bluuebunny/crossref_metadata_2025 huggingface dataset:
Serial ctDNA tracking reveals clonal evolution dynamics in advanced urothelial carcinoma (UC).
Authors: Villamar Dario Martin , Price Kristin Sedgwick , Nagy Rebecca , Tagawa Scott T. , Molina Ana M. , Nanus David M. , Grivas Petros , Sonpavde Guru , Vogelzang Nicholas J. , Faltas Bishoy Morris
Published: March 2019

401

Background: UC is characterized by extensive genomic heterogeneity. Access to genomic DNA from all metastatic lesions is infeasible. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) may recapitulate heterogeneity and offer an opportunity for continuous tracking of tumor evolution. Methods: We analyzed a cohort of advanced UC patients with serial (2 time points) ctDNA NGS using Guardant360. Restaging scans were examined to determine the relationship between ctDNA dynamics and radiologic progression. We performed whole exome sequencing (WES) of a subset of the corresponding tumors to define patterns of genomic heterogeneity. Results: NGS was performed on 214 individual ctDNA samples from 78 advanced UC patients (61 M, 17 F). A minimum of 2 serial ctDNA tests per patient (range 2-8) were collected over an average 21.5 (2-108) weeks between samples. Molecular alterations (MAs) were identified in 188 (88%) of samples with a mean of 4.3 alterations (1-31) per sample. 184 (85%) samples harbored SNVs, 30 (14%) harbored indels and 36 CNVs (17%). Most commonly mutated genes were TP53 (18%), ARID1A, NF1 (4.5% each ), EGFR (3.5%), FGFR3 (3.4%), ERBB2 and PIK3CA (3.4% each ). The most frequently amplified genes were ERRB2 and CCNE1. Serial analysis of maximum variant allele frequency (mVAF) revealed a mean 7.5-fold change between 1st and 2nd and a 6-fold change between 2nd and 3rd ctDNA samples. Interestingly, the mean rate of mVAF fold change/week was stable between serial testing time points (0.35, 0.32 p = 0.7). We observed that patients with higher initial mVAF ( > 3%) experienced a significantly larger mean fold decrease compared to patients with initial mVAF below this threshold (p = 0.008). In patients with available restaging scans timed with ctDNA testing, all patients with radiologic progression exhibited increasing mVAF (mean: 8-fold). Interestingly, ctDNA identified several clinically-significant somatic MAs not present on matching tumor WES including PIK3CA (T727R, M1043I), TP53 (Q331*, P190L), RB1 (R556*, Q257*), APC (D2527H), and BRCA2 (P2804S).WES is ongoing in more patients. Conclusions: ctDNA sequencing enables dynamic monitoring of therapy-driven clonal evolution patterns of advanced UC.
Comparative analyses of trends and survival in patients with urothelial versus nonurothelial bladder carcinoma: National Cancer Database (NCDB) analysis.
Authors: Aragon-Ching Jeanny B. , Trump Donald L. , Wang Hongkun
Published: March 2019

402

Background: Bladder cancer is estimated to occur in 81,190 patients in 2018 with estimated death in 17,240. Urothelial cancers make up the majority of cancers but non-urothelial cancers are known to have more aggressive phenotype with worse survival. We have demonstrated previously that non-urothelial histologic subtypes have worse survival outcomes compared to urothelial cancers in a population-based analysis (Aragon-Ching J et al.; J Clin Oncol 36, 2018 (suppl 6S: abstr 425). Methods: The primary objective of this review is to gather data on trends and differences between urothelial versus non-urothelial histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and compare the demographics, disease characteristics (incidence of metastases, stage presentation, etc), and survival according to the NCDB. Results: Data from diagnosis in year 2004 – 2013 were extracted from the NCDB. A total of 76,858 and 5560 patients were included for urothelial and non-urothelial, respectively. More men were diagnosed with urothelial carcinoma (75%) and non-urothelial carcinoma (61%) than women. The median age was 71 years and 69 years of age, respectively for urothelial and non-urothelial. Majority were Caucasian at 91% and 86%, respectively though there seemed to be more African-Americans in the non-urothelial (11%) compared to 6% in the urothelial cohorts. More patients were diagnosed with higher stages of III and IV in the non-urothelial group (62%) compared to 36% in the urothelial group, although the sites of metastases in the brain, bone or liver were fairly equivalent for both urothelial and non-urothelial cohorts. Median survival time from diagnosis was better in the urothelial compared to non-urothelial arms [69.91 (69.39 – 70.54) vs 64.53 (61.5 – 67.45 months), p-value < 0.001]. Conclusions: Non-urothelial cancers have distinct demographics different from non-urothelial cancers. Patients often present at a higher stage and survival appears to fare worse than urothelial cancers. Further studies to refine treatment options to optimize treatment outcomes are an area of increased unmet need.
Carcinomas of the renal pelvis, ureters, and urinary bladder arise by similar carcinogenic pathways: A pathoepidemiological analysis.
Authors: Nizam Amanda , Henson Donald , Aragon-Ching Jeanny B.
Published: March 2019

