bluuebunny/crossref_metadata_2025 huggingface dataset:
TAS3681, a novel type of AR antagonist with AR downregulating activity, as a new targeted therapy for aberrant AR-driven prostate cancer.
Authors: Seki Masanao , Minamiguchi Kazuhisa , Kajiwara Daisuke , Mizutani Hiroya , Yoshida Shohei , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu
Published: February 2018

298

Background: Recent reports suggest that AR aberrations are involved in the development of metastatic castration-resistant prostate cancer and in resistance to AR-targeted therapies. These aberrations include point mutations, copy number gain, and alternatively spliced AR forms. TAS3681 has demonstrated activity as a pure AR antagonist against several AR mutations and has shown an antitumor effect in an AR-v7 positive xenograft model. In order to further characterize the properties of TAS3681, we investigated its effects in cell-based AR overexpression/stabilization models and assessed the subcellular localization of FL-AR and AR-v7 in enzalutamide (Enz) -resistant cells. Methods: The Nano-bit assay was performed to analyze dimerization of FL-AR and AR-v7 proteins. Prostate cancer (PCa) cells expressing AR-v7 were treated with TAS3681, and nuclear and cytoplasmic fractions were prepared. Then the levels of FL-AR and AR-v7 protein in each fraction were determined by western blotting. AR-overexpressing PCa cells transfected with a wild-type AR expression vector were treated with TAS3681 in the presence of androgen. AR-stabilized PCa cells were transfected with a Speckle-type POZ protein (SPOP) mutant expression vector and then were treated with TAS3681. Results: AR antagonism by TAS3681 caused dose-dependent inhibition of FL-AR homodimerization (HD) and FL-AR/AR-v7 heterodimer formation in the presence of androgen. TAS3681 had no direct inhibitory effect on HD of AR-v7. However, AR downregulation by TAS3681 reduced nuclear AR-v7 protein in Enz-resistant cells under castration conditions. In AR-overexpressing PCa cells, TAS3681 reduced the AR protein and effectively suppressed both AR transactivation and cell proliferation. In contrast to Enz, TAS3681 also effectively reduced the AR protein in AR-stabilized PCa cells harboring SPOP mutation. Conclusions: TAS3681 suppresses aberrant AR activation, including AR overexpression and expression of constitutively active nuclear localized AR-v7, via downregulation of AR/AR-v7. These findings suggest that TAS3681 has the potential to overcome resistance to current AR-targeted therapies.
Evaluation of ability of low-molecular-weight protein tyrosine phosphatase expression to predict primary hormone therapy efficacy among men with metastatic hormone-naïve prostate cancer.
Authors: Hayashi Yutaro , Miyoshi Yasuhide , Yasui Masato , Ohtaka Mari , Kawahara Takashi , Yokomizo Yumiko , Hayashi Narihiko , Yao Masahiro , Uemura Hiroji
Published: February 2018

316

Background: Protein tyrosine phosphorylation is an important event associated with the processes of cellular metabolism and is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Recent studies showed that low-molecular-weight protein tyrosine phosphatase (LMW-PTP) could be a biomarker for predicting overall survival among men with metastatic hormone-naïve prostate cancer (mHNPC). In this study, we evaluated the value of LMW-PTP expression for predicting primary hormone therapy efficacy among men with mHNPC. Methods: A total of 45 men with mHNPC diagnosed from 2003 to 2009 were enrolled in this retrospective study. All patients had received androgen ablation therapy as first-line treatment. Prostate cancer tissues obtained by needle biopsies before treatment were immunohistochemically stained for LMW-PTP. Correlations between the baseline clinical factors of age, PSA, Gleason scores, T stage, N stage, extent of disease on bone scan (EOD), LMW-PTP expression and primary hormone therapy efficacy (time to castration-resistant prostate cancer [CRPC]) were investigated by multivariate analysis using the Cox proportional hazard model. Continuous variables were classified as dichotomous. Results: Median age and PSA were 70.0 years and 87.8 ng/mL, respectively. Distribution number of Gleason score 8-10/6-7, T4/≤3, N1/0, and EOD 3-4/0-2 were 30 (66.7%)/15 (33.3%), 13 (28.9%)/32 (71.1%), 25 (55.6%)/20 (44.4%), and 7 (15.5%)/38 (84.5%). Median time to CRPC was 40.2 months. Patients with high LMW-PTP expression had significantly shorter time to CRPC than those with low expression (p = 0.005). Multivariate analysis showed that age (≥70 vs < 70, HR 2.5, 95%CI 0.96-6.32, p = 0.060) and LMW-PTP expression (high vs low; HR 3.3, 95%CI 1.2-8.6, p = 0.02) were significant prognostic biomarkers for predicting time to CRPC. Conclusions: LMW-PTP expression could be a potential biomarker for predicting primary hormone therapy efficacy among men with mHNPC.
Loss of RSPO3 as a potential mechanism of greater invasiveness in prostate cancer.
Authors: Mesci Aruz , Huang Xiaoyong , Shin David , Hoey Christianne , Ray Jessica , Liu Stanley K.
Published: February 2018

