bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylation-associated miR193b silencing activates master drivers of aggressive prostate cancer.
Authors: Mazzu Ying Zhang , Chakraborty Goutam , Yoshikawa Yuki , Nandakuma Subhiksha , Armenia Joshua , Jehane Lina E. , Lee Gwo-Shu Mary , Mucci Lorelei , Kantoff Philip W.
Published: March 2019

240

Background: Epigenetic changes in DNA methylation, histone modifications and miRNA expression have major roles in prostate cancer (PC) initiation and progression. Previous screening for epigenetically regulated miRNAs in PC revealed hypermethylation of the miR-193b promoter, but no related functional studies in PC have been reported. Methods: Methylation was measured by methylation-specific PCR. Quantitative RT-PCR was used to validate the regulation of potential miR-193b targets. Luciferase reporter assays were applied to detect the regulation of miR-193b-targets. The promoter methylation status was modified by DNMT and HDAC inhibitors (5-azacytidine and mocetinostat). Results: miR-193b level is inversely correlated with the degree of its promoter’s methylation in the TCGA cohort. Distinct miR-193b promoter methylation patterns were detected in multiple normal and PC cell lines. Overexpression of miR-193b in PC cells with low miR193b level induced cell growth inhibition, apoptosis, or inhibition of invasion. Previously reported top 150-downregulated genes by miR-193b in liposarcoma showed a high correlation with PC progression in multiple PC cohorts. We further identified FOXM1 and RRM2 as the direct targets of miR-193b. Knockdown of FOXM1 and RRM2 in PC cells phenocopied miR-193b with respect to inhibition of invasion and induction of apoptosis. Furthermore, combination treatment with DNMT and HDAC inhibitors released the methylation-regulated silencing of miR-193b in PC cells, resulting the inhibition of FOXM1 and RRM2 expression. Conclusions: We revealed the tumor suppressive function of miR-193b in PC. Overexpression of miR-193b in PC cells with low miR193b level induced cell growth inhibition, apoptosis, or inhibition of invasion. A gene set identified in liposarcoma cells by overexpression of miR-193b showed a high correlation with PC progression in multiple PC cohorts. FOXM1 and RRM2 may be the key targets of miR-193b in PC. Our findings suggest that methylation-silencing miR-193b in PC may release the inhibition of some key oncogenes to contribute PC progression, which could provide a possible therapeutic mechanism for PC therapy.
The effect of a structured exercise intervention on CTCs and platelet cloaking in patients with metastatic prostate cancer.
Authors: Brady Lauren , Hayes Brian , Sheill Grainne , Baird Anne-Marie , Guinan Emer M. , Stanfill Bryan , Vlajnic Tatjana , Casey Orla , Greene John Patrick , Allott Emma , Hussey Juliette M. , Cahill Fidelma , Van Hemelrijck Mieke , Peat Nicola , Rudman Sarah Maria , Mucci Lorelei , Sheils Orla , John O'Leary , McDermott Ray , Finn Stephen P.
Published: March 2019

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Background: Physical activity has been described as an effective adjunct for improving quality of life in patients with metastatic prostate cancer (PrCa). Circulating tumor cells (CTCs) are a morphologically distinct set of cancer cells, involved in disease progression. Platelet cloaking, the surrounding and subsequent attachment of platelets to CTCs, has been proposed as effective in aiding extravasation, thus enhancing metastatic spread. The ExPeCT (Exercise, Prostate Cancer and Circulating Tumor Cells) trial aimed to examine the impact of a structured exercise intervention on the mechanisms of metastasis, including CTC cloaking, in patients with metastatic PrCa. Methods: ExPeCT was a multi-center, randomized trial for patients with metastatic PrCa (n=61). Participants were randomized to either control or exercise arms. Participants in the exercise arm (n=29) completed six months of prescribed aerobic exercise. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analyzed for the presence of CTCs, CTC clusters and platelet cloaking. Results: No significant difference in CTC number between the exercise and control arms was observed (p=0.2630), however significant alterations in CTC number were observed within group over time (p<0.001). Platelet cloaking was modelled as a binary response (presence/absence). A trend towards higher levels of platelet cloaking in the control group was observed (p=0.1005). Further, all findings were compared to a range of clinical variables. CTC clusters were positively correlated with PSA levels (p=0.0393) and a positive correlation between CTC number and white blood cell count (p<0.001) was determined. Conclusions: No significant relationship between CTCs and physical activity was observed, however the exercise program was well tolerated by ExPeCT participants. This study has, for the first time, shown platelet cloaking of CTCs in metastatic PrCa, in addition to a significant positive correlation between CTCs and white blood cells. These findings provide critical insight into immune crosstalk and the metastatic cascade in metastatic PrCa. Clinical trial information: NCT02453139.
Aberrations in androgen receptor ctDNA varies by race in metastatic castrate-resistant prostate cancer.
Authors: Christensen Bryce Raymon , Ledet Elisa , Vu James , Steinwald Peter , Chapman Lynne , Ko Leta , Ranasinghe Lahiru , Schiff Joshua , Moses Marcus Marie , Cotogno Patrick , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Sartor A. Oliver
Published: March 2019