403

Background: Urothelial carcinomas comprise the most common malignant tumors in the urinary tract. Kidney epithelial cancers, on the other hand, have a different pathoepidemiologic incidence and characteristics. We report a population-based analysis of the histopathology of upper and lower urinary tract cancers as an approach to exploring the relationship of tumors that share similar morphologic phenotypes. Our results depend on observations made 65 years ago that age of diagnosis and age specific incidence rates generated straight lines when plotted as logarithms. Methods: Data from 2000 through 2014 from the SEER Program were used to calculate incidence rates of renal, renal pelvis, ureter and urinary bladder cancers. Graphic plots of the epidemiologic patterns were analyzed relating to incidence and age-specific rates of these upper and lower tract carcinomas. The graphic analysis included evaluation of age frequency density plots and double logarithmic plots (log-log) of age-specific incidence rates and age at diagnosis. Results: Cancers of the kidney are initially more frequent than cancers of the urinary bladder, but after age 60, cancers of the bladder become more common with age-specific rates rapidly rising in all age groups. The age frequency density plot for renal cancers peaks earlier, around age 60, indicating a potentially different tumorigenic process. While the log-log plots reveal near parallel proportional rate patterns for cancers of the renal pelvis, ureters, and urinary bladder, while the rate for the cancer of the kidney was not parallel on inspection. Similar slopes indicate that cancer incidence is increasing at near similar rates regardless of the incidence of each cancer. Thus, the percentage change per unit time for cancers of the renal pelvis, ureters, and bladder is comparable. Conclusions: Tumors that arise from the renal pelvis, ureters, and urinary bladder are pathogenically related and share a common carcinogenic field based on pathoepidemiologic analyses.
Prostate cancer-related quality of life and risk for anxiety and depression.
Authors: McManus Shauna , Olson Julie , Miller Melissa F. , Clark Kelly , Stein Kevin
Published: March 2019

41

Background: Due to side effects of invasive treatments, prostate cancer (PC) patients face long-term quality of life (QoL) concerns and enduring psychosocial distress. We explored how QoL is linked to distress among a national sample of men with PC. Methods: 214 men with PC enrolled in the Cancer Support Community’s Cancer Experience Registry. Participants provided demographic/clinical background and completed the Prostate Cancer-Related QoL Scales, covering 6 QoL domains ( urinary control, sexual intimacy, sexual confidence, masculine self-esteem, cancer control, and treatment regret). Psychosocial distress was captured by CancerSupportSource, a 25-item tool with 2-item depression and anxiety screening subscales. Scores ≥3 indicate risk for clinically significant depression or anxiety respectively, and signal need for referral and further assessment. We examined bivariate correlations between demographic/clinical background, QoL, and prevalence of ‘risk for clinically significant anxiety and depression’, and used logistic regression to calculate odds of anxiety and depression risk by QoL, adjusting for demographic/clinical variables. Results: Participants were 93% White; mean ( SD) age=64 (12) years; mean ( SD) years since diagnosis=4.3 (4.9); 25% had metastatic disease. 54% underwent radiation; 55% surgery. 40% were at risk for clinically significant anxiety; 35% depression. Poorer QoL scores for sexual intimacy, sexual confidence, masculine self-esteem, cancer control, and treatment regret were bivariately associated with anxiety ( p<.05) and depression ( p<.001) risk. In logistic regression, poorer perceived cancer control predicted anxiety risk (R2=.44; OR=0.97; p<.01). Lower masculine self-esteem predicted depression risk (R2=.68; OR=0.88; p<.05). Conclusions: Questioning treatment efficacy and worrying about disease progression (i.e., lower perceived cancer control) predicts greater likelihood of anxiety risk. Lower masculine self-esteem predicts odds of depression risk. These findings elucidate the ways that PC patients’ perceptions of advancing disease and diminishing masculinity are linked to distress, thus identifying areas for psycho-educational and supportive interventions.
FGFR3 mutation as a prognostic indicator in patients with urothelial carcinoma: A systematic review and meta-analysis.
Authors: Khalid Sidra , Basulaiman Bassam Mohammed , Emack Jeff , Booth Christopher M. , Hernandez-Barajas David , Duran Ignacio , Smoragiewicz Martin , Amir Eitan , Vera-Badillo Francisco
Published: March 2019

411

Background: Mutations in the fibroblast growth factor receptor-3 (FGFR3) have been implicated in urothelial tumorigenesis. The role of FGFR3 inhibitors in urothelial carcinoma is being explored in clinical trials. Here we explore the association between FGFR3 mutations and survival in urothelial carcinoma. Methods: We conducted a systemic review of electronic databases to identify studies published 1985-2018. Studies were included if they described the associated between FGFR3 mutations and outcomes of non-muscle invasive (NMI) and muscle invasive (MI) urothelial carcinomas. We used a composite endpoint of progression-free and recurrence-free survival (PRFS). Analysis was performed in Revman software. Hazard ratios (HR) and the 95% confidence intervals (CI) were obtained and entered; and then weighted and pooled in a meta-analysis with random effect modelling. The statistical tests were two sided. Results: Twelve retrospective and prospective studies comprising a total of 2162 patients were included. Analysis was done for two groups. The first group, included 1651 patients with NMI urothelial carcinomas; 886 (53.6%) of these had FGFR3 mutation. Compared to FGFR3 wild type, FGFR3 mutation did not influence PRFS (HR = 1.01, CI = 0.79-1.29, p = 0.95); I2 42%. In the second analysis, 511 patients with NMI and MI urothelial carcinomas were evaluated; 30% (n = 151) of which had FGFR3 mutation. In this group, FGFR3 mutation was not associated with PRFS (HR = 1.46, CI = 0.45-4.71, p = 0.53); I2 90%. Conclusions: Our meta-analysis does not show an association between FGFR3 mutation status and PRFS in urothelial carcinoma. [Table: see text]
Outcomes of patients following dose-dense neoadjuvant chemotherapy for muscle-invasive bladder cancer: Implications for organ-sparing strategies.
Authors: Dumont Clement , Gauthier Helene , Mongiat-Artus Pierre , Masson-Lecomte Alexandra , Desgrandchamps Francois , Culine Stephane
Published: March 2019