333

Background: While prostate cancer can often manifest as an indolent disease, locally-advanced or metastatic disease can cause significant morbidity or mortality. Better understanding of molecular mechanisms leading to more aggressive presentations can lead to identification of prognostic or predictive biomarkers, as well as to possible therapeutic targets. Methods: We describe the generation of prostate cancer cell lines that have been selected through a course of hypofractionated radiotherapy. We show that R-spondin 3, a protein implicated previously as a marker of aggressive disease in colorectal and non-small cell lung cancer, is downregulated in these cell lines compared to parental cells. Then, we test the functional consequences of R-spondin 3 downregulation by siRNA-mediated interference using in vitro assays of radiation resistance, proliferation, and invasiveness . Experiments investigating any change in metastatic propensity following R-spondin 3 downregulation are forthcoming. We further investigate signaling pathways that may be implicated in the mechanism of R-spondin 3 action. Lastly, we use the Oncomine Platform to look for any changes in R-spondin 3 levels between normal prostate tissue and prostate adenocarcinoma. Results: Although siRNA-mediated loss of R-spondin 3 does not confer radiation resistance in vitro, it does result in increased invasiveness in Matrigel assays. Paradoxically, R-spondin 3 downregulation results in decreased proliferation. Interference with R-spondin 3 also results in decreased β-catenin, ERK, and Akt signaling, but increased JNK signaling. In support of our in vitro results, R-spondin 3 expression is lower in human prostate adenocarcinoma compared to normal prostate in several gene expression datasets. Conclusions: Our preliminary data suggest that R-spondin 3 loss may lead to increased disease aggression via altered cell signaling. R-spondin 3 downregulation may represent a potential biomarker to identify patients at greater risk of developing locally advanced or metastatic disease, or a potential mechanism to target in future therapeutic efforts.
Will second-line nonsteroidal antiandrogen drugs (NSAA) after the failure of bicalutamide affect the therapeutic efficacy of the sequential abiraterone treatment?
Authors: Zhao Jinge , Sun Guangxi , Zhang Xingming , Shen Pengfei , Chen Junru , Zeng Hao
Published: February 2018

337

Background: Even in the era of novel targeted agents, second-line antiandrogens still have its effect on treating metastatic castration-resistant prostate cancer (mCRPC), especially for patients from undeveloped areas. Yet, it’s still uncertain if the prior use of second-line Non-steroidal antiandrogen Drugs (NSAA) would impact the efficacy of the sequential abiraterone (Abi) therapy. Methods: Eighty-seven patients from 2015 to 2017 were studied. All men were diagnosed with metastatic prostate cancer, and administrated with maximal androgen blockade (surgical or medical castration plus bicalutamide). After the median 32.0-Mo follow up, mCRPC was confirmed in the whole cohort. Abi was then administrated in these patients. Among them, 21 men previously received flutamide (FLU) as second-line NSAA hoping to postpone the initiation of the more expensive treatment. Therapeutic efficacy of Abi was analyzed and compared between those with and without prior second-line NSAA by Kaplan-Meier curves, Log-rank test and Cox regression models. Results: For patients with mCRPC, the prior exposure to FLU had no effect on the sequential treatment of Abi, in terms of either PSA progression-free survival (PSA-PFS, p = 0.967), radiographic progression-free survival (rPFS, P = 0.272), overall survival (OS, p = 0.606), or PSA response ( p = 0.370). However, when bringing ahead the observation point to the time of CRPC, those with second-line FLU showed better survival than those without, in either PSA-PFS (15.1 vs. 12.2-Mo, p = 0.120), rPFS (23.3 vs. 18.2-Mo, p = 0.029) or OS (not reach vs. 30.7-Mo, p = 0.306), though the difference of PSA-PFS and OS were not statistically significant. Conclusions: We firstly address the impact of the secondary NSAA on the efficacy of the sequential Abi treatment in mCRPC patients. Our study supported that, whether the patients received second-line NSAA prior to Abi should not be considered as an impact factor interfering physicians’ decision making of Abi treatment. Also, the switching treatment before Abi seemed to have a potential to extend the survival time of mCRPC patients by prolonging their PFS.
Cardiovascular comorbidities in German prostate cancer patients under androgen deprivation therapy: Results from a retrospective analysis of patient data in urological outpatient centers.
Authors: Eisenhardt Andreas , Vosgerau Sebastian , Gedamke Michael , Schneider Tim
Published: February 2018

339

Background: Androgen deprivation therapy (ADT) with LHRH agonists leuprolide/goserelin compared to GnRH antagonists has been associated with higher risk for cardiovascular (CV) disease in patients with hormone-sensitive prostate carcinoma (hsPCa). Real life data from German PCa-patients with CV disease treated with ADT are lacking. Our study aimed to analyze occurrence of comorbidities with a focus on CV disease in hsPCa-patients treated with ADT. Methods: HsPCa-patients with initiation of ADT (1999–2014) and an ADT duration of a minimum of 12 months were included. Data were collected retrospectively from medical records and documented in a standardized electronic case report form by three German urological outpatient centers. Primary outcomes of interest were frequency of CV disease and hospitalization due to CV events. Descriptive statistics were performed. An ethics committee approval was obtained from Ärztekammer Nordrhein. Results: Data from 753 patients were evaluated. The mean and median age of patients was 75.4 years and 77 years. 556 patients were treated with a LHRH agonist, 59 with an antiandrogen, 132 with a LHRH agonist and an antiandrogen and 6 with a GnRH antagonist. CV disease was the most common comorbidity (241 patients), also when patients with hypertension as the sole CV comorbidity were disregarded (111 patients). 44 patients were hospitalized due to a CV event during or subsequently to an ADT. Of these, 27 patients initiated ADT with pre-existing CV disease. Overall, 21 patients were hospitalized due to myocardial infarction or stroke. Conclusions: Our results show CV disease as the most common comorbidity in German hsPCa-patients, yet our methods could be underestimating CV disease in this interdisciplinary field. Before initiating an ADT, the patient's CV risk profile should therefore be evaluated carefully. The literature suggests that different ADT types are associated with different CV risk, thus the choice of ADT should be considered to reduce the risk of additional CV events. Besides cost savings to health care systems, patients gain quality of life through prevented CV events.
Difference of genomic signatures and opportunities for targeted and immunotherapies in castrate resistant TMPRSS2:ERG fusion positive and TMPRSS2:ERG wild type refractory acinar (CRPC) and neuroendocrine prostate cancer (CRNEPC).
Authors: Bratslavsky Gennady , Fisher Hugh A.G. , Byler Timothy , Jacob Joseph M , Chung Jon , Elvin Julia Andrea , Vergilio Jo-Anne , Ramkissoon Shakti , Suh James , Severson Eric Allan , Daniel Sugganth , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. , Kotula Leszek , Ross Jeffrey S.
Published: February 2018