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Background: Characterization of circulating free DNA (ctDNA) may aid understanding of the pathophysiology of metastatic castrate resistant prostate cancer (mCRPC). The goal of this study was to evaluate and compare somatic alterations in ctDNA between African-American (AA) and Caucasian (C) mCRPC patients. Methods: 24 AA were retrospectively case-matched by prior treatment with 45 CA mCRPC; ctDNA was assessed with Guardant360 assay (Guardant Health, Redwood City, CA). Mutant allelic fraction, mutations, and gene amplification were compared. Results: Prior to testing, 6 AA pts and 12 CA pts had 0 lines of CRPC therapy, 7 AA pts and 10 CA pts had 1-2 lines, 5 AA and 17 CA had 3-4 lines, 5 AA and 2 CA had 5-6 lines, and 1 AA pt and 4 CA pts had >6 lines. The median Gleason score was 8, regardless of race. The median ctDNA mutant allelic fraction was 0.40% for AA pts and 0.60% for the CA pts. Mutations and/or amplifications in individually assessed genes are shown in the Table. No statistically significant differences were detected except for the androgen receptor (AR) gene where alterations (mutations and/or amplifications) were more frequent in AA as compared to C (p=0.04). Conclusions: AR alterations were more commonly detected in ctDNA in AA men as compared to C suggesting that AR driven pathophysiology may predominate in this setting. Additional analyses with a larger cohorts are warranted. Data from prospective trials in mCRPC using abiraterone/prednisone (George et al. LBA 5009, ASCO 2018) similarly suggest that mCRPC may be comparatively more AR driven in this racial setting. Alterations in ctDNA compared between AA and C men with mCRPC. [Table: see text]
Preliminary results of a two stage phase II study of 18F-DCFPyL PET-MR for enabling oligometastases ablative therapy in subclinical prostate cancer.
Authors: Glicksman Rachel , Metser Ur , Vines Doug , Chan Rosanna , Valliant John , Chung Peter W. M. , Gospodarowicz Mary K. , Bayley Andrew , Catton Charles N , Warde Padraig Richard , Helou Joelle Antoine , Lalani Nafisha , Green David E , Perlis Nathan , Fleshner Neil Eric , Hamilton Robert James , Zlotta Alexandre , Finelli Antonio , Jaffray David A. , Berlin Alejandro
Published: March 2019

250

Background: Despite maximal local therapies (MLT) (radical prostatectomy followed by radiotherapy [RT]), 20-30% of men will have incurable progression of prostate cancer (PC). Most recurrences in this scenario are characterized by continuous PSA rises and failure of standard imaging (bone scan [BS] and computed tomography [CT]) to detect recurrence sites. We conducted a phase II trial for men with rising PSA after MLT using 18F-DCFPyL PET-MR followed by targeted ablation of PET positive foci. We report the results of our pre-defined analysis. Methods: Patients with rising PSA (0.43.0 ng/mL) after MLT, negative BS/CT and no prior salvage ADT were eligible. All patients underwent 18F-DCFPyL PET-MR followed by immediate PET-CT acquisition. Those with limited disease, where possible, underwent stereotactic ablative RT (SABR) or surgery. No ADT was used. The primary endpoint was biochemical response rate (complete [undetectable PSA] or partial [PSA decline ≥50% compared to baseline]). A Simon’s two stage study design was employed. Stage 1 included 12 response evaluable patients, requiring 1 or more responses in the absence of grade 3+ toxicities to proceed to stage 2 (additional 25 response evaluable patients). Results: After a median of 58 months (range 29-120) post MLT, 20 patients underwent PET-MR/CT to have 12 response evaluable patients. Median PSA at enrollment was 1.3 ng/mL (range 0.4-2.8). Three patients had negative PET-MR/CT, while 17 had positive scans, of which 12 (60%) were amenable to response evaluable ablation. The median number of detected lesions in those treated was 2 (range 1-5). Ten patients underwent SABR (27-30 Gy/3 fractions) and 2 had surgery. One patient (8%) had complete and 4 (33%) had partial PSA responses at a median of 3.3 months (range 2.8-6.0) after ablation, while the remaining 7 (59%) did not have biochemical response. No grade 3+ toxicities were observed. Conclusions: 18F-DCFPyL PET/MR has high detection rates in men with rising PSA after MLT. We observed favorable early results with SABR or surgery (41% RR). Trial completion will inform if this approach offers potential for cure in an early molecularly-defined PC oligometastatic state. Clinical trial information: NCT03160794.
Evaluation of circulating tumor DNA (ctDNA) with respect to germline alterations in metastatic castrate resistant prostate cancer patients.
Authors: Steinwald Peter , Chapman Lynne , Christensen Bryce Raymon , Ko Leta , Vu James , Schiff Joshua , Ranasinghe Lahiru , Moses Marcus Marie , Cotogno Patrick , Manogue Charlotte , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver , Ledet Elisa
Published: March 2019