426

Background: Locoregional management of muscle-infiltrating bladder cancer (MIBC) after neoadjuvant chemotherapy (NAC) is controversial, because of both the morbidity of radical cystectomy (RC). Bladder preservation may be feasible after complete tumor response. Methods: This single-center retrospective study included 120 MIBC patients (stages ypT2-4aN0-3M0) treated between 2011 and 2017 with up to 6 cycles of neoadjuvant dose-dense Methotrexate, Vinblastin, Doxorubicin and Cisplatin (DD-MVAC). The primary outcome was relapse-free survival (RFS) depending on pathological findings on RC specimens, classified as either pathological complete response (pCR: ypT0N0/x), residual organ-confined disease (yOCD: ypTa/is/1/2N0/x), residual non-organ-confined disease (yNOCD: ypT≥3Nany or ypTanyN1-3). Secondary objectives included the rate of pCR in RC patients, the rate of ypT0 in the intention-to-treat population, and RFS in ypT0 patients according to locoregional management. Results: After a median number of 5 cycles of NAC, RC was performed in 75% of the patients, concurrent radiochemotherapy (CRC) in 11% and cystoscopic surveillance (CS) in 8%. In the intention-to-treat population, the ypT0 rate was 47%. Among 90 patients who underwent RC, 49% achieved pCR, 16% had yOCD and 34% yNOCD. Median follow-up in RC patients alive at last follow-up was 40 months. Three-year RFS was 86% in RC patients with pCR, 69% in patients with yOCD and 21% in patients with yNOCD (p < 0.0001). Outcomes were similar between ypT0 patients treated with either RC or CRC/CS (3-year RFS: 81% vs 100%, p = 0.20). Limitations to this study included its restrospective design and the lower number of patients treated with CRC/CS. Conclusions: Patients reaching ypT0 after dose-dense NAC show improved prognosis regardless of locoregional treatment. Patients with yOCD are frequently cured by RC, as opposed to patients with yNOCD. Prospective trials are needed to compare upfront cystectomy and bladder-sparing management in patients with both pCR or yNOCD.
Prognostic value of genomic alterations in DNA damage response (DDR) genes in relapsed/advanced bladder cancer (BCa).
Authors: Yin Ming , Grivas Petros , Folefac Edmund , Clinton Steven K. , Emamekhoo Hamid , Holder Sheldon L. , Drabick Joseph J. , Woo Michele Sue-Ann , Vasekar Monali K. , Pal Sumanta K. , Joshi Monika
Published: March 2019

427

Background: DDR defects play an important role in tumorigenesis, progression, treatment response and outcomes of BCa. We previously showed DDR mutations were associated with better prognosis in relapsed/advanced (TxN2-3M0-1) BCa. In this study, we aimed to update and validate our findings in 3 independent datasets. Methods: 81 BCa patients (pts) who had FoundationOne tumor tissue genomic sequencing (315 cancer-related genes) were used as discovery dataset. Validation dataset 1 consisted of additional 91 pts with FoundationOne test. Validation dataset 2 consisted of 129 relapsed/advanced pts from TCGA BCa cohort. Overall survival (OS) was measured from time of initial BCa diagnosis to death or last follow-up. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Logistic regression analysis was performed to calculate odds ratio (OR) and 95% CI. A panel of 32 DDR genes (excluding ATM) were used for analyses because ATM mutation was a negative prognostic factor in our prior study. Results: DDR mutations were present in 76.5% (62/81), 40.7% (37/91) and 51.2% (66/129) pts of the 3 datasets. They were associated with longer OS (adjHR = 0.39, 95% CI 0.21–0.73, p = 0.003) in the discovery dataset, which were confirmed in two validation datasets (Validation 1: adjHR = 0.51, 95% CI 0.26–1.03, p = 0.059; Validation 2: adjHR = 0.62, 95% CI 0.39–0.97, p = 0.038). There was a trend for longer OS with increased number of DDR mutations in individual pts. Pts carrying ≥3 DDR mutations had the best prognosis (data not shown). In 144 cisplatin or carboplatin-treated pts pooled from the 3 cohorts, pts with DDR mutations were more likely to have objective response (OR = 1.81, 95% CI 0.85–3.92 for any DDR mutations; OR = 3.65, 95% CI 0.91–14.7 for ≥3 DDR mutations) and longer overall survival (HR = 0.61, 95% CI 0.38–0.98 for any DDR mutations; HR = 0.49, 95% CI 0.19–1.27 for ≥3 DDR mutations). Conclusions: DDR mutations (excluding ATM gene and especially ≥3) correlated with better outcomes in relapsed/advanced BCa. Further exploration of the deleterious nature and functional impact of alterations is critical along with prospective validation in ongoing trials.
Clinical outcomes of muscle-invasive bladder cancer patients with hydronephrosis treated with tetra-modality bladder sparing therapy incorporating consolidative partial cystectomy.
Authors: Kijima Toshiki , Fukuda Shohei , Fukushima Hiroshi , Moriyama Shingo , Uehara Sho , Yasuda Yosuke , Yoshida Soichiro , Yokoyama Minato , Ishioka Junichiro , Matsuoka Yoh , Saito Kazutaka , Fujii Yasuhisa
Published: March 2019

