of tumors resected, and complication rate were chosen as surrogate markers of learning curve. Differences in individual surgeon outcomes were evaluated and variables including re-do surgery and surgical approach were considered. Significant differences found among quartiles or among surgeon were evaluated with multivariate logistic regression analysis. Results: A total of 300 MPN's were identified. In the quartile analysis, there were no significant differences in OD, EBL, numbers of tumors resected or rates of complication. Among surgeon factors, there were differences in surgical approach and EBL (table). In a multivariate analysis of factors associated with EBL, open approach (95%CI 245-831), p < 0.0001) and number of tumors (95%CI 43-82), p < 0.0001) were independently associated. No factors were associated increased rate of complication. Conclusions: As surgeons progressed through their first 100 operations, no true learning curve was appreciated, with similar outcomes in each quartile. Among surgeon factors, open surgical approach appears to drive difference in EBL.[Table: see text]
Using high-resolution magic angle spinning magnetic resonance spectroscopy to characterize the metabolomic profile of renal cell carcinoma.
Authors: Huynh Melissa Jessica , Gusev Andrew , Palmas Francesco , Vandergrift Lindsey , Wu Chin-Lee , Cheng Leo , Feldman Adam S.
Published: February 2020

710

Background: Renal cell carcinoma (RCC) is a metabolic disease, with the various subtypes exhibiting aberrations in different metabolic pathways. Metabolomics may offer greater sensitivity for revealing disease biology than evaluation of tissue morphology. In this study, we investigate the metabolomic profile of RCC using high resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Methods: Tissue samples were obtained from radical or partial nephrectomy specimens that were fresh frozen & stored at -80ºC. Tissue HRMAS MRS was performed by a Bruker AVANCE spectrometer. Metabolomic profiles of RCC & adjacent benign renal tissue were compared, and false discovery rates (FDR) were used to account for multiple testing. Regions of interest (ROI) with FDR < 0.05 were selected as potential predictors of malignancy. The Wilcoxon rank sum test was used to compare median MRS relative intensities for the candidate predictors. Logistic regression was used to determine odds ratios for risk of malignancy based on abundance of each metabolite. Results: There were 38 RCC (16 clear cell, 11 papillary, 11 chromophobe) & 13 adjacent normal tissue specimens (matched pairs). Metabolic predictors of malignancy based on FDR include histidine, phenylalanine, phosphocholine, serine, phosphocreatine, creatine, glycerophosphocholine, valine, glycine, myo-inositol, scylla-inositol, taurine, glutamine, spermine, acetoacetate & lactate. Higher levels of spermine, histidine & phenylalanine at 3.15-3.13 ppm were associated with a decreased risk of RCC (OR 4x10−5, 95% CI 7.42x10−8, 0.02), while 2.84-2.82 ppm increased the risk of malignant pathology (OR 7158.67, 95% CI 6.3, 8.3x106), and the specific metabolites characterizing this region remain to be identified. Tumor stage did not appear to affect the metabolomics of malignant tumors, suggesting that metabolites are more dependent on histologic subtype. Conclusions: HRMAS-MRS identified many metabolites that may predict RCC. We demonstrated that those in the 3.14-3.13 ppm ROI were present in lower levels in RCC, while higher levels of metabolites in the 2.84-2.82 ppm ROI substantially increased the risk of RCC.
Metastatic renal cell carcinoma (mRCC) in young patients: A comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Necchi Andrea , Grivas Petros , Shapiro Oleg , Jacob Joseph , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Williams Erik , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Schrock Alexa Betzig , Chung Jon , McGregor Kimberly , Reddy Prasanth , Alexander Brian Michael , Danziger Natalie , Ross Jeffrey S.
Published: February 2020