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Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing tumoral alterations. We report ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Guardant360 (Guardant Health, Inc.) assesses ctDNA using sequencing to identify genomic alterations in 73 cancer-related genes. Alterations were categorized by type which included amplifications, deletions, frameshift mutations, insertions, missense mutations, splice mutations, truncations, and other. A total of 186 PCa pts in various stages of therapy had both ctDNA and germline DNA tested. Results: Of the 186 pts tested for germline mutations, 26 (14%) were germline positive. The most common germline mutation was BRCA2 with 12 (46%) pts, followed by ATM with 3 (11%). Of the total gene alterations were detected on ctDNA analysis of germline positive pts, with the most common genes being TP53 (n = 14/73, 19%), NF1 (n = 6/73, 8%), PIK3CA (n = 6/73, 8%), and BRCA2 (n = 5/73, 7%). Of the total gene alteration were detected on ctDNA analysis of germline negative pts, with the most common genes being TP53 (n = 94/588, 16%), AR (n = 90/588, 15%), EGFR (n = 31/588, 5%), and BRAF (n = 29/588, 5%). Germline negative pts showed had more amplifications (p = 0.008) while germline positive patients had more frameshift mutations (p = 0.025). Other alterations (deletion, missense, insertion, other, splicing, and truncating) were not significantly different. Missense mutations were the most prevalent type of gene alteration in germline negative (n = 306/609, 44%) and germline positive (n = 45/77, 48%), followed by amplifications (n = 210/609, 25% germline negative and n = 15/45, 18% germline positive). The median percent ctDNA values for missense mutations in germline negative and positive patients were 0.5% and 0.3% respectively. Of the germline positive pts, BRCA2 mutation was associated with the highest number of genes with alterations (n = 39), followed by RECQL4 (n = 8), ATM (n = 5), and MSH2 (n = 5). Conclusions: Germline positive pts had a higher number of frameshift mutations compared to germline negative pts. Additionally, pts with BRCA2 had the highest number of genes altered in ctDNA.
Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor.
Authors: Le Moigne Ronan , Zhou Han-Jie , Obst Jon K. , Banuelos C. Adriana , Jian Kunzhong , Williams David , Virsik Peter , Andersen Raymond J , Sadar Marianne , Perabo Frank , Chi Kim N.
Published: March 2019

257

Background: Aniten compounds bind to the N-terminal domain (NTD) of the androgen receptor (AR) and inhibit AR dependent transcription. EPI-506, the pro-drug of EPI-002, was the first AR NTD inhibitor tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC). The drug was well-tolerated but required high doses. At doses >1280 mg, EPI-506 treatment resulted in PSA declines; however, these were minor and of short duration, reflecting EPI-506’s low potency and short half-life. To understand EPI-506’s metabolic vulnerabilities, patient plasma samples were analyzed to identify metabolites. Methods: PSA serum levels were assessed after a month of dosing. Patient plasma samples were analyzed and pharmacokinetic (PK) parameters calculated. Three plasma samples from patients (one 80 and two 3,600 mg doses), were pooled across timepoints and metabolites were analyzed. EPI-506 metabolism was assessed in in vitro ADME assays and metabolite activity was measured. Results: EPI-002 patient plasma profiles exhibited dose-proportional Cmax and AUC following once or twice-daily EPI-506 administration. PSA declines (range of 8-29%) were observed, especially at higher doses (≥ 1,280 mg). A total of 19 metabolites were identified. Metabolite M19, a glycerol-moiety oxidant, was the major drug-related component. Other metabolic pathways included O-glucuronidation, sulfation, carboxylic acid formation, and oxidative chlorine loss. The major metabolites were tested in an AR driven reporter assay and were shown to be inactive. Interestingly, in vitro ADME assays predicted glucuronidation and sulfation but not cytochrome dependent metabolism. Conclusions: EPI-506 was tested in a phase 1 trial and showed minor PSA declines. The drug was well-tolerated but was highly metabolized. Patient plasma samples identified 19 metabolites. Newer molecules have been synthesized to address EPI-002’s metabolic liabilities and demonstrate > 20-fold improved potency and higher stability. These next generation Anitens are currently being characterized for IND filing. Clinical trial information: NCT02606123.
ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi , Snyder Lawrence B , Willard Ryan R , Vitale Nicholas , Pizzano Jennifer , Gordon Deborah A , Bookbinder Mark , Macaluso Jennifer , Dong Hanqing , Ferraro Caterina , Wang Gan , Wang Jing , Crews Craig M , Houston John , Crew Andrew P , Taylor Ian
Published: March 2019

259

Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often relatively short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC degrader, ARV-110, that promotes ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, and DMPK, toxicology and preclinical efficacy studies. Results: ARV-110 robustly degrades AR in all cell lines tested, with an observed half-maximal degradation concentration (DC50) of ~1 nM. ARV-110 treatment leads to highly selective AR degradation, as demonstrated by proteomic studies. In VCaP cells, PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces apoptosis at low nanomolar concentrations. Further, ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling has been achieved in LNCaP, VCaP and prostate cancer patient derived xenograft (PDX) models. Notably, ARV-110 demonstrates in vivo efficacy and reduction of AR-target gene expression in a long term, castrate, enzalutamide-resistant VCaP tumor model. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader, ARV-110, that demonstrates efficacy in multiple prostate cancer models. ARV-110 has completed IND-enabling studies and FIH studies are planned for 1Q2019.
PARP-1 regulation of DNA repair factor availability.
Authors: Schiewer Matthew Joseph , Mandigo Amy C , Gordon Nicolas , McNair Christopher , Lallas Costas D. , Trabulsi Edouard John , Leiby Benjamin , Knudsen Karen E.
Published: March 2019