430

Background: Trimodality bladder sparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As the presence of hydronephrosis may reduce complete response rate and survival in trimodality therapy, some investigators deem hydronephrosis as a contraindication for bladder sparing. We have developed a tetra-modality bladder sparing therapy (TeMT) consisting of maximal transurethral resection (TUR), induction chemoradiotherapy (CRT), and partial cystectomy (PC) (Koga et al, BJU Int 2012). TeMT which enables surgical consolidation of the original MIBC site, including uretero-vesical anastomosis if necessary, may provide more chance of bladder sparing for patients with hydronephrosis. Methods: In total, 151 patients with cT2-3N0M0 MIBC (median age 69 years, female/male = 33/118, cT2/3 = 100/51) entered tetra-modality bladder-sparing protocol. After maximal TUR and CRT (40 Gy + cisplatin), response was evaluated via cytology, imaging, and tumor-site rebiopsy. Consolidative PC was performed in complete responders, while radical cystectomy was recommended for others. Extension of ipsilateral intrapelvic ureter in pretreatment computed tomography was graded following the Society for Fetal Urology grading system, then patients with grade 2-3 were classified as with hydronephrosis. Response rate to CRT, MIBC recurrence-free survival, and cancer-specific survival (CSS) were compared between patients with or without hydronephrosis. Results: Hydronephrosis was found in 19 patients (14%), and was associated with lower response rate to CRT (42% in hydronephrosis vs 77% in normal, p = 0.03). On an intent-to-treat basis, patients with hydronephrosis (n = 19) had lower 5-yr CSS than those without it (n = 132) (62% vs 85%, p < 0.01). Among the 106 patients who underwent PC as per protocol, patients with (n = 9) and without hydronephrosis (n = 97) had comparable 5-yr MIBC recurrence-free survival (100% vs 97%, p = 0.11) and CSS (100% vs 93%, p = 0.46). Conclusions: Patients with hydronephrosis should not necessarily be excluded from tetra-modality bladder sparing therapy.
Association between stromal/TGF-β/EMT gene expression signature and response to pembrolizumab monotherapy in cisplatin-ineligible patients with locally advanced (unresectable) or metastatic urothelial carcinoma.
Authors: Grivas Petros , Castellano Daniel E. , O'Donnell Peter H. , Cristescu Razvan , Frenkl Tara L. , Keefe Stephen Michael , Loboda Andrey , Souza Sandra C. , Ma Hua , Snyder Alex , Zhang Chunsheng , Albright Andrew , Lunceford Jared , Balar Arjun Vasant
Published: March 2019

433

Background: PD-L1 immunohistochemistry and an 18-gene T cell–inflamed gene expression profile (GEP) are associated with response to anti–PD-1/PD-L1 therapy across tumor types, including urothelial carcinoma. A gene expression signature representing convergent biology related to stromal/EMT/TGF-β pathways was developed and prespecified for testing for association with pembrolizumab response in urothelial carcinoma patients treated on the KEYNOTE-052 trial (NCT02335424). Methods: KEYNOTE-052 was a single-arm phase 2 trial of pembrolizumab in cisplatin-ineligible patients with previously untreated, advanced urothelial carcinoma. Primary objective of this analysis was to assess the association between the Stromal/EMT/TGF-β signature and outcomes (best overall response [BOR], PFS, OS) as an independent biomarker and to understand its potential prognostic/predictive role beyond the T cell–inflamed GEP score or PD-L1 assessed using combined positive score (CPS). Cox regression models for PFS and OS and a logistic regression model for BOR evaluated associations between Stromal/EMT/TGF-β signature and outcomes adjusting for ECOG performance status (PS) and level of the GEP or CPS (1-sided P value). Results: RNA-Seq data from baseline tumor specimens were available for 187/370 patients on KEYNOTE-052. Lower Stromal/EMT/TGF-β score was associated with favorable BOR rate ( P < 0.001), PFS ( P < 0.001), and OS ( P = 0.002) after adjustment for ECOG PS and GEP (which remained significant at the 0.05 level in all cases). The patterns indicated a very consistent downward trend in the distribution of the Stromal/EMT/TGF-β score for responders versus nonresponders, regardless of GEP. In models that adjusted for both ECOG PS and PD-L1 CPS, the Stromal/EMT/TGF-β score remained significant (BOR rate, P = 0.002; PFS, P = 0.013; OS, P = 0.029). Conclusions: Higher Stromal/EMT/TGF-β signature was associated with resistance to pembrolizumab independently of GEP or PD-L1 in urothelial carcinoma patients on the KEYNOTE-052 trial. Clinical trial information: NCT02335424.
Impact of concurrent medications on outcomes with PD1/PD-L1 inhibitors for metastatic urothelial carcinoma.
Authors: Agarwal Archana , Pond Gregory Russell , Curran Catherine , Nassar Amin , Nuzzo Pier Vitale , Kumar Vivek , McGregor Bradley Alexander , Wei Xiao X. , Harshman Lauren Christine , Choueiri Toni K. , Kilbridge Kerry L. , Sonpavde Guru
Published: March 2019