727

Background: We studied the genomic alterations (GA) in patients with mRCC under 40 years of age (<40) and patients 40 years of age or older (>40). Methods: 2,128 mRCC underwent hybrid-capture based CGP. Clear cell (ccRCC), papillary (pRCC), sarcomatoid (sRCC), NOS (nosRCC), chromophobe (chrRCC), medullary (medRCC) and collecting duct (cdRCC) were separately evaluated. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Male preponderance in all subsets increased in the >40 patients. The GA/tumor increased significantly in the >40 cohorts except for in medRCC. The relatively low TMB was higher in all >40 and MSI high status was infrequent in all groups. PD-L1 expression was generally low, the 44% high positive PD-L1 in sRCC was noteworthy. Significant differences in GA in <40 vs >40 RCC included increased PBRM1 and SETD2 GA in >40 vs <40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in >40 vs <40 pRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in >40 vs <40 sRCC; increased TP53, VHL and TERT in >40 vs <40 nosRCC. Changes in GA in <40 vs >40 chrRCC, medRCC and cdRCC were noted but insufficient cases prevented statistical evaluation. Conclusions: When evaluated by age, CGP of mRCC demonstrates significant differences in the genomic landscapes with >40 cases featuring increasing male preponderance and higher GA/tumor, TMB and increases in TP53, CDKN2A/B and TERT GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of mRCC.[Table: see text]
Safety and outcome of stereotactic body radiation therapy (SBRT) with rectal hydrogel spacer for prostate cancer.
Authors: Chen Lily , Gao Ang , Gannavarapu Bhavani S. , Garant Aurelie , Desai Neil Bipinchandra , Folkert Michael Ryan , Ahn Chul , Roehrborn Claus G. , Lotan Yair , Timmerman Robert D. , Hannan Raquibul
Published: February 2020

76

Background: Ultra-hypofractionated radiotherapy delivered using stereotactic body radiotherapy (SBRT) is a cost-effective treatment for localized prostate cancer. Optimal dosing remains unclear, as commonly used 30-40Gy/5fx regimens appear to overestimate hypofractionation’s control benefits. Here, we report the largest experience of 45Gy/5Fx of SBRT for prostate cancer patients treated with hydrogel peri-rectal spacer (‘hydrogel’). Methods: An IRB-approved retrospective protocol was used to conduct a registry search identifying all patients with prostate cancer who received 45Gy/5Fx between 2015-2019 with hydrogel. Genitourinary (GU) and gastrointestinal (GI) toxicities were defined using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. The ASTRO-Phoenix failure definition of Nadir+2 ng/mL was used for biochemical failure. Results: We analyzed 250 low (9.2%), intermediate (85.2%), and high-risk (5.6%) prostate cancer patients with a median follow-up of 9.9 months (range: 0-45.7 months). Acute GU and GI grade ≥ II toxicities were noted in 15.2% and 7.2% of patients, respectively. Late GU grade II and III toxicities occurred in 24.0% and 1.2% of patients, respectively, while late GI grade II and III toxicities occurred in 4.0% and 0.4% of patients, respectively. In patients (N=44) with follow-up >2 years, late GU and GI grade III toxicities occurred in 4.55% and 2.27% of patients, respectively. A significant correlation was noted for acute GI and GU toxicity predicting the respective late GI and GU toxicity (p-value < 0.001 for both). Physician-reported Grade ≥ II new onset erectile dysfunction was 17.2%. A gradual decline in prostate-specific antigen with a mean nadir of 0.04 (95% CI: [0.018, 0.067]) at 36 months was noted. The actuarial freedom from biochemical failure was 96.33% at 3 years. Overall survival was 94.09% at 3 years with no deaths attributed to prostate cancer. Conclusions: SBRT treatment of 45Gy/5Fx with hydrogel is well tolerated with GU/GI toxicities comparable to those reported for conventional fractionation. Although short, the 3-year biochemical control rate is encouraging. Longer follow-up and prospective evaluation are warranted.
Propensity score matched comparison of docetaxel and androgen receptor axis-targeted (ARAT) agents in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Yamamoto Akiyuki , Kato Masashi , Tsuzuki Toyonori , Gotoh Momokazu
Published: February 2020