269

Background: PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Previously, it was determined that PARP-1 ins involved in regulation of androgen receptor activity. Methods: Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity.Results: Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance “BRCA-ness”. Conclusions: These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.
Ductal and acinar carcinomas of the prostate: A comparative comprehensive genomic profiling study.
Authors: Liu Nick , Kotula Leszek , Byler Timothy , Jacob Joseph , Alexander Brian Michael , Gay Laurie M. , Shapiro Oleg , Millis Sherri Z. , Elvin Julia Andrea , Chung Jon , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Killian Jonathan Keith , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , Necchi Andrea , de La Roza Gustavo , Ross Jeffrey S.
Published: March 2019

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Background: Prostatic ductal carcinoma (PDC) is an uncommon centrally located prostate with a characteristic tubulopapillary histology. PDC shares some biomarker features with the more common prostatic acinar carcinoma (PAC) including PSA expression. Methods: In this comparative comprehensive genomic profiling (CGP) study, FFPE samples from 61 clinically advanced PDC and 4,132 PAC were profiled for all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, frequency of genomic alterations (GA) per tumor and TP53 GA of PDA and PAC were similar (Table). TMPRSS2:ERG fusions and AR GA were more often identified in PAC than PDC whereas PTEN GA were more common in PDC than PAC. Targetable GA were identified at similar frequencies in both groups focused on BRCA2 (PARP inhibitors), BRAF (BRAF/MEK inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDA and PAC as were the frequencies of MSI-High status, median TMB and high TMB levels. Conclusions: The pathologic features of PDC and PAC have been classically maintained as representative of 2 different tumor types with potentially contrasting histogenesis. In the current CGP-based study, PDA and PAC did not display significant differences in genomic signatures. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) in both PDA and PAC. [Table: see text]
Sipuleucel-T to modify the B7-H3 immune checkpoint in men with castrate resistant prostate cancer.
Authors: Tan Wei Phin , Barton Gregory John , Chang Andrew , Nair Smita , Inman Brant Allen
Published: March 2019

273

Background: B7-H3 is a T cell costimulatory molecule whose expression correlates with increased prostate cancer stage and mortality. We measured serum B7-H3 (sB7-H3) levels in men undergoing sipuleucel-T (sip-T) immunotherapy for castrate-resistant prostate cancer (CRPC) to determine if sip-T modified B7-H3 levels. Methods: We analyzed 41 banked serum specimens before and after sip-T treatment for CRPC. An ELISA test for sB7-H3 was used to measure serum sB7-H3 levels using a standard curve consisting of B7-H3 fusion protein, and a 4 parameter logistic model fit to back-calculate sB7-H3 levels. Each sample was measured in duplicate and the average of these two measurements used. Generalized additive and segmented regression models were used to model the relationship between sB7-H3 level and time to (and from) sip-T treatment. Results: We found that the sB7-H3 assay had a high degree of reproducibility with a Pearson correlation coefficient of 0.9 between the two measurement occasions. Importantly, sB7-H3 had no correlation with prostate specific antigen (PSA) level, indicating that sB7-H3 was providing incremental biological information not contained in the PSA level. Median PSA before sip-T treatment was 6.2 ng/mL [IQR 3.9-14.7] and median PSA post sip-T treatment was 23.4 ng/mL [IQR 9.8-107.4). Median serum sB7-H3 before sip-T treatment was 24.2 ng/dL [IQR 20.3-27.1] and median serum B7-H3 after sip-T treatment was 23.1 ng/mL [IQR 21.8-26.6]. Using a generalized additive model to measure the level of sB7-H3 from time to sip-T treatment, we found a statistically significant relationship between sB7-H3 levels and sip-T treatment, p=0.038. Using segmented linear regression, we found that sB7-H3 levels increased gradually as CRPC worsened prior to sip-T immunotherapy then, at a mean of 24 days after sip-T initiation, sB7-H3 levels started to fall. Conclusions: We found that sB7-H3 levels increased in men with CRPC and that sip-T treatment reversed this trend. Therefore, sip-T may have a positive immunological effect in CRPC irrespective of PSA change. These results suggest that one potential mechanism of action of sipuleucel-T is the reduction of sB7-H3 production by prostate cancer cells.
Treatment facility volume and survival in patients with advanced prostate cancer.
Authors: Joshi Shreyas , Handorf Elizabeth A. , Srivastava Abhishek , Masic Selma , Cahn David B. , Kadow Brian T. , Zibelman Matthew R. , Ghatalia Pooja , Uzzo Robert , Kutikov Alexander , Smaldone Marc C. , Greenberg Richard E. , Viterbo Rosalia , Chen David , Horwitz Eric M. , Hallman Mark A , Sobczak Mark Leslie , Geynisman Daniel M.
Published: March 2019