435

Background: The impact of concurrent medications (meds) on outcomes with PD1/PD-L1 inhibitors in metastatic urothelial carcinoma (mUC) is unclear. We investigated whether candidate concurrent meds (NSAIDS [N], metformin [M], antibiotics [A], statins [S] and corticosteroids [C]) have an association with outcomes in mUC patients (pts) receiving a PD1/PD-L1 inhibitor. We hypothesized that A and C compromise outcomes, while N, M and S improve outcomes. Methods: Data from mUC pts who received PD1/PD-L1 inhibitors at the Dana-Farber Cancer Institute (DFCI) was obtained. The concurrent medication was required to be administered within 1 month before starting to anytime during PD1/PD-L1 inhibitor therapy. A Cox regression analysis was done to study the association of variables with response and survival. Results: Data was available for 101 pts with mUC who received atezolizumab [n = 52], pembrolizumab [n = 39], nivolumab [n = 9] and durvalumab [n = 1]. Prior platinum had been administered in 74 pts (73.2%), 25 were chemonaive (24.8%) and prior therapy status was unknown in 2 pts (2%). The concurrent meds were N (n = 30), M (n = 7), A (n = 26), S (n = 33) and C (n = 12). The median survival was 57.9 weeks. Response was seen in 26 pts [25.7%]. A was associated with a lower probability of response (11.5%) than those not on A (30.7%), and worse survival (HR = 1.93, 95% CI 1.93 – 3.42, P = 0.024). Pts who received neither A nor C, one of them or both had a response rate (RR) of 30.6%, 20% and 0%, and median survival of 65.3, 53.1 and 14.9 weeks, respectively (HR = 3.02, 95% CI = 1.34-6.83, p = 0.027). Pts who did not receive N, M and S (n = 52) exhibited a median OS of 39.6 weeks, while those who received ≥1 of these meds (n = 49) exhibited a median survival of 160.3 weeks (p = NS). The study is limited by the retrospective design and modest sample size. Conclusions: In this hypothesis-generating study, concurrent antibiotics or corticosteroids compromised outcomes in mUC pts receiving a PD1/PD-L1 inhibitor and receiving both further compromised outcomes. The numerically higher survival with concurrent N, M or S did not attain statistical significance, but requires further study in larger datasets.
Correlation of myeloid-derived suppressor cells (MDSC) with pathologic complete response (pCR), recurrence free survival (RFS), and overall survival (OS) in patients with urothelial carcinoma (UC) undergoing cystectomy.
Authors: Fallah Jaleh , Diaz-Montero C. Marcela , Rayman Patricia A. , Wei Wei (Auston) , Sheng Iris Yeong- Fung , Finke James , Kim Jin Sub , Pavicic Paul G. , Dann Priscilla , Company Donna , Stephenson Andrew J. , Campbell Steven , Haber Georges-Pascal , Lee Byron H , Mian Omar Y. , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. , Grivas Petros , Ornstein Moshe Chaim
Published: March 2019

437

Background: MDSCs play an important role in maintaining a tumor immunosuppressive microenvironment. The association of circulating levels of MDSCs with pCR (pT0N0) and outcomes was investigated in patients (pts) with non-metastatic UC undergoing cystectomy. Methods: Peripheral blood samples from pts with non-metastatic UC was collected. MDSCs were measured in freshly purified peripheral blood mononuclear cells, using flow cytometry. Total (T) MDSC was defined as CD33+/HLADR-. T-MDSC subtypes were polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+], and uncommitted (UC-MDSC: CD15-/CD14-]. MDSC populations were presented as % of live nucleated blood cells. Wilcoxon rank sum test was used to compare MDSCs between pCR groups. Kaplan-Meier and log-rank test were used to analyze RFS and OS. Results: MDSC data were available for 124 pts (106 male, 18 female), median age 68, 28 (23%) never smokers, 93 (75%) pure UC. Thirty four pts (27%) received intravesical BCG; 49 (39%) received neoadjuvant chemotherapy (NAC); 22 (19%) had pCR (pT0N0) following surgery. PMN-MDSC was the dominant subtype (42%) and frequency of UC-MDSC and M-MDSC was 40% and 17%, respectively. Circulating levels of T-MDSC and PMN-MDSC were significantly lower in pCR patients than those in non-pCR patients (Table). Sixteen deaths were observed and 21 pts recurred after surgery. The median follow-up time of patients alive was 18.7 months (range 0.3-42.4). The median OS or RFS of all patients was not reached. One-year and two-year OS rates were 94% and 83%, respectively. One-year and two-year RFS rates were 82% and 69%, respectively. There was no association between MDSC subtypes with OS or RFS. Conclusions: Total- and PMN-MDSC subtypes in blood were significantly correlated with pCR in pts with non-metastatic UC who undergo cystectomy. The relatively short follow-up may impact the association with RFS and OS; additional follow-up is needed. [Table: see text]
Identifying factors associated with poor genitourinary cancer clinical trial accrual using a novel data extraction algorithm.
Authors: Stensland Kristian D. , Reinstatler Lael Suzanne , Moinzadeh Alireza , Galsky Matt D.
Published: March 2019

439

Background: Poor accrual to clinical trials is the most cited barrier to efficient trial completion, yet information regarding accrual adequacy is limited. Comparisons of planned (or anticipated) accrual to actual accrual have previously been limited by siloed information. Even ClinicalTrials.gov presents only one type of accrual (actual OR anticipated) for each trial. We developed a novel approach to extract both anticipated and actual trial accrual. We apply these previously unavailable data to describe accrual adequacy and identify predictors of poor accrual. Methods: Records for all GU cancer clinical trials started since 2005 were extracted from ClinicalTrials.gov. We employed a custom Python web scraper to extract anticipated and actual accrual information and trial characteristics from the ClinicalTrials.gov archives. Logistic regression was used to identify predictors of failing to meet 50% or 85% of anticipated accrual. Results: A total of 3,976 completed or terminated genitourinary cancer trials were extracted, of which 1,322 unique trials had complete records. Only 42% of trials met their anticipated accrual goals, and 30% enrolled fewer than half of their anticipated patients (Table). Of trials reported as completed, only 54% reached their accrual goals; 17% failed to reach 50% of anticipated accrual. On logistic regression, prostate (OR 0.64, 95% CI 0.45-0.91) and testicular (OR 0.44, 95% CI 0.18-0.96) trials, as well as trials with sites within and outside the USA (OR 0.55, 95% CI 0.35-0.86) were more likely to accrue > 50% of anticipated patients. Conclusions: Genitourinary cancer clinical trials frequently fail to meet anticipated accrual goals. Whether this represents overly ambitious goals or modified endpoints after a trial opens remains uncertain. These data should be transparent and applied to the interpretation of results. Future work in this regard should be used to aid in planning future trials. [Table: see text]
Analysis of real-world PD-L1 testing in patients with urothelial carcinoma.
Authors: Krigsfeld Gabriel S , Prince Emily , Zerba Kim , Chizhevsky Vladislav , Ragheb Josette William , Novotny James , White James William
Published: March 2019