80

Background: Several studies have reported that intraductal carcinoma of the prostate (IDC-P) is a pathological adverse prognostic factor in patients with prostate cancer. However, the optimal treatment has not been established. The present study aimed to evaluate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with castration-resistant prostate cancer (CRPC) with IDC-P using a propensity score-matched analysis. Methods: We retrospectively identified 309 patients with CRPC from February 2007 to February 2016. They received initial androgen deprivation therapy (ADT) and after progression to CRPC, they received docetaxel or ARAT (abiraterone or enzalutamide) as the first-line life-prolonging therapy. The primary outcome of interest was OS from the time of CRPC diagnosis. We also investigated PFS from the time of docetaxel or ARAT initiation. Results: Propensity score-matching identified 85 patients in each group. There were no significant differences in patient characteristics between the groups. The median OS in the docetaxel group was 38.2 months versus 58.3 months in the ARAT group (HR 0.57; 95% CI 0.37–0.89; P =.01). Regarding patients with IDC-P, OS was significantly longer in the ARAT group than the docetaxel group (HR 0.48; 95% CI 0.26–0.86; P =.01), and there was no significant difference in each group, as in patients without IDC-P (HR 0.75; 95% CI 0.37–1.52; P =.43). The median PFS in the docetaxel group was 6.7 versus 7.8 months in the ARAT group (HR 0.65; 95% CI 0.45–0.94; P =.02). A multivariate analysis demonstrated that the presence of IDC-P, duration of primary ADT, visceral metastasis, and administration of ARAT as the first treatment for CRPC were independent prognostic factors for OS. Conclusions: Administration of ARAT as the first treatment for CRPC may prolong OS more than that of docetaxel, especially in patients with IDC-P.
Bicalutamide with or without metformin for biochemical recurrence in prostate cancer patients (BIMET-1).
Authors: Bilusic Marijo , Zibelman Matthew R. , Ghatalia Pooja , Wroblewski Susan , Madan Ravi Amrit , Karzai Fatima , Dahut William L. , Gulley James L. , Plimack Elizabeth R. , Geynisman Daniel M.
Published: February 2020

85

Background: Metformin (MET) may play a role as an anti-proliferative and anti-carcinogenic agent. Epidemiological studies have demonstrated that MET is associated with decreased prostate cancer (PCa) incidence, including decreased PCa specific mortality in diabetic men with PCa. Preclinical studies have shown synergistic effect of MET with bicalutamide, thus prompting this clinical trial evaluating the combination (NCT02614859). Methods: This was an open label, randomized, phase II trial of pts with biochemically recurrent PCa, PSA doubling time 3-9 months, normal testosterone, and BMI > 25. Pts were randomized (2:1) either to MET 1000 mg twice daily orally or observation for initial 8 weeks. Bicalutamide 50 mg orally daily was added to both arms after 8 weeks. Total duration of treatment was 32 weeks. The primary objective was to determine number of pts with undetectable PSA ( < 0.2 ng/mL) at the end of study with key secondary objectives of evaluating PSA declines of ≥ 85%, PSA responses to MET alone and safety. An early stopping rule for futility was set at 39 pts, but due to slow accrual, an unplanned interim analysis was undertaken. Results: 28 patients were randomized between December 2015 and September 2019. Treatment was well tolerated with no dose reductions or treatment discontinuation. No Grade 3 treatment-related adverse events were observed. Conclusions: PSA responses were seen in 50% pts with MET monotherapy after 8 weeks. Although well tolerated, there was no difference in PSA at 32 weeks between the two arms. The trial will be stopped early due to poor accrual and inability to achieve its primary endpoint. Ongoing larger studies of MET in PCa (STAMPEDE) will define it’s utility in prostate cancer. Clinical trial information: NCT02614859. [Table: see text]
Disulfiram (DSF) pharmacokinetics (PK) and copper PET imaging in a phase Ib study of intravenous (IV) copper loading with oral DSF for patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Zhang Tian , Kephart Julie , Bronson Elizabeth , Anand Monika , Daly Christine , Spasojevic Ivan , Berg Hannah , James Olga G. , Healy Patrick , Halabi Susan , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J.
Published: February 2020

