bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marker lesion study of oral FGFR inhibitor BGJ398 in patients with FGFR3-altered intermediate-risk nonmuscle-invasive bladder cancer.
Authors: Cha Eugene K. , Iyer Gopa , Funt Samuel Aaron , Regazzi Ashley Marie , Francis Jasmine , Heinemann M.H. , Ostrovnaya Irina , Dalbagni Guido , Bajorin Dean F. , Bochner Bernard H. , Rosenberg Jonathan E. 
Published: February 2020

510 Background: FGFR3 alterations are prevalent in non-muscle-invasive bladder cancer (NMIBC). We conducted a marker lesion study of the oral FGFR inhibitor BGJ398 in patients with intermediate-risk NMIBC. Methods: Patients with recurrent clinical high-grade papillary NMIBC following intravesical BCG were eligible. FGFR3 alteration status was determined via testing of pre-treatment or archival tumor tissue. BGJ398 was administered at 125 mg PO daily for a 3 week on, 1 week off schedule (1 cycle). Response was determined after 2 cycles (at 7 weeks). Patients with a complete response (CR) had the option to continue therapy. Results: We enrolled four patients on trial, which we closed secondary to low accrual. Three patients had a CR at the 7-week evaluation. The other patient had a smaller, necrotic lesion after prematurely discontinuing treatment at 4 weeks. Clinically significant toxicities included eye disorders, skin and nail disorders, and elevations in LFTs. Two patients required dose reductions for toxicities. Two patients discontinued treatment before the 7-week evaluation, one for Grade 2 skin toxicity and the other for Grade 3 LFT elevation. All other toxicities were Grades 1 and 2. The other two patients continued treatment beyond a CR at 7 weeks but stopped after 3 and 4 cycles (after 11 and 16 weeks) for vision/skin toxicities and nail infection/mucositis, respectively. Conclusions: The oral FGFR inhibitor BGJ398 showed antitumor activity in a marker lesion study of patients with recurrent high-grade papillary NMIBC. Treatment was discontinued secondary to toxicities in all subjects, after a range of 4 to 16 weeks. Further investigation may be warranted for lower doses of oral BGJ398 or other formulations, such as intravesical delivery. Clinical trial information: NCT02657486. [Table: see text]
Defining the genetic evolution of epigenetic alterations in bladder cancer.
Authors: Clinton Timothy Nguyen , Wise Hannah , Almassi Nima , Chavan Shweta S. , Hu Wenhuo , Gao Sizhi Paul , Hanrahan Aphrothiti , Dason Shawn , Pietzak Eugene J. , Carlo Maria Isabel , Funt Samuel Aaron , Teo Min Yuen , Iyer Gopa , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Arcila Maria E. , Al-Ahmadie Hikmat , Taylor Barry S. , Solit David B. 
Published: February 2020

529 Background: Large-scale efforts have sought to define the genomic landscape of urothelial carcinomas of the bladder with the goal of identifying novel therapeutic targets. Many bladder cancers harbor mutations in genes that regulate chromatin state, such as KDM6A, ARID1A and KMT2D. There remains uncertainty as to the timing at which alterations in chromatin modifying genes (CMG) arise during the evolution of urothelial cancer. Methods: We leveraged a prospective genomic profiling initiative to characterize driver alterations in urothelial cancer. To define the timing at which mutations arose during disease pathogenesis, we performed whole exome (WES) or targeted sequencing analysis of matched pairs of primary and metastatic tumors. Results: CMG mutations were identified in 76% of UC samples in the prospective MSK-IMPACT tumor sequencing cohort (N=1057); most frequent in KDM6A (31%), KMT2D (28%) and ARID1A (27%). Comparison of primary low-grade (N=65), high-grade (N=742) and metastatic (N=250) samples revealed KDM6A, FGFR3 and KMT2C were more frequently mutated in low-grade tumors. WES and targeted sequencing of 63 matched pairs demonstrate a high degree of concordance among likely oncogenic mutations. Notably, 100% (18/18) of pairs were concordant for mutations in KDM6A suggesting that, when present KDM6A mutations arise early during tumor development. Mutations in ARID1A were present only in the metastatic samples of a subset of tumors (29%) suggesting that ARID1A mutations arise later in disease pathogenesis. Several additional oncogenic drivers were found in only the metastatic sample ( FGFR3, TSC1, PIK3CA) of select tumor pairs. Conclusions: Primary and metastatic pairs were largely concordant for known and likely oncogenic mutations. Evolutionary analysis of sequencing data suggested that KDM6A mutations arise early in tumor development whereas ARID1A mutations were enriched and present only in the metastatic samples of a subset of patients. Despite the high frequency of FGFR3 mutations in low grade tumors, discordance of FGFR3 mutational status was observed in small fraction of patients suggesting that profiling of metastatic tumors or cell free DNA would be preferable to identify patients for FGFR inhibitor therapy.
Expression of nectin-4 in bladder cancer with variant histology.
Authors: Hoffman-Censits Jean H. , Choi Woonyoung , Lombardo Kara , Hahn Noah M. , McConkey David James , McGuire Bridget , Parimi (Parini) Vamsi , Matoso Andres 
Published: February 2020