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Background: Despite improvements in the medical management of advanced prostate cancer (aPC), it continues to be the 2nd leading cause of cancer death in American men. The contemporary management of men with aPC is increasingly complex and can vary based on access to up-to-date treatments, which is often found at busier treatment centers. We thus evaluated the relationship between facility volume and survival outcomes in aPC. Methods: The National Cancer Database (NCDB) was queried from 2004-2014 for aPC, defined as T4, N+, or M+ disease. Six pre-defined patient cohorts were evaluated. Cohort A = patients with aPC (N = 64,815); cohort B = M0 patients (N = 27,155); cohort C = M0 patients undergoing active treatment (N = 21,755); cohort = all M1 patients (N = 37,660); cohort E = M0 patients undergoing active treatment (N = 30,643); and cohort F = M1 patients who underwent active treatment and who had known metastatic sites (N = 12,452). Treatment facilities were divided into quartiles based on median treatment volume: <1.8 patients/year, 1.8-3.3 patients/year, 3.4-5.6 patients/year, and >5.6 patients/year. Regression models were adjusted along a set of covariates available in the NCDB. The primary outcome was overall survival (OS). Results: OS improved with each increase in volume quartile. The top quartile (>5.6 pts/yr) demonstrated significantly greater OS compared to the bottom quartile (<1.8 pts/yr) [HR 0.82, 95% CI 0.77-0.88, p<0.001]. The improved OS in the top volume quartile remained consistent when analyzed across the six pre-defined patient cohorts. Sensitivity analyses were conducted on Cohort A, adjusting for Gleason score and facility type, which did not change the effect of volume on survival. Conclusions: In this retrospective analysis of nearly 65K men who presented with aPC, we demonstrate that management at a high-volume facility (top quartile, >5.6 pts/yr) confers a significant OS advantage when compared to management at a facility in the lowest quartile (<1.8 pts/yr). This OS advantage persisted with similar magnitudes of effect after narrowing the cohorts by disease and treatment characteristics. These findings may have implications on the optimal management of men with advanced PC.
EphB4-EphrinB2 receptor-ligand pair as a novel target in prostate cancer (PC).
Authors: Sadeghi Sarmad , Li Grace , Siddiqi Imran , Sali Akash , Liang Gangning , Gill Inderbir , Pinski Jacek K. , Quinn David I. , Gill Parkash S.
Published: March 2019

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Background: Studies have shown that EphB4 (B4), a receptor kinase, is upregulated in PC. The ligand for B4, EphrinB2 (B2) has not been studied in PC thus far. In our PTEN null mouse PC model, B4 and B2 are both upregulated in PC, but not in normal prostate. Furthermore, Soluble B4-albumin (sB4) decoy receptor blocks B4-B2 bidirectional signaling, inhibits PI3K/AKT signaling and is currently in phase II clinical trials in multiple tumor types. We thus studied B2 expression in human PCs and normal tissues. Methods: B2 levels were studied in 180 clinically localized human PCs and normal prostates. Tissue staining was performed with specific monoclonal antibody, using LEICA platform. B2 expressions in tumor vessel, tumor cell and stromal cells were scored by a pathologist. In addition, a CRPC patient was treated with sB4 under an IND approved by the FDA and IRB. The patient’s prostate cancer was diagnosed in 2014, Gleason’s score 4+3, treated with radical prostatectomy (pT3bN0) with subsequent metastases bone/bone marrow and progression on sipuleucel T, enzalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. Tumor and blood samples were obtained and analyzed after informed consent. Results: B2 was not expressed in any of the 40 normal prostate gland or normal vessels in bladder, pancreas, small intestine, liver, adrenal glands, skeletal muscle, and bone marrow tissues. B2 was expressed 50% of the human prostate cancer tissues, being positive in tumor cells and negative in vascular and stromal cells. Expression was correlated with Gleason score (p = 0.003). B2 was also upregulated in PC cell lines that are characterized for genomic, and epigenomic alterations to study mechanisms of B2 induction. Metastatic tumor tissue from the CRPC patient showed high elevation of B2. After a 4-week course of sB4, PSA level declined by 45% (from 2284 to 1257). PI3K and AR levels in tumor tissue declined compared to baseline. PI3K/AKT/pS6 and AR levels in tumor tissue ex-vivo studies were also reduced with sB4 exposure. Conclusions: B2 is expressed in half of PCs and our experiments suggest a significant role for the EphB4-EphrinB2 pair through regulation of PI3K and AR signaling. Given the central role of AR in PC, sB4 may offer a novel approach to targeting AR.
3βHSD1 immunohistochemistry and HSD3B1 genotype in prostate cancer.
Authors: Zhang JJ Haijing , Nicolas Marlo , Hardaway Aimalie , Bohn Kelsey , Hettel Daniel , Klein Eric A. , Sharifi Nima
Published: March 2019