348

Background: We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with refractory CRPC and CRNEPC. Methods: DNA was extracted from 40 µm of FFPE sections of 2,424CRPC and 143 CRNEPC. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median ages for all 4 groups was similar (Table). TMPRSS2+( TMP+) CRPC features significantly greater TP53 and PTEN GA and TMPRSS2-( TMP-) CRPC featured higher MYC and ATM GA. Differences in BRCA2 and RB1 GA were not significant in the CRPC group. RB1 GA were more frequent in CRNEPC than CRPC. TP53 GA were higher in TMP+ CRNEPC than in TMP+ CRPC whereas GA in PTEN and MYC were similar in comparative groups. GA in AR and ATM were more frequent in CRPC than CRNEPC. The median TMB was higher in CRNEPC than CRPC and higher in TMP- than TMP+ tumors. TMP- CRPC and TMP- CRNEPC had higher TMB levelsthan TMP+ tumors in both groups. MSI-High status was more frequent in the TMP- CRPC and TMP- CRNEPC groups. Conclusions: For CRPC but not CRNEPC, the frequency of TMP+CRPC cases appears lower in advanced vsearly stage disease (TCGA data). CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMP+ and TMP- CRPC and CRNEC. Thus, when CRPC and CRNEPC areevaluated as to their TMPRSS2:ERG fusion status, significant genomic differences emerge which may impact therapy selection.[Table: see text]
Effect of bypass kinase pathways on acquired CDK4/6 inhibitor resistance.
Authors: De Leeuw Renee , McNair Christopher , Schiewer Matthew Joseph , Neupane Neermala Poudel , Augello Michael , Li Zhen , Cheng Larry , Yoshida Akihiro , Diehl Alan , Hazard Starr , Courtney Sean , Hardiman Gary , Hussain Maha , Drake Justin , Kelly William Kevin , Knudsen Karen E.
Published: February 2018

379

Background: Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors have shown clinical benefit in treatment of solid tumor types, including breast cancer. However, resistance is common, and the underpinning mechanisms of action are not well understood. Given the dependence of CDK4/6 inhibitors on retinoblastoma tumor suppressor (RB) function for activity, this class of agents may be particularly effective in tumor types for which RB loss is infrequent or occurs late in tumor progression. Methods: Here, models of acquired palbociclib resistance were generated in early stage, RB positive cancers, wherein it was shown acquired palbociclib resistance resulted in cross-resistance to other CDK4/6 inhibitors under clinical testing. Results: Cells showing acquired resistance exhibited aggressive in vitro and in vivo phenotypes without genetic loss of RB or RB pathway members, including enhanced proliferative capacity, migratory potential, and characteristics of epithelial to mesenchymal transition. Further analyses through integration of RNA sequencing and phospho-proteomics identified activation of the MAPK signaling pathway as a mediator of CDK4/6 inhibitor resistance, capable of bypassing CDK4/6 activity. However, this altered kinase dependence resulted in sensitization to MEK inhibitors, suggestive of new clinical opportunities in CDK4/6 resistant tumors. Conclusions: In sum, the studies herein not only identify activation of the MAPK pathway as capable of bypassing the CDK4/6 requirement and promoting aggressive tumor characteristics, but nominate MEK inhibitors as potential mechanisms to treat or prevent CDK4/6 inhibitor resistance.
Evaluating the impact of African American ancestry among men with localized prostate cancer treated with radical prostatectomy.
Authors: Canter Daniel , Reid Julia E. , Latsis Maria , Variano Margaret , Halat Shams , Gurtner Kristen E. , Brawer Michael K. , Stone Steven , Bardot Stephen
Published: February 2018

41

Background: Prostate cancer (PC) is the most common male malignancy. Prior data has suggested that African American (AA) men present with more aggressive disease relative to men of other ancestries. Here, we examined the effects of ancestry on clinical and molecular measures of disease aggressiveness as well as pathologic outcomes in men treated with radical prostatectomy (RP) for localized PC. Methods: Data was collected from patients undergoing RP at the Ochsner Clinic from 2006 to 2011. Formalin−fixed paraffin embedded biopsy tissue was analyzed for the RNA expression of 31 cell cycle progression (CCP) genes and 15 housekeeping genes to obtain a CCP score (a validated molecular measure of PC aggressiveness). Cancer of the Prostate Risk Assessment (CAPRA) scores were also determined based on clinicopathologic features at the time of diagnosis. Clinical (Gleason score, tumor stage, CAPRA score) and molecular (CCP score) measures of disease aggressiveness were compared based on ancestry (AA versus non−AA). Cox proportional hazards models were used to test association of ancestry to biochemical recurrence (BCR) and progression to metastatic disease. Fisher’s exact and Wilcoxon rank sum tests were used to compare ancestries. Results: A total of 384 patients were treated with RP, including 133 (34.8%) AA men. At the time of diagnosis, the median age was 62 years (interquartile range (IQR) 56, 66) and PSA was 5.4 ng/mL (IQR 4.2, 7.6). When compared by ancestry, there were no significant differences in biopsy Gleason score (p = 0.26), clinical stage (p = 0.27), CAPRA score (p = 0.58), or CCP score (p = 0.87). In addition, there was no significant difference in the risk of BCR between ancestries (p = 0.55). Only non−AA men progressed to metastatic disease within the ten years of follow−up. Conclusions: Contrary to prior reports, these data appears to indicate that men of AA ancestry do not necessarily present with or develop a more biologically aggressive form of PC. Although these data represents only one institution’s experience, it contains a highly robust AA population compared to prior reports. Further research is required to account for the discrepancy in the previously published literature.
Perceptions about cancer clinical trials among prostate cancer survivors.
Authors: Buzaglo Joanne S. , Miller Melissa F , McManus Shauna , Johnson Jamese , Zaleta Alexandra Katherine
Published: February 2018