447

Background: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are FDA-approved for urothelial carcinoma (UC) among other tumor types. PD-L1 immunohistochemistry (IHC) testing for UC has evolved with several diagnostic approvals. As of August 2018, the Dako PD-L1 IHC 22C3 pharmDx is a companion diagnostic, while the Dako PD-L1 IHC 28-8 pharmDx and the Ventana PD-L1 (SP263) assays are complementary diagnostics. The Ventana PD-L1 (SP142) assay has complementary status for platinum-treated patients with UC but gained companion status in July 2018 for cisplatin-ineligible patients with PD-L1-expressing UC. Here, we assess PD-L1 testing with the 22C3, 28-8, and SP142 assays on real-world UC samples. Methods: Analyses on 55,652 tumor samples from Symphony Health Solutions were performed between October 2015 and March 2018. PD-L1 results were linked to clinical characteristics using unique identifiers. PD-L1 testing on UC samples was performed at NeoGenomics Laboratories, Inc. based on the manufacturer’s protocols at the time. Results from the Dako assays were reported as % of tumor cells with PD-L1 expression. Test failure (TF) was defined as the absence of adequate sample with measurable PD-L1. Turnaround time (TAT) was defined as the time from sample receipt by the laboratory to test-report delivery. Paired 28-8 and 22C3 testing was performed on 13 samples. Results: 251 confirmed PD-L1 IHC tests (0.4% of tests conducted for the entire dataset) were performed on 223 UC samples, 98.2% of which had quantifiable PD-L1 expression. Mean TAT was 3.0 (1.0–4.2) days and the TF rate was 2.0% for all tests. The 22C3, 28-8, and SP142 assays were used in 52.2%, 9.6%, and 38.3% of tests, respectively. Paired testing with the 22C3 and 28-8 assays was highly correlated (Spearman’s r = 0.94; n = 13). Further analyses of UC PD-L1 prevalence will be presented. Conclusions: Based on the total tests conducted by this US national reference laboratory, PD-L1 testing was not commonly requested for UC during the analysis period. However, PD-L1 tests that were conducted displayed high success rates and reasonable TAT. This is the first comparison of the 22C3 and 28-8 assays on real-world UC samples, adding to the literature on PD-L1 testing concordance.
SPEAR-Bladder (Study informing treatment Pathway dEcision in bladder cAnceR): Influence of treatment sequencing on time to treatment failure and overall survival in the United States.
Authors: Doshi Gurjyot K. , Kearney Mairead , Bharmal Murtuza , Phatak Hemant , Boyd Marley , Aguilar Kathleen , Kim Ruth , Bhanegaonkar Abhijeet
Published: March 2019

453

Background: With the introduction of immunotherapy (IO) for locally advanced or metastatic urothelial carcinoma (mUC), optimal treatment sequence should be considered. This study aimed to compare time to treatment failure (TTF) and overall survival (OS) among these patients (pts) treated with first-line (1L) systemic chemotherapy followed by second-line (2L) IO ( C-IO) vs 1L and 2L chemotherapy ( C-C) sequence within the US community oncology Network (USON). Methods: This was a retrospective study of adult locally advanced or mUC pts who initiated systemic therapy between 1/1/15 – 4/30/17 within USON and had a minimum of two-month follow-up. Descriptive analyses were performed, with Kaplan-Meier used for comparisons between pts who received C-IO vs C-C sequence. Pts considered for this analysis did not receive a third-line treatment. Regression analyses were performed to assess variables associated with TTF and OS. Results: 117 pts were included in the analysis ( C-IO n = 79, C-C n = 38). Median age (range) was 69 years (38, 90+), with 74.4% male. Baseline demographic and clinical characteristics were similar between the groups. The median (range) duration between start of 1L and start of 2L therapy was significantly longer among C-IO vs C-C pts (29.0 [4.1, 102.1] vs 20.0 [0.1, 63.1] weeks; P = 0.0047). Median TTF and OS were longer among C-IO vs C-C pts but the trends were not significant (Table). The duration between initial diagnosis and advanced disease status was associated with TTF (P = 0.0124) in univariate analysis. Conclusions: These results suggest that patients receiving C-IO demonstrated greater (>30 weeks) but statistically non-significant improvement in OS versus those receiving C-C. Considering these OS trends, future research should explore prognostic characteristics of IL chemotherapy treated pts who may benefit from an earlier switch to IO therapy. [Table: see text]
Invasive urothelial cancer (iUC) with FGFR3 hotspot mutation/fusion (FGFR3+): A molecularly and clinically distinctive entity?
Authors: Mota Jose Mauricio S. C. , Teo Min Yuen , Li Han , Balar Arjun Vasant , Milowsky Matthew I. , Funt Samuel Aaron , Lee Chung-Han , Regazzi Ashley Marie , Berger Michael F. , Solit David B. , Bajorin Dean F. , Rosenberg Jonathan E. , Iyer Gopa
Published: March 2019