96

Background: In preclinical models of prostate cancer (PC), DSF reduced tumor growth when co-administered with copper (Cu). Further, intracellular Cu uptake is partially regulated by androgen-receptor signaling. Given these data, we conducted a phase Ib clinical trial of mCRPC patients (pts) receiving Cu with DSF. Methods: Pts with mCRPC were assigned to 1 of 3 cohorts: neuroendocrine PC (NEPC) (A), adenocarcinoma (adenoCA) mCRPC with non-liver/peritoneal metastases (B), and adenoCA mCRPC with liver and/or peritoneal metastases (C). IV CuCl2 was given weekly for 3 doses with oral daily DSF. After CuCl2 dosing, daily oral Cu gluconate was started and DSF continued until disease progression as defined by Prostate Cancer Working Group Three (PCWG3). DSF and metabolite MeDDC levels in plasma were sampled at 0, 2, 4, 6 and 8 hours after the first dose and on Cycle 2 Day 1, and measured by HPLC. DSF and MeDDC were evaluated for cytotoxicity in 3 PC cell lines (22Rv1, LnCAP, and PC3) and a prostate epithelial cell line (PWR-1E). mCRPC Cu avidity was measured by 64Cu PET scan at baseline for all pts. Results: We treated 9 pts with mCRPC, 6 on cohort B and 3 on cohort C. No confirmed PSA declines or radiographic responses were observed in either cohort. Common adverse events included fatigue and psychomotor depression; no grade 4/5 AEs were observed. PK analysis: No DSF was detected in plasma (LOQ = 0.032 ng/mL, LOD = 0.01 ng/mL), whereas MeDDC was measurable in all study samples (LOQ = 0.512 ng/mL). MeDDC exhibited no cytotoxicity activity in PC cell lines. On 64Cu PET scans, bone metastases showed differential and heterogeneous Cu uptake. Lymph node and pulmonary metastases were evaluable, but not liver metastases due to significant Cu uptake in the liver. Conclusions: Oral DSF is not an effective treatment for mCRPC because it is quickly metabolized into the non-cytotoxic inactive metabolite, MeDDC. As such, this trial has stopped enrollment. Further work is needed to identify a stable DSF formulation so that the conditional lethality of Cu and DSF may be evaluated for treatment of mCRPC. Clinical trial information: NCT02963051.
Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) versus placebo plus enza for metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-641.
Authors: Graff Julie Nicole , Burgents Joseph , Liang Li Wen , Stenzl Arnulf
Published: February 2020

TPS258

Background: The mechanisms of action of pembro, a PD-1 inhibitor, and enza, an androgen receptor inhibitor, may be synergistic in the treatment of patients (pts) with mCRPC. The phase 1b/2 KEYNOTE-365 (NCT02861573) study showed antitumor activity with pembro + enza in pts with mCRPC pretreated with abiraterone acetate. A phase 2 study (NCT02312557) of enza-pretreated patients with mCRPC showed that some pts had a profound and durable anticancer response to pembro + enza. Methods: KEYNOTE-641 (NCT03834493) is a randomized, double-blind, phase 3 trial to evaluate efficacy and safety of pembro + enza versus placebo + enza in pts with mCRPC. An estimated 1200 patients will be randomly assigned 1:1 to receive enza 160 mg/day + pembro 200 mg IV Q3W or enza 160 mg/day + placebo. Treatment will be stratified by prior abiraterone acetate treatment (yes/no), metastases location (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who experienced biochemical or radiographic progression, ECOG PS 0/1, and adequate organ function are eligible. Pts will be required to provide tissue for biomarker analysis. Intolerance to or progression while receiving prior abiraterone acetate therapy is permitted, but not required. Prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor is prohibited. Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG3-modified RECIST v1.1 Q9W during the first year and Q12W thereafter. Treatment will continue until progression, unacceptable toxicity, or consent withdrawal, with up to 2 years of pembro/placebo. Dual primary end points are OS and rPFS by blinded independent central review. Secondary end points are time to subsequent anticancer therapy or death, ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to soft tissue progression, time to symptomatic skeletal-related event, and safety. Accrual began July 28, 2019. Clinical trial information: NCT03834493.
A single-arm phase II study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.
Authors: Hawley Jessica , Bowler Timothy Geoffrey , Guo Xinzheng Victor , Dallos Matthew , Lim Emerson A. , Hu Jianhua , Lowy Israel , Drake Charles G. , Stein Mark N.
Published: February 2020