42

Background: Recruitment into cancer clinical trials (CCTs) remains challenging despite efforts to enhance patient understanding of and access to CCTs. We examined perceptions of CCTs among prostate cancer (PC) survivors. Methods: 86 PC survivors enrolled in Cancer Support Community’s Cancer Experience Registry online research platform, provided demographic and disease history, and rated their agreement (0 = strongly disagree; 4 = strongly agree) with 8 CCT statements. We examined bivariate associations between CCT counseling and individual factors via Spearman’s rank correlation and chi-square tests. Results: Participants were 95% White; mean (SD) age = 65 (7) years; time since diagnosis 4 (4) years. 24% had surgery, 34% underwent radiation, 20% both; 31% currently and 18% previously received hormone therapy. 32% were diagnosed 5+ years ago; 22% reported recurrence, 31% metastatic disease. 33% reported that their health care team spoke to them about participating in a CCT, with a non-significant trend for lower prevalence if all or part of care was received at a community hospital/cancer center (24%) vs. at an academic or comprehensive cancer center or private oncology practice (47%; χ2= 3.03, p = .082). 25% did not receive information about CCTs from the health care team prior to making a treatment decision. 21% reported there was a CCT available to them; 35% considered a CCT for treatment; 11% participated in a CCT. Regarding beliefs about CCTs (% agree or strongly agree): 64% felt uncomfortable with treatment random assignment; 52% feared receiving a placebo; 40% feared treatment side effects; 23% believed health insurance would not cover a CCT; 16% believed no clinical trials are available in their community; 16% felt mistrust and fear of being used as a “guinea pig” for research; 11% had concern about logistical barriers, e.g., transportation; 6% did not understand what CCTs are. Conclusions: Many prostate cancer survivors are uncomfortable with random assignment to treatment in a CCT and fear receiving a potentially ineffective placebo. Our findings underscore the need for comprehensive treatment decision counseling and patient education via health care providers and patient advocacy organizations.
Differences in survival among non-urothelial bladder cancers: Analyses of SEER 1988-2008.
Authors: Aragon-Ching Jeanny B. , Henson Donald
Published: February 2018

425

Background: Non-urothelial cancers of the urinary bladder are rare, and typically < 5% incidence. They are generally considered more aggressive without clear guidelines for treatment. Methods: Incident cases of non-urothelial bladder cancers that included squamous cell carcinoma, adenocarcinoma, small cell carcinoma and sarcomas were identified in the SEER (Surveillance, Epidemiology, and End Results) Database. Demographic information, pathologic characteristics and 5-year disease-specific survival were calculated and compared using multivariate Cox regression and Kaplan-Meier curves. Results: A total of 235,537 incident cases of bladder carcinomas were identified in the years 1998 – 2008, of which 3096 cases were squamous cell carcinoma, 1175 were neuroendocrine carcinoma where small cell carcinomas made up the majority with 859 patients, 671 was comprised of adenocarcinomas, representing 0.28%, and sarcomas were 88 cases, making up 0.03% of all cases combined. The majority of patients were White (90%) although more African-Americans (15%) were seen with adenocarcinoma. The table shows the number of cases and 5-year survival according to stage. Median survival was greatest for adenocarcinoma at 179 months with a 5–year survival rate of 58%, followed by sarcomas with a median survival of 23 months, with a 5-year survival rate of 47%, followed by squamous cell carcinomas with a median survival time of 15 months and a 5-yr survival rate of 37% and the least favorable survival was for small cell carcinoma, 17 months median time, with a 5-yr survival rate of 31%. Conclusions: Non-urothelial cancers have a uniformly less favorable survival compared to urothelial cancers, highlighting the need for improved therapeutic strategies in these cohorts of patients. [Table: see text]
A genomic classifier for identifying a neuroendocrine-like bladder cancer subtype.
Authors: Wright Jonathan L. , Dall'era Marc , Bivalacqua Trinity , Seiler Roland , Liu Yang , Gibb Ewan , Wang Natalie Qiqi , Erho Nicholas , Alshalalfa Mohammed , Davicioni Elai , Efstathiou Jason A. , Douglas James G. , Boormans Joost L , Van Der Heijden Michiel Simon , Lotan Yair , Black Peter C.
Published: February 2018