459

Background: FGFR3+ is ubiquitous in non-invasive UC but found in ~16% of iUC. We sought to characterize the genomic landscape and response to platinum-based chemotherapy (ctx) of FGFR3+ iUC in the neoadjuvant (NAC) and metastatic (mUC) setting. Methods: Two molecularly-characterized cohorts were used for the study objective: (1) NAC-treated muscle invasive UC, incorporating consecutively sequenced standard of care UC and patients (pts) from a phase II trial (Iyer et al, JCO 2018); (2) mUC treated with platinum ctx, with FGFR3- mUC from a published work (Teo et al, CCR 2017) serving as comparator. iUC with hotspot mutations / fusions were considered FGFR3+. Clinical outcomes and frequency of altered genes were compared. Results: In the NAC cohort, 87 pts were identified (NAC response: pT0 [n = 20, 23%], <pT2 [n = 22, 25%], ≥pT2 [n = 45, 52%]). FGFR3+ (n = 11, 13%) was associated with a trend towards poor NAC response and was found in 0/20 pT0 (0%), 3/22 <pT2 (14%) and 8/45 ≥pT2 (18%) (Cochran-Armitage, p=0.06). Among ≥pT2 tumors, FGFR3+ was associated with shorter recurrence-free survival (3.7 vs 17.6 months; HR 4.8 95% CI 1.9–12.1). 49 FGFR3+ mUC pts were identified and compared to FGFR3- mUC (n = 82). FGFR3+ had a numerically higher rate of lung metastasis (42% vs 29%, p = 0.25). 1st line therapies included: platinum-based ctx (n = 27), non-platinum ctx (n = 4), immunotherapy (IO, n = 13), ctx + IO (n = 4), and FGFR inhibitor (n = 1). Platinum ctx response rate for 21/27 evaluable FGFR3+ pts was 40%. FGFR3+ mUC had similar overall survival (OS, median 25.7 vs 15.8 months, HR 0.7, 95%CI 0.4-1.2; 1-year OS: 70% vs 59%) and progression-free survival (median: 7.2 vs 7.1 months, HR 1.3, 95% CI 0.8-2.1). Frequencies of altered genes are tabulated. No differences in mutational load were seen. Conclusions: FGFR3+ iUC is a genomically distinct subset of iUC. Despite low responses to NAC ctx, FGFR3+ had similar responses, PFS, and OS in the mUC setting. [Table: see text]
Regulation of stem cell-like phenotype and response to chemotherapy in bladder cancer by beta-arrestins.
Authors: Hennig Martin Jp , Kallifatidis Georgios , Smith Diandra K , Morera Dailey S , Hupe Marie C , Kuczyk Markus A , Merseburger Axel S. , Lokeshwar Vinata B
Published: March 2019

461

Background: Identification of molecular drivers that promote a muscle invasive phenotype and chemoresistance in bladder cancer, as well as an understanding of their mechanism of action should help in designing potential prognostic markers and effective targeted treatments for patients with advanced bladder cancer. β-arrestins (ARRBs) are classic attenuators of G-Protein coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. Methods: β-arrestin-1 (ARRB1) and β-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63; n = 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated using CRISPR-Cas9 mediated gene-knockout of ARRB1. The consequence of forced expression of ARRBs on tumor growth and response to gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. Results: ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared to normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ~ 80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity towards gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. Conclusions: β-Arrestins regulate response towards gemcitabine and are therefore potential targets and predictive markers for chemotherapy failure in bladder cancer. The present work shows for the first time that β-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer.
Let-7f microRNA expression within established bladder cancer subtypes and upregulation with recombinant interferon-alpha.
Authors: Narayan Vikram M , Lim Amy , Mokkapati Sharada , Manyam Ganiraju C. , Plote Devin , Sundi Debasish , Choi Woonyoung , Dinney Colin P.N.
Published: March 2019

462

Background: Let7f is a microRNA (miR) that may act as a tumor suppressor in multiple human malignancies. In patients with BCG-refractory non-muscle invasive bladder cancer, detectable let7f levels in the urine of patients undergoing treatment with adenoviral vector-mediated IFNα gene therapy (clinical trial setting) were found to be prognostic of treatment response at 12 months. Here we sought to define the association of let7f with clinical bladder cancer phenotypes within The Cancer Genome Atlas (TCGA) cohort and characterize the role of let7f in preclinical models. Methods: Using miRNA sequencing data from the published TCGA 2018 bladder cohort (n = 412), let7f miR expression was characterized and stratified by molecular subtype (basal-squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal). Kaplan-Meier analyses were performed to compare survival (upper vs lower median, by let7f expression level). The murine urothelial carcinoma cell line MB49 was cultured in colonies of 105 and in vitro administrations of 100U/mL of recombinant mu-IFNα were performed with cells harvested at 0, 2, 8, 12, and 24 hours. Let7f miR expression levels were then determined by qRT-PCR. Results: Within the TCGA cohort, let7f expression levels were found to be lower in the more aggressive basal-squamous (median = 12.8), luminal-infiltrated (median = 12.9), and neuronal (median = 12.4) subtypes relative to the luminal (median = 13.2) and luminal-papillary (median = 13.3) subtypes (p < 0.001). Survival analysis demonstrated a trend towards improved survival in the high let7f expressers, but this did not reach statistical significance. In MB49 cells treated with mu-IFNα, there was a time-dependent increase in let7f miR expression suggesting that IFNα may play a role in upregulation of this potential tumor suppressor. Conclusions: Let7f miR is downregulated in more aggressive subtypes of MIBC. IFNα upregulates let7f expression in MB49 cells, and the inability to do so may comprise an escape mechanism for IFNα-treated tumors. Let7f miR may serve as a novel biomarker to identify aggressive phenotypes and treatment failures for bladder tumors treated with IFNα-based gene therapy.
Comparison of investigator-initiated and industry-initiated trials in Canada and other countries.
Authors: Wong Bryan , North Scott A. , Tran Ben , Sridhar Srikala S.
Published: March 2019