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Background: 3β-hydroxysteroid dehydrogenase (3βHSD1), encoded by HSD3B1, catalyzes intratumoral androgen synthesis from adrenal precursors. The HSD3B1(1245A>C) germline variant encodes a more stable enzyme that promotes increased DHT synthesis and more rapid clinical progression in men treated with androgen deprivation therapy (ADT). 3βHSD1 localization and expression in prostate tissue has not been rigorously characterized. We hypothesized that HSD3B1 homozygous variant genotype is associated with elevated 3βHSD1 immunoreactivity compared with wild-type (WT) genotype. Methods: In a pilot study, HSD3B1 genotypes were obtained from prostatectomy tissues of 30 patients with prostate cancer (10 WT, 10 heterozygous, and 10 homozygous variant). Following prostatectomy, tumor tissue with adjacent benign prostate was formalin-fixed and paraffin-embedded. Immunostaining for 3βHSD1 using a validated mouse monoclonal antibody was performed. Human placenta was used as a positive control. Immunostaining patterns and histology was qualitatively assessed by a GU pathologist. Immunoreactivity was quantitatively assessed using ImagePro7. Results: Qualitative IHC scoring localizes 3βHSD1 to epithelial cells in prostatic glands and urothelium, with faint muscle and stromal staining. 3βHSD1 was immunoreactive in 100% of prostates in both benign and malignant regions. When stratified by HSD3B1 genotype, the mean density/intensity was significantly greater for HSD3B1 homozygous variant prostate (670.10u) compared to heterozygous (174.69u) and WT (176.19u) (p=0.044). (Density/Intensity) per square micron demonstrated higher mean values for homozygous variant (35.79)> heterozygous (28.67) >WT (22.56) (p=0.52). Conclusions: These pilot data demonstrate differential tissue expression of 3βHSD1 according to HSD3B1 genotype: importantly, homozygous variant HSD3B1 (1245A>C) specimen showed the most robust 3βHSD1 expression compared to heterozygous and WT prostates. These results explore the potential for 3βHSD1 as a prostate biomarker to predict aggressive disease.
Plasma-based exploratory biomarker analysis to evaluate GT0918 in a phase I/II study in mCRPC patients.
Authors: Yu Jianjun , Wang Amy , Zhao Zhixin , Jia Shidong , Zhang Phoebe , Zhou Karl
Published: March 2019

279

Background: GT0918, a novel potent androgen receptor antagonist, has been evaluated in a ph 1/2 study in mCRPC patients for its safety and efficacy. Here using patient plasma samples, we explored cell-free DNA & RNA-based biomarkers to assess their associations with clinical response of GT0918. Methods: Blood samples were prospectively collected from mCRPC patients at baseline, on- and after study during the trial. PredicinePLUS cfDNA+cfRNA assay, a 180-gene targeted NGS Panel, was used to detect genomic alterations in plasma. Statistical analyses were performed in R 3.5.1. Results: Genomic alterations were detected in all 50 blood samples. Top mutated genes are TP53 (52.5%) and AR (32.5%). When combing variants from genes in a signaling pathway, mutation rates in PI3K axis and homologous recombination pathway are 32.0% and 34.0% respectively. Importantly, AR hotspot mutations (W742C, T878A, and S889G) and amplifications are detected in multiple subjects at baseline, suggesting that it may be the driving events for resistance of prior therapies. AR splicing variants (AR-V3, AR-V7) and TMPRSS2-ERG fusion were also detected by cfRNA profiling. Interestingly, patient 001-001 harboring both AR W742C and T878A mutations detected in cfDNA with high mutation frequency didn’t carry corresponding mutations in cfRNA at the baseline but started to accumulate the mutations in C3D1. Patient 004-002 remained in the study with stable disease for 10 treatment cycles while having continuous increase of PSA. cfDNA profiling indicates frequency of prostate-specific SPOP mutation continued to decrease during the treatment. Conclusions: This is a preliminary analysis to explore potential predictive or pharmacodynamic biomarkers in mCRPC in response to GT0918 treatment. As an non-invasive assay, PredicinePLUS assay was able to detect genomic alterations in blood with a high sensitivity and provided useful molecular insights for treatment monitoring and drug sensitivity & resistance mechanisms. Clinical trial information: NCT02826772.
Clinical risk-based associations of lymph node dissection and detection of metastasis among men treated with radical prostatectomy.
Authors: Abello Alejandro , Kenney Patrick Aloysius , Leapman Michael
Published: March 2019

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Background: Pelvic lymph node dissection (PLND) is recommended for most men at risk for lymph node involvement at the time of radical prostatectomy (RP) yet is frequently omitted. We aimed to examine the probability of PLND based on clinical risk status, and evaluate the impact of increasing lymph node yield on cancer detection rate across risk strata. Methods: We queried the National Cancer Database from 2004 to 2014 to identify patients with clinically localized PCa who underwent RP as their primary treatment. We extracted patient clinical and sociodemographic variables. Risk status was assessed using UCSF Cancer of the Prostate Risk Assessment (CAPRA) score. We fit conditional logistic regression models to estimate likelihood of PLND and incremental value of increasing lymph node count by risk strata. Results: We identified 698,728 men with PCa treated with RP including 380.201 (54.41%) whit PLND. Mean age at diagnosis was 62.6. PLND was omitted (Nx) in 56.1% of patients with low CAPRA-risk disease, 31.44% with intermediate and 24.72% high. Proportion of patients with >30 lymph nodes removed decreased from 9.3% on 2004 to 3.64% on 2014. Adjusting for clinical and pathologic factors, treatment in a community versus academic (Odds Ratio, OR=1.62, 95% CI 1.59-1.66; P <0.001) and black race (OR=1.13, 95% CI 1.09-1.17, P: 0.01) was associated with pNx status. Increasing lymph node count was independently associated with greater likelihood of detection of lymph node metastasis in all risk strata (11-20 nodes: OR: 3.13 , 95% CI 2.90-3.37, P<0.001; 20-30 nodes: OR: 5.07 , 95% CI 4.50-5.73, P<0.001; >30 nodes OR: 6.58, 95% CI 5.38-8.05, P<0.001) including patients with CAPRA-0 (11-20 nodes: OR: 3.28 , 95% CI 3.06-3.53, P<0.001; 20-30 nodes: OR: 5.77, 95% CI 5.16-6.45, P<0.001; >30 nodes OR: 7.90, 95% CI 6.56-9.51, P<0.001). Conclusions: PLND continues to be omitted in a substantial proportion of intermediate and high risk patients. Increasing lymph node yield was associated with greater odds of detecting lymph node metastasis in all groups of patients, including those at the lowest level of risk by clinical criteria.
What is the clinical utility of next generation sequencing (NGS) in advanced urologic malignancies?
Authors: Mark James Ryan , Kucherov Victor , Pintauro Michael , Leong Joon Yau , Mann Mark , Trabulsi Edouard John , Lallas Costas D. , Chandrasekar Thenappan , Handley Nathan , Kelly William Kevin , Gomella Leonard G.
Published: March 2019