440

Background: Neuroendocrine (NE) carcinoma is a rare and aggressive variant of muscle invasive bladder cancer (MIBC). Molecular subtyping studies found 5-15% of bladder tumors had transcriptome profiles consistent with NE carcinoma but lacked NE histology (Robertson 2017, Sjödahl 2017). Identifying NE variants may have prognostic implications and modify treatment recommendations. In this study, we present a robust genomic classifier trained to identify NE carcinoma. Methods: Transcriptome-wide expression profiles were generated for 576 MIBC patients collected from seven institutions. Model training included profiles generated from TURBT and RC specimens from 320 patients prior to treatment with NAC or chemo-radiation. The validation cohort consisted of 256 RC specimens (no prior systemic treatment). Using 10 MIBC-related gene sets, a GLMNET model was built to predict patients with a NE carcinoma expression profile. Uni- and multi-variable survival analyses were used to characterize outcomes of the predicted NE tumors. Results: In the training set, hierarchical clustering using a panel of 54 genes showed a cluster of 17 patients (5.3%) with a NE carcinoma expression profile. These patients had significantly worse 1 year progression free survival (65% vs 82% for NE vs overall; p = 0.046). In the validation set, 7 tumors were classified (2.7%) as NE with 4 (57%) patients dying from the disease at 1 year after RC. Within 3 years of RC, 100% (7/7) of patients with NE tumors had died. After adjusting for various clinical and pathological factors, patients with predicted NE tumors had a 6.40 increased risk of all-cause mortality (p = 0.001). Conclusions: We have developed a gene expression signature that predicts a particularly high-risk group that may need treatment intensification, alternative chemotherapy or clinical trials. Validation will be required to assess the potential clinical utility of this NE carcinoma classifier.
Outcomes in bone predominant (BP) urothelial carcinoma (UC).
Authors: Nelson Ariel Ann , Opneja Aman , Nezami Behtash Ghazi , Fu Pingfu , Dawsey Scott , Wright Matthew David , Eitman Cheryl , Kim Simon P. , Cooney Matthew M. , Grivas Petros , MacLennan Gregory , Hoimes Christopher J.
Published: February 2018

441

Background: The clinical phenotype of BP UC includes those patients (pts) with at least as many or more bone lesions than non-bone lesions. UC molecular subtypes that may correlate with prognosis have been defined. Better understanding of the clinical BP phenotype, which might correspond to the p53-like molecular subtype, is needed. Methods: We searched our biorepository to identify pts with metastatic UC. Electronic records of identified pts were reviewed and those with accessible records who received treatment at our institution were selected. Demographic, pathologic, treatment, response, progression-free and overall survival (PFS, OS) data were recorded. Imaging was reviewed to identify non-bone predominant (NBP) or BP disease based on imaging criteria. Results: 23 NBP and 9 BP pts, (59% men) were identified. Of BP pts, 44% had bone metastatic disease present at diagnosis (dx) vs. none of the NBP. Only 8% of NBP pts developed bone metastases during their course. The median number of lines of therapy in the metastatic setting was 2 for each cohort. All BP pts received platinum therapy vs. 74% of NBP. 11% of BP pts were treated with checkpoint immunotherapy (CPI) vs. 34% of NBP. 70% of BP pts received palliative radiation (all to bone) vs. 4% of the NBP cohort. The median OS from date of UC dx was 27.5 months. There was a significant difference in OS between BP and NBP cohorts from UC dx date (16.9 vs. 30.6 months, p < 0.0001) as well as from muscle invasive bladder cancer (MIBC) dx date (15.2 vs. 22.8 months, p = 0.019), respectively. OS from initiation of 1st line treatment in the metastatic setting for the entire cohort was 12.5 months and was not significantly different between the cohorts (p = 0.633). PFS from dx of MIBC to date of 1st progression or death was not significant (p = 0.08) with median PFS of 8.4 vs. 13.6 months for BP vs. NBP cohorts, respectively. Conclusions: BP pts require more frequent palliative radiation and have shorter OS measured from time of dx, but not significantly different when measured from the initiation of 1st line treatment, compared to NBP pts. Further analysis with a larger cohort is ongoing for validation. Molecular analysis on pathological specimens is planned.
Genomic analysis of same-patient metachronous upper-tract and bladder urothelial carcinoma.
Authors: Petros Firas G. , Qi Yuan , Choi Woonyoung , Li Roger , Su Xiaoping , Guo Charles , Dinney Colin P.N. , McConkey David , Matin Surena F.
Published: February 2018

449

Background: Despite similarities between upper-tract (UTUC) and bladder urothelial carcinoma (BUC), distinctive clinicopathologic and genomic differences are being described. We further investigate the genomic landscape of these two interrelated malignancies in same-patient metachronous (m) UTUC and BUC using next generation sequencing (NGS). Methods: Following institutional board approval, UTUC and BUC samples were obtained from patients via surgical resection or endoscopic biopsy. Tumors were macrodissected from unstained formalin-fixed, paraffin-embedded slides. Study inclusion was untreated patient samples of UTUC and/or BUC divided into 4 groups: 1) UTUC with mBUC, 2) BUC with mUTUC, 3) Synchronous BUC and UTUC, 4) UTUC with no bladder history. Exclusions were for inadequate clinical data or histological tumor purity < 30%. Whole transcriptome RNA sequencing was performed and analyzed using BASE47 panel (includes basal, luminal, p53-like and cell cycle genes). Results: A total of 95 (UTUC = 61, BUC = 34) samples from 40 patients were analyzed. UTUC samples were 33 primary ureter and 28 renal pelvis cancer. Median age was 72 years, 68% male, 76% Caucasian, 60% former smokers. Groups samples were: 1) UTUC (n = 19), mBUC (n = 12); 2) BUC (n = 12), mUTUC (n = 9); 3) Synchronous UTUC/BUC (n = 10); and 4) UTUC (n = 23). Unsupervised hierarchical clustering segregated tumors into basal-like and luminal subtypes, with 87.5% of metachronous tumors displaying conserved subtype membership. For the groups with UTUC and BUC, only 3/24 (12.5%) clusters (2 patients in Group 2, and 1 patient in Group 3) had unmatched basal/luminal subtypes. Conclusions: NGS analysis of same-patient metachronous UTUC and BUC shows that the majority stay within the same molecular subtype regardless of chronologic development or anatomic origin. Additional studies are necessary to explore differences that may occur within the subtypes, the role of methylation, and clinical correlates.
Low testosterone at first PSA failure and assessment of the risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials.
Authors: Atkins Katelyn Mae , Chen Ming-Hui , Wu Jing , Renshaw Andrew A. , Loffredo Marian , Kantoff Philip W. , Small Eric Jay , D'Amico Anthony Victor
Published: February 2018