464

Background: Investigator-initiated trials (IITs) developed by academic investigators without inherent commercial interests have contributed significantly to oncology. However, costs and regulatory complexity may negatively impact IITs. Little is published about current trends in cancer IITs. We focused on IITs in genitourinary cancers (GU IITs) in Canada and other countries and compared these to industry-initiated trials conducted over the same time period. Methods: We collected data using searches of the ClinicalTrials.gov registry for bladder, kidney, and prostate cancer trials conducted in Canada, US, and France from 2007 to 2017. IITs were defined as trials funded by individuals, universities, or organizations. We then characterized trials based on type, purpose, phase, participants, masking, assignment, and allocation. Results: Of the 498 GU trials conducted in Canada from 2007 to 2017, 201 (40%) were IITs, and 254 (51%) were industry-initiated. On average, GU IITs in Canada increased by 88% from 2007 to 2017, while industry-initiated trials increased by 30%. Although the increase of GU IITs in Canada was greater than industry-initiated trials, the growth was larger in US and France. In US, 746 (29%) of the 2537 GU cancer trials were IITs and increased by an average of 106% from 2007 to 2017, while industry-initiated trials increased by 61%. In France, 164 (41%) of the 405 GU cancer trials were IITs and increased by an average of 125% from 2007 to 2017, while industry-initiated trials increased by 83%. For GU IITs in Canada, most studies were interventional (85%) with purpose of treatment (47%). Phase 2 trials (23%) and trials with 20 to 49 participants (29%) accounted for the majority. Most trials were randomized (41%), open-label (70%), and used single group assignment (43%). GU IITs in US and France shared these same patterns in their characteristics. Conclusions: The increase in GU IITs from 2007 to 2017 was lower in Canada than US and France. In all three countries, more GU trials were industry-initiated than IITs. More emphasis must be placed on IITs in Canada through increased commitment and funding by institutions to promote development of IITs and maintain their distinctive, academically driven intentions.
Sites of metastases (mets) and their association with clinical outcomes (CO) in urothelial cancer patients (pts) treated with immunotherapy (IO).
Authors: Shabto Julie M. , Martini Dylan J , Liu Yuan , Ravindranathan Deepak , Kline Meredith R , Hitron Elise , Russler Greta , Caulfield Sarah , Kissick Haydn , Alemozaffar Mehrdad , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Carthon Bradley Curtis , Bilen Mehmet Asim
Published: March 2019

473

Background: Several IO agents have been approved for treatment of advanced urothelial cancer pts. We investigated the association between sites of mets and CO in urothelial cancer pts treated with IO in the real world setting. Methods: We performed a retrospective review of 67 urothelial cancer pts treated with PD-1 or PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were measured from first dose of IO to date of death or hospice referral and radiographic or clinical progression, respectively. Sites of mets were collected from radiology and clinic notes at baseline. Univariate analysis (UVA) and multivariable analysis (MVA) used Cox proportional hazard. Results: The median age was 70 and most (79.1%) were men. Pts had mets to sites such as lymph node (73.1%), bone (29.9%), liver (20.9%), lung (31.3%), and brain (1.5%). Pts with bone or liver mets had significantly shorter OS and PFS in UVA. Pts with bone mets also had significantly shorter OS and PFS in MVA (Table). The median OS of pts with bone mets was 2.2 months (12-month survival=28.0%), while those without bone mets had a median OS of 21.9 months (12-month survival=52.5%) per Kaplan-Meier estimation. The median OS of pts with liver mets was 2.2 months (12-month survival=28.6%), while those without liver mets had a median OS of 12.8 months (12-month survival=50.1%) per Kaplan-Meier estimation. Conclusions: Bone and liver mets are poor prognostic factors in urothelial cancer pts receiving IO in the real world setting. These findings should be validated in a larger study. [Table: see text]
Comparative analysis of biopsy proven lymph node positive bladder cancer patients to those with biopsy proven lymph node negative disease prior treatment.
Authors: Lim Amy , Narayan Vikram M , Seif Mohamed , Matulay Justin T. , Dinney Colin P.N. , Navai Neema
Published: March 2019

475

Background: Many studies assessing the efficacy of chemotherapy before surgery include few clinically node positive patients or completely exclude them which make response rates in this particular subset of patients difficult to determine. Additionally, these patients are clinically node positive, making true nodal response rates unable to be determined. We report a descriptive analysis of patients with clinically node positive disease who underwent lymph node biopsy prior to any treatment and their outcomes. Methods: Data was obtained retrospectively from patients with cTanyN1-3M0 bladder cancer from 2006-2017 who underwent radical cystectomy at MD Anderson. SPSS was used for statistical analysis. Results: Among the 120 patients with cTanyN1-3M0 (median follow up 27.4 months), 40 patients underwent lymph node biopsy (LNBx). 26 (65%) patients had a positive LNBx, 14 (35%) were negative. 100% of the patients with a positive LNBx underwent primary chemotherapy. On final cystectomy, 9 (34.6%) of those patients had complete nodal response (pN0) and 9 (34.6%) had complete bladder response (pT0). 7 were pT0N0. Of the patients with a negative LNBx, 11 (78.6%) underwent neoadjuvant chemotherapy and of those patients, 7 (63.6%) were pN0 and 4 (36.4%) were pT0. Of patients that did not undergo LNBx that received primary chemotherapy (78 patients), 41 (52.6%) were pN0 and 22 (28.2%) were T0. There was no significant difference in overall or recurrence free survival between patients with a positive or negative biopsy or who did not undergo biopsy (p = .474). There was a significant improvement in overall and recurrence free survival in patients with negative nodal disease on final pathology compared to those with positive nodal disease (p < 0.001). Conclusions: Patients that had a negative LNBx were less likely to undergo primary chemotherapy. Pathologic bladder response rates correlate with nodal response rates. In cN+ patients, overall survival and recurrence free rates are not significantly different in patients without a lymph node biopsy, a positive biopsy or a negative biopsy. Finally, advanced final pathologic stage predicts worse outcomes.