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Background: Widespread availability of NGS and an expanding repertoire of targeted therapies has garnered significant enthusiasm for the concept of NGS directed therapy. FoundationOne (Foundation Medicine, Cambridge, MA) is a validated comprehensive genomic profiling (CGP) assay intended to guide therapy decisions based upon tumor specific genetic variations. We reviewed our experience with FoundationOne testing in advanced genitourinary (GU) cancer and examined whether NGS effected therapy in a meaningful way. Methods: Retrospective review of patients with advanced GU cancer seen between 2/1/2013–8/13/2018 who had FoundationOne CGP testing. We then compared the duration patients were maintained on NGS directed therapy to the duration of each non-NGS therapy. Results: A total of 73 patients were identified with NGS testing for prostate (25, 34%), urothelial (30, 41%), and kidney (18, 25%) cancer. 11 (15%) of these patients had therapy directed against a genetic alteration indicated by NGS. Of the treated patients, 46% (5) had urothelial, 36% (4) had kidney, and 18% (2) had prostate cancer. The average duration that each non-NGS therapy was effective in patients with urothelial, kidney, and prostate cancer was 165, 417, and 382 days respectively. Duration of NGS directed therapy averaged 226, 367, and 278 days for urothelial, kidney, and prostate cancer. The range of the duration of response to NGS directed therapy for urothelial, kidney, and prostate cancer was 66-616 days, 106-467 days, and 28-528 days. Four (36%) patients treated with NGS directed therapy achieved a duration of response greater than the average duration of all other non-NGS directed therapy they had received (Table). Conclusions: A minority of patients received NGS directed therapy following NGS testing. Treated patients demonstrated varying responses with 4 patients experiencing a longer duration of response compared to non-NGS directed therapy. Our experience illustrates that NGS has a limited but evolving role in the management of advanced GU malignancies at this time while also demonstrating a benefit to a subset of patients. Future studies should focus on identifying which patients are most likely to benefit from this technology.
Obesity and metastatic castration resistant prostate cancer: Results from the control arms of ASCENT2, MAINSAL and VENICE trials.
Authors: Martini Alberto , Waingankar Nikhil , Brown Nicholas M , Sfakianos John P. , Tewari Ashutosh , Galsky Matthew
Published: March 2019

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Background: Previous findings regarding the correlation between body mass index (BMI) and survival in patients with prostate cancer are conflicting and may be disease-state dependent. We aimed to test whether BMI among patients with metastatic prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific mortality (CSM). Methods: We identified 1577 patients with mCRPC from the control arms of 3 randomized trials. The role of BMI was investigated both as a continuous and categorical variable ( < 20 vs. 20-25 vs. 25-30 vs. > 30 km/m2). A BMI > 30 kg/m2 was considered obese. Analyses were adjusted for age, PSA, ECOG, # of metastasis and prior treatment. A Cox semi-proportional hazard model was used to predict OS, whereas the competing risks regression was used for predicting cancer-specific mortality (CSM). Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25-31) kg/m2. Of the 1577 patients included, 655 had died during follow-up (median follow-up for survivors = 12 months). BMI emerged as a protective factor for OS both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p = 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p = 0.027). The effect BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p = 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p = 0.018). No interaction was detected between the BMI categories and docetaxel dose. Conclusions: Obesity, compared with lower weight categories, is associated with improved CSM and OS in mCRPC treated with docetaxel. The mechanistic basis for this observation warrants further study.
The prognostic value of mid-treatment prostate-specific antigen level in patients receiving salvage radiotherapy.
Authors: Homza Jason , Nawrocki John T. , Brereton Harmar D. , Peters Christopher A.
Published: March 2019