45

Background: Low testosterone at prostate cancer diagnosis has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at first PSA failure following definitive therapy and prior to the documentation of metastatic disease has not been elucidated and was studied. Methods: Between 1995 to 2001, 58 men with unfavorable-risk prostate cancer treated on clinical trials with radiation and androgen deprivation therapy (ADT) had testosterone levels at PSA failure available. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone at PSA failure was associated with the risk of prostate cancer-specific, other-cause and all-cause mortality (PCSM, OCM, ACM) adjusting for age, salvage ADT use and known prostate cancer prognostic factors. Results: After a median follow-up of 6.68 years following first PSA failure, 31 men (53.4%) died; 10 from prostate cancer (32.3%), of which 8/11 (72.7%) versus 2/47 (4.3%) occurred in men with low versus normal testosterone at PSA failure, respectively. A significant increase in the risk of ACM (adjusted hazard ratio, AHR [2.54, 95% CI 1.04-6.21]; P = 0.04) and PCSM (AHR [13.71, 95% CI 2.4-78.16]; P = 0.003), with a reciprocal trend toward decreased risk of OCM (AHR [0.18, 95% CI 0.02-1.55]; P = 0.12) was observed in men with low versus normal testosterone at first PSA failure. Conclusions: Low testosterone at first PSA failure confers a very poor prognosis. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic prostate cancer and possibly in men with localized high-risk prostate cancer provides rationale to support their use with ADT in men with low testosterone at PSA failure in the setting of a phase II trial.
Long-term results of organ preservation rate and progression risk in high-risk non-muscle-invasive bladder cancer (NMIBC) patients treated with radiofrequency-induced thermochemotherapy effect (RITE) with the Synergo system.
Authors: Kilb Jill-Isabel , Hauptmann Arne , Wagenlehner Florian , Luedecke Gerson
Published: February 2018

456

Background: High risk NMIBC is a dangerous BC with a challenging treatment by BCG or early cystectomy to cure. The first has bad treatment tolerance and a remission of about 35%, whereas the last offer a curing perspective of 84% with extremely bad living conditions. RITE checked prospectively the therapy in respect to organ preservation, curing rate and risk of progression over 10 years in a single institution experience. Methods: All patients were EORTC high risk NMIBC. Treatment with induction phase: 8 treatments weekly with 2x40 mg Mitomycin C, 42°C intravesically induced by RITE. Followed by a re-resection of the bladder at week 11 to ensure complete remission and maintenance with treatments every 6 weeks with 2x20 mg Mitomycin C for 6 times. Cystoscopy controls were performed first 2 years every 3 month and following in 6 month until now. Study started in 2006 ongoing until today. Results: We enrolled 67 patients (4 female, 63 male), 65.7% Cis positive rate. 85% of the patients were treated alternatively to BCG with primary RITE whereas 15% were BCG failure patients treated alternatively to indicated cystectomy. Tumor persistence at week 11 after induction therapy proven by TURB was (10/67) 14.9% resulting in early cystectomy (4/10). Mean recurrence free time 3.5 years. In case of recurrence 10.4% progressed to MIBC including 6% metastatic tumors, high risk NMIBC was observed in 6% resulting in cystectomy and low risk NMIBC recurrence was 1.5% with organ preservation. BC death rate was 1 out of 67. Incomplete treatments induced by SAE of RITE was 9%. Bladder preservation rate was 80.6% with a long-lasting effectiveness ( > 5 years) of 14/26 (53.8%). Conclusions: The RITE method is in short- and long-term manner a powerful procedure to cure and maintain a recurrence free BC status in high risk NMIBC with a very low risk for cystectomy and a minimal risk for systemic progression resulting in BC death. The organ preservation rate was achieved in 80.6% lasting for up to 11 years longest. RITE is an alternative to BCG and preferable to early cystectomy in high risk NMIBC.
Association of somatic mutational burden with depression and anxiety in patients with metastatic urothelial cancer (mUC).
Authors: Bergerot Cristiane Decat , Clark Karen L. , Bergerot Paulo Gustavo , Ashing Kimlin Tan , Hahn Andrew W , Obenchain Richard , Dizman Nazli , Hsu Joann , Philip Errol James , Loscalzo Matthew J. , Pal Sumanta K.
Published: February 2018