TPS271

Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. Reprogramming the immune system in the mHSPC setting is a novel approach to delay progression to CRPC. In the hormone-sensitive setting, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules (PD-1 and PD-L1). These effects diminish as castration resistance emerges. Docetaxel causes immunogenic tumor cell death and stimulates antigen presentation. We hypothesize that leveraging the immunogenic effects of ADT with PD-1 blockade and docetaxel will promote antitumor immune killing and improve clinical outcomes. Methods: This is an open-label, single-arm, phase II study of ADT, cemiplimab, and docetaxel in patients with de novo mHSPC (N=20). Subjects will receive continuous ADT, followed by a two-cycle lead-in of cemiplimab prior to the standard six cycles of docetaxel. Cemiplimab will be continued q3weeks for one year or until disease progression or intolerable side effect. The primary endpoint is undetectable PSA at 6 months. Secondary endpoints include time to development of CRPC and radiographic response. Subjects will be monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Correlative studies will determine the effects of ADT and PD-1 blockade on the TME by comparing baseline and on-treatment biopsies using transcriptional data from single-cell RNA-sequencing and standard immunohistochemistry (IHC). Serum samples will also be collected to quantify the effects of therapy on circulating levels of immunosuppressive cytokines. The study is open with 3 patients currently enrolled at the time of submission. Clinical trial information: NCT03951831.
A phase Ib/II, open-label, platform study evaluating the efficacy and safety of AB928-based treatment combinations in participants with metastatic castrate-resistant prostate cancer.
Authors: Wise David R. , Gardner Olivia , Gilbert Houston N. , Rieger Aimee , Paoloni Melissa Constance , Krishnan Kartik
Published: February 2020

TPS272

Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.
A phase II study of sEphB4-HSA in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Burns Michael C. , Sagar Vinay , Jovanovic Borko , Morgans Alicia K. , VanderWeele David James , Quinn David I. , Stadler Walter Michael , Abdulkadir Sarki , Hussain Maha H. A.
Published: February 2020

TPS274

Background: The EphB4/EphrinB2 pathway is a promising therapeutic target for patients with mCRPC. EphB4 expression is increased in prostate cancer tissue and cell lines, and retained in castration resistant states. EphB4 crosstalks with the PI3K/AKT and MAPK pathways to regulate cell survival and proliferation, and its interaction with the transmembrane ligand EphrinB2 leads to T-cell suppression and immune evasion. A soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) binds to EphrinB2 and blocks interaction with the cell surface EphB4 receptor to promote immune infiltration and induce tumor cell death. Here we report an ongoing phase II study exploring the preliminary efficacy and safety of sEphB4-HSA in patients with progressive disease after frontline therapy for mCRPC. Methods: Eligibility criteria include mCRPC with disease progression after second generation AR targeted therapy (i.e., abiraterone or enzalutamide), ECOG PS ≤ 2, and adequate renal, hepatic and hematological functions. Pts having received 4 or more prior treatment therapies for mCRPC are excluded. The primary objective is efficacy as reflected by PSA response using PCWG3 criteria. Secondary objectives include safety and tolerability by CTCAE v 5.0, time to PSA progression, overall response by RECIST 1.1 and PCWG3 (bone) criteria, and rPFS. Translational endpoints include expression of EphB4 and EphrinB2 in metastatic tumor samples by immunohistochemistry and correlation with alterations in MYC, PTEN/PI3K, AR, and p53 pathways. sEphB4-HSA is administered as IV infusion over 60 min every 14 days with spacing to every 21 days after 6 cycles. Therapy will continue till disease progression, unacceptable toxicity, treatment delay ≥4 weeks, or patient withdrawal. Preliminary efficacy will be assessed using PSA response rate (PR and CR) with a Simon two stage minimax trial design assuming the undesirable overall response rate (null hypothesis) to be approximately 10% or less, and the alternate hypothesis suggesting success to be approximately 30% or more. Toxicity will be evaluated by the DSMC after the first stage including 15 patients. If 2 or more respond, then an additional 10 patients will be added. Clinical trial information: NCT04033432.