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Background: Salvage radiotherapy (SRT) may be employed as a potentially curative intervention for patients experiencing biochemical failure (serum prostate-specific antigen [PSA] ≥ 0.2 ng/mL) after prostatectomy for localized prostate cancer. Patients not showing a favorable response to SRT alone may require additional therapies and may benefit from earlier identification of this need. Methods: 131 consecutive patients received SRT during the timeframe of this study. 76 were deemed eligible based on the following criteria: prostatic adenocarcinoma diagnosis receiving SRT, no clinical evidence of metastasis, no hormone use prior to/during SRT, serum PSA measurement halfway through SRT, and minimum follow-up time of 3 months. Median follow-up time was 51.6 months. Eligible patients were divided into three groups based on PSA response by the midpoint of treatment: no change, decrease, or increase in PSA. The primary endpoint of the study was clinical failure (measured from SRT completion), defined as serum PSA value ≥0.2ng/mL above the post-radiotherapy nadir, initiation of androgen deprivation therapy, development of bone metastasis, or death from prostate cancer. Results: 13.1% experienced no change in PSA halfway through SRT (group 0), 68.4% of patients experienced a decrease (group 1), 18.4% experienced an increase (group 2). Four-year freedom from clinical failure was 60.0% for group 0, 58.3% for group 1, and 41.7% for group 2. Median time to clinical failure was 71.7 months for group 1, 26.8 months for group 2, and was not reached for group 0. Pairwise multiple comparison demonstrated a significant difference in four-year freedom from clinical failure between groups 1 and 2 (p = 0.036). Conclusions: These data strongly suggest that changes in PSA are apparent midway through SRT and are associated with 4-year freedom from clinical failure. Further study is warranted to determine whether mid-treatment PSA during SRT may be used to identify a subset of patients that may benefit from treatment intensification.
Exploratory study of prognostic factors in mCRPC patients who administered enzalutamide focusing on early PSA decline and PSA kinetics at PSA progression: Results of retrospective multicenter study.
Authors: Miyazawa Yoshiyuki , Shimizu Nobuaki , Takezawa Yutaka , Nakamura Toshiyuki , Miyao Takeshi , Nakayama Hiroshi , Kurihara Sota , Syuto Takahiro , Nomura Masashi , Sekine Yoshitaka , Koike Hidekazu , Matsui Hiroshi , Shibata Yasuhiro , Suzuki Kazuhiro
Published: March 2019

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Background: Recent studies have shown that an early PSA response to AR-targeting agents in mCRPC is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA Velocity while monitoring oncologic outcomes and survival in Japanese patients. Methods: A total of 241 patients with mCRPC treated with ENZ were analyzed. Patients’ median age is 75±7.9 (range 53-93). The patients pre-docetaxel settings were 171 cases (71 %), post-docetaxel settings were 70 cases (29 %). The PSA-PFS and OS were assessed according to PCWG2 criteria. This study was approved by the institutional review board of Gunma University Hospital (No.1595). Results: A case where PSA did not decline at all was defined as Primary Resistance (PR). A case in which PSA once declined after treatment but then progressed was defined as Acquired Resistance (AR). Those in which PSA remained low after treatment were defined as Good Response (GR). We observed 77 PR cases (31.9 %), 125 AR cases (51.9 %) and 39 GR cases (16.2 %).PSA-PFS and OS pre-docetaxel were significantly increased as compared to patients’ post-docetaxcel (PSA-PFS; 47.0 wks vs. 13.4 wks p < 0.001, OS; Not Yet Reached vs. 80.7 wks p < 0.001). Multivariate analysis of prognostic factors, including the PSA response at 4 weeks, was performed using a Cox regression analysis. The PS (0 or 1-2), Hb (≧11.4 or < 11.4), time to CRPC(≧12 m or < 12 m), docetaxel treatment history (none or done) and a PSA decrease of 50% at 4 weeks were all significant factors for the prediction of OS (all variables, p < 0.05). In cases of acquired resistance (n = 125), a multivariate analysis using PSA kinetics factors such as PSADT and PSA Velocity (ng/mL/month) at PSA progression, Hb, time to CRPC(≧12 m or < 12 m), PSADT (≧2 months or < 2 months) and PSA Velocity ( < 20 ng/mL/month or≧20 ng/mL/month), were all factors predicting OS following PSA progression (p < 0.05). Conclusions: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostication factor for mCRPC patients.
Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A retrospective study.
Authors: Hamada Kosuke , Iguchi Taro , Tamada Satoshi , Kato Minoru , Yamasaki Takeshi , Takeyama Yuji , Shimizu Yasuomi , Yasuda Sayaka , Nakatani Tatsuya
Published: March 2019

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Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely used for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide (FLU) after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The AAT response rate was 20–30%, and there is no evidence of prolonged overall survival (OS), but we have encountered effective clinical cases. Currently, two prospective clinical studies are ongoing, but this is the first retrospective study comparing FLU and enzalutamide (ENZ) for castration-resistant prostate cancer (CRPC). Methods: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered FLU or ENZ between May 2014 and December 2017. Patients with FLU failure then received ENZ. The study evaluation included 1) prostate-specific antigen (PSA) best response with initial therapy, 2) PSA progression-free survival with initial therapy (PSA-PFS), 3) PSA best response with ENZ therapy, 4) PSA-PFS of ENZ therapy (PSA-PFS-ENZ), and 5) OS. Results: As first-line CRPC therapy, patients received ENZ (n=29) or FLU (n=26). In the FLU group, 18 patients showed disease progression and then received ENZ. The PSA best response was statistically higher in the ENZ group. PSA-PFS was significantly statistically longer in the ENZ group (hazard ratio (HR) 1.85, 95% confidence interval (CI) 0.53–0.64, p=0.02). However, there was no significant difference in PSA best response with ENZ therapy and PSA-PFS-ENZ between the ENZ and post-FLU ENZ groups (HR 0.80, 95% CI 0.33–1.94, p=0.62) or in OS between the ENZ and post-FLU ENZ groups (HR 1.85, 95% CI 0.53–6.42, p=0.33). Conclusions: AAT with subsequent FLU after CAB therapy with bicalutamide may be suitable for some CRPC patients. (NCT02346578 and NCT02918968).