471

Background: Depression and anxiety are highly prevalent in patients (pts) with genitourinary tumors, including UC (Yang et al PLoS ONE 2016). Given that mUC has a high rate of somatic genomic alterations (GAs), we sought to determine if tumor mutational burden (TMB) or specific alterations were related to the incidence of these psychiatric disorders. Methods: From a single institution, we identified consecutive pts with mUC who had comprehensive genomic profiling done in the course of routine clinical care. In a CLIA-certified laboratory, DNA was extracted from 40 microns of FFPE sections. Hybridization-captured, adaptor ligation based libraries were used to a mean coverage depth of 718X for up to 315 cancer-related genes plus introns from up to 28 genes frequently rearranged in cancer. TMB was estimated based on the cumulative number of GAs. ICD-9 diagnoses corresponding to adjustment disorder (309.28), anxiety (300) and depression (311) were derived from detailed chart review, including review of established diagnoses and medication history. Results: A total of 43 pts (74.4% M / 25.6% F) were assessed with a median age of 65.5 (range, 49-81). Formal diagnoses of adjustment disorder, anxiety and depression were noted in 16.3%, 9.3% and 7.0% pts, respectively. An average of 6.3 GAs/pt (range, 0-14) were observed over the entire cohort. The rate of GA was higher in pts with anxiety vs adjustment disorder or depression (8.5 vs 6.8 or 4.0, P=0.01). No significant difference was observed in adjustment disorder or depression based on the frequency of GAs. GAs in BAP1, PIK3CB, NOTCH1, ALK, CDH1 and FANCC were noted to be associated with higher rates of anxiety (P=0.02). Similarly, GAs in FGFR1 was noted to be associated with higher rates of depression (P=0.002) and in CHEK2 in depression and adjustment disorder (P=0.03). Conclusions: Our study represents the first pyschogenomic analysis of pts with mUC. While higher TMB has been associated with favorable prognosis (Isharwal et al EU Focus 2017), we paradoxically found this to be related to higher rates of anxiety. Our findings suggest that genomically selected subsets of patients may be prime candidates for early psychosocial screening and intervention.
Size-focality-invasion in upper tract urothelial carcinoma (SFI-UTUC): A novel imaging-based score to predict survival outcomes.
Authors: Hamilton Zachary , Haifler Miki , Krabbe Laura-Maria , Ryan Stephen , Reddy Madhumitha , Berquist Sean , Clinton Timothy N , Bloch Aaron , Field Charles , Patel Sunil , Cotta Brittney , Margulis Vitaly , Uzzo Robert , Derweesh Ithaar
Published: February 2018

475

Background: Upper tract urothelial cell carcinoma (UTUC) is an uncommon malignancy with disparate outcomes. We developed a novel morphometric scoring system for prediction of oncologic and survival outcomes before nephroureterectomy (NU). Methods: Retrospective, multicenter analysis of UTUC patients who underwent NU after negative metastatic workup. Preoperative CT-urography was used to evaluate scores, based on 3 factors (Tumor Size, Focality, Invasion of architecture) with a score of 1-3 based on degree of each factor (total score 3-9). Primary outcome was overall survival (OS). Secondary outcomes were recurrence and recurrence free survival (RFS). Multivariable (MVA) and Kaplan-Meier (KMA) analyses were utilized. Results: We analyzed 244 patients (mean age 70.9, mean follow up 29.5 months). 61% with SFI-UTUC score 3-6 and 39% were score 7-9. No difference in age, gender, comorbid conditions, surgical approach, or complications between groups. Score 7-9 had a higher rate of pN+ disease (24.2% vs. 8.1%, p=0.002) but similar nuclear grade. All-cause mortality was higher for score 7-9 (47.4% vs. 28.9%, p=0.004). On MVA for all-cause mortality, age (OR 1.1), recurrence (OR 4.4) and score 7-9 (OR 2.0) were significant (p<0.05). KMA for OS demonstrated 5 year OS of 57.0% for score 3-6 and 34.1% for score 7-9 (p<0.01). KMA for RFS was significant for renal UTUC location with 5 year RFS of 72.3% for score 3-6 and 54.2% for score 7-9, (p<0.01). Conclusions: A novel scoring system for UTUC preoperative imaging may predict OS for tumors in renal and ureteral locations, as well as RFS for renal locations. Renal location. [Table: see text]
Transcriptome-wide analysis of alternative splicing events in bladder cancer: Novel biomarkers discovery for early diagnosis.
Authors: Jeldres Claudio , Bouchard Sabrina , Carmel Michel , Richard Patrick O , Sabbagh Robert , Bisaillon Martin
Published: February 2018

483

Background: Cystoscopy, an invasive, painful and expensive method, is currently the main clinical tool for new diagnosis and disease recurrence detection of bladder cancer (BCa). The need for new biomarkers discovery that is costless, sensitive and specific is urgent. This project aims to study and compare alternative splicing events (ASE) in BCa tissues and normal bladder tissues and ultimately, identify specific spliced events coding for proteins detectable in urine by liquid chromatography–mass spectrometry. Methods: In this study, alterations to the global RNA splicing landscape of cellular genes were investigated in a large-scale screen from 408 BCa tissues and 19 normal tissues provided by The Cancer Genome Atlas (TCGA). Three statistical thresholds were used to determine substantial modifications. All events showing a p-value<0.05 and a level of expression ≥ 50 transcripts per million; -10 ≥ Δ percent splice index ≤10; and a q-value<0.05 were conserved. Next, mRNA expression levels between cancer and normal tissues were compared for all splicing factors and the spliceosome to determine the impact of gene dysregulation on alternative splicing events. Using multiple bioinformatic platforms such as EASANA, MultAlin, ExPasy, NLS Mapper and Pfam, splicing events responsible for significant protein structural changes between cancer and healthy tissue were selected. From this sample chosen, ASEs coding for proteins that could be detected in urine were conserved. Results: Our study identifies modifications in the alternative splicing patterns of 107 transcripts encoded by 97 genes. STRING analysis revealed that many of the gene products interact either directly or indirectly with each other (enrichment p-value = 1x10-10). 61 ASEs are causing important protein changes from which 27 can be detected in urine. Finally, 16 ASEs coding for easily recognizable peptide sequences in urine represented significant targets for potential BCa biomarkers. Conclusions: The TCGA data show the relevance to investigate alternative splicing events in bladder cancer. 16 significant events were detectable in urine and may potentially discriminate between presence or absence of bladder cancer.
Effectiveness of adjuvant radiotherapy after radical cystectomy for locally advanced bladder cancer.
Authors: Fischer-Valuck Benjamin Walker , Michalski Jeff M. , Christodouleas John Paul , Kim Eric , DeWees Todd A. , Andriole Gerald L. , Arora Vivek , Carmona Ruben , Figenshau Robert S. , Grubb Robert L. , Guzzo Thomas J. , Knoche Eric Marshall , Malkowicz S. Bruce , Mamtani Ronac , Pachynski Russell Kent , Picus Joel , Venigalla Sriram , Roth Bruce J. , Gay Hiram Alberto , Baumann Brian Christopher
Published: February 2018

484

Background: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemo and is associated with high morbidity/mortality. Adjuvant radiotherapy (adjRT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of adjRT would improve OS in LABC in a large multi-institutional cohort. Methods: We identified ≥pT3 pN0-3, M0 LABC pts in the NCDB diagnosed in 2004 – 2013 who underwent RC +/- adjRT. AdjRT cohort included pts treated to ≥40Gy to the pelvis within 1 yr of diagnosis. Propensity matching was performed to match RC pts who received adjRT vs. those who did not. OS was calculated using Kaplan-Meier. Factors significant on univariate analysis were entered into Cox proportional hazards regression model to identify predictors of OS. Results: 15,246 RC pts were identified, with 450 (3.0%) receiving adjRT. Median OS was 23.0 mo (95% CI, 22.4-23.6) for RC vs. 19.7 mo (95% CI, 17.7-21.7) for adjRT [Log-rank P = 0.002; Wilcoxon P = 0.862]. Propensity score matching on demographic, clinical, & treatment variables yielded 742 pts (371 in each group). In the matched cohort, OS was 17.1 mo [95%CI, 14.5 - 19.6] for RC vs. 20.1 mo [95% CI, 17.8– 22.5] for adjRT [Log-rank P = 0.044]. On MVA in the matched cohort, factors predictive of OS were sex, pT stage, pN+ status, surgical margin status, number of nodes removed, adjRT, & chemo (p < 0.01 for all). On MVA of subgroups, adjRT was associated with significantly improved OS in pts with positive margins [HR 0.55 (95% CI, 0.43 – 0.71), P < 0.001], pN+ disease [HR 0.62 (95% CI, 0.49 – 0.79), P < 0.001], & pT4 disease [HR 0.68 (95% CI, 0.55 – 0.85), P = 0.001]. In MVA of pts with urothelial carcinoma (N = 578), adjRT remained associated with improved OS in pts with positive margins [HR 0.57 (95% CI, 0.43 – 0.76), P < 0.001], pN+ disease [HR 0.65 (95% CI, 0.50 – 0.86), P = 0.002], & pT4 disease [HR 0.68 (95% CI, 0.54 – 0.85), P = 0.001]. Conclusions: In this observational study, adjRT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of adjRT in selected pts with LABC, regardless of histology. Prospective trials of adjRT are warranted.
Association between circulating tumor DNA (ctDNA) detection and radiographic tumor burden (rTB) in advanced bladder and upper tract (UT) cancer patients.
Authors: Maia Manuel C. , Almeida Lorena , Dizman Nazli , Bergerot Paulo Gustavo , Lanman Richard B. , Banks Kimberly , Vogelzang Nicholas J.
Published: February 2018

485

Background: In a series of 217 patients (pts) with advanced bladder cancer, ctDNA was detected in 89% (Grivas P et al ASCO GU 2017). We hav e previously reported an association between ctDNA detection and rTB in metastatic renal cell carcinoma (Maia et al ASCO 2017); it is unknown whether the same correlation exists in advanced bladder/UT cancers. Methods: Data was obtained from pts with advanced bladder or UT cancer from a single institution. Pts received ctDNA profiling as part of routine clinical care using a CLIA-certified platform assessing a panel of up to 73 genes. Clinicopathologic and radiographic data was obtained, including histology, Bajorin risk criteria and sum of longest diameter (SLD - a surrogate for rTB) from most proximal scan to ctDNA test. Results: A total of 36 pts (27:9 M:F) with a median age of 68 (range, 43-99) were assessed, with a total of 59 ctDNA tests. 3 tests were excluded due to lack of associated radiographic data. Primary site was bladder and UT for 26 and 10 pts, respectively. In total, 31 pts had metastatic disease and 5 pts locally advanced disease. Metastatic pts were characterized as having good and intermediate Bajorin risk in 15 and 16 cases, respectively (no poor risk pts were identified). Most proximal therapy to ctDNA test was cytotoxic chemotherapy in 19 cases, immunotherapy in 10 cases and a combination in 2 cases, while 5 pts did not receive any systemic treatment. Median number of genomic alterations (GAs) was 3 (range, 0-18). A significant association between ctDNA detection and SLD was found (p = 0.029). Furthermore, a correlation between cumulative mutant allele fraction and SLD was detected (R2 = 0.39; p = 0.003). The most frequent GAs in the cohort were in TP53, MET and KRAS, occurring in 10%, 5.6% and 5.6% of the cases, respectively. Serially collected ctDNA assessments and corresponding rTB data will be presented at the meeting. Conclusions: Detection of ctDNA was significantly associated with rTB, and a positive correlation between rTB and cumulative mutant allele fraction was also observed. Given the modest sample size, we are confirming these findings in larger validation series.