546 Background: The antibody-drug conjugate enfortumab vedotin is poised to change the bladder cancer (BC) treatment landscape by targeting Nectin-4, near ubiquitously expressed in urothelial cancer (UC). Less is known about this and other targets in BC with pure or mixed variant histology (VH). Methods: Immunohistochemistry (IHC) was performed on a Ventana Discovery Autostainer (Roche Diagnostics) using an ultraView DAB detection kit (Roche Diagnostics) and a Nectin-4 polyclonal antibody (1:100 dilution; Abcam, Cambridge, UK). The intensity and extent of Nectin-4 expression was determined by the histochemical scoring (H-score) used in preclinical testing, defined as the sum of the products of the staining intensity (score of 0–3) x % of cells (0–100) stained at a given intensity. Specimens were assessed by H score as: negative (0–14), weak (15–99), moderate (100–199), and strong (200–300). Results: Forty UC and VH BC were evaluated for Nectin-4 expression by IHC: 15 small cell (SCBC) (8 pure SCBC, 6 mixed SCBC/UC, 1 SCBC/CIS), 8 carcinosarcomas (CS) (7 pure CS, 1 HGUC/sarcomatoid features), and 17 pure HGUCs. Normal urothelium and stroma were negative. Eight of 8 (100%) pure SCBC were negative for Nectin-4. Six of 7 (85.3%) mixed SCBC+HGUC/CIS had weak staining and 1/7 (14.7%) had moderate staining in the urothelial components (comp) while 7/7 (100%) of the SCBC comp were negative. Seven of 7 (100%) pure CS were negative and 1/1 (100%) mixed CS+HGUC showed weak staining in the HGUC comp while the sarcomatoid comp was negative. Expression in UC was: 1/17 (5.9%) strong, 3/17 (17.6%) moderate, 10/17 (58.8%) weak, and 3/17 (17.6%) negative. Gene expression profiling confirmed Nectin-4 was downregulated in VH compared to UC samples, as was ERBB2 and Trop2. Conclusions: There is heterogeneity of expression of Nectin-4 and other targets in BC with VH compared to UC. This may have therapeutic implications, and highlights need for additional research in VH.[Table: see text]
Validation of 3-factor clinical-genomic model to predict response to atezolizumab as first-line or post-platinum therapy for advanced urothelial carcinoma.
Authors: Sonpavde Guru , Banchereau Romain , Tayama Daren , Shen Xiaodong , Nassar Amin , Kwiatkowski David J. , Price Richard , Mariathasan Sanjeev 
Published: February 2020

552 Background: Previously, we reported a 3-factor model including tumor mutation burden (TMB), peripheral blood neutrophil/lymphocyte ratio (NLR) and visceral metastasis status to predict tumor regression (c-statistic=0.90) when using ICIs for mUC regardless of line of therapy. We conducted an external validation of this model to determine its ability to predict response. Methods: We utilized data from a phase II trial, IMvigor210, which evaluated atezolizumab (atezo) for post-platinum pts or as first-line therapy for cisplatin-ineligible pts with mUC. Pts with TMB, NLR, visceral metastasis and RECIST1.1 response status available were evaluable. Tumor genomic analysis was performed using FoundationOne, which sequences 324 cancer-related genes. Multivariable regression studied the association of TMB (<10 vs. ≥10 mutations/megabase), NLR (<5 vs. ≥5) and visceral metastasis status (yes vs.no) with RECIST 1.1 response status (≥partial response [PR] vs no PR). Model discrimination performance was assessed using the concordance (c)-index. Results: A total of 234 pts were evaluable for analysis, of whom 185 (79%) were men. 164 (70.1%) pts received post-platinum therapy and 70 (29.9%) received first-line therapy with atezo. 60 pts exhibited RECIST 1.1 ≥PR. On multivariate analysis, all 3 factors were independently and significantly associated with ≥PR: TMB ≥10 mutations/megabase (HR -4.254, p=2.1 x 10−5), low NLR (HR=2.591, p=0.00958) and absence of visceral metastasis status (HR=4.105, p=4.04 x 10−5). The c-index of this 3-factor model to predict ≥PR was 0.77. Presence of all 3 favorable factors (TMBhigh, NLRlow, no visceral metastases) was associated with ≥PR in 15/21 pts (71.4%), while the absence of all 3 factors (TMBlow, NLRhigh, visceral metastases) was associated with ≥PR in 2/37 pts (5.4%). Conclusions: A 3-factor model combining readily available clinical and genomic variables including TMB, NLR and visceral metastasis status was validated to robustly predict RECIST 1.1 response in pts with mUC receiving atezo as first-line or post-platinum therapy. This model may improve the therapeutic index and cost efficacy of atezo.
Can serum cytokeratin 19 fragments predict postoperative early progression in patients with upper urinary tract urothelial carcinoma?
Authors: Endo Yuki , Kimura Go , Hodotsuka Naoto , Hasegawa Hiroya , Minaguchi Shigehito , Mikami Hikaru , Takeda Hayato , Akatsuka Jun , Hayashi Tatsuro , Kondo Yukihiro 
Published: February 2020

557 Background: Current guidelines do not yet provide recommendations for any serum tumor markers in patients with upper tract urothelial carcinoma (UTUC) who received nephroureterectomy (NU). The criteria for adjuvant chemotherapy is also controversial. Previous studies have shown that serum cytokeratin levels (sCK) were correlated with depth of tumor invasion and metastases in patients with bladder cancer. We found that preoperative sCK was correlated with cancer specific survival(CSS) after NU. In this study we evaluated whether postoperative sCK (poCK) could predict early progression in patients who received NU. Methods: 160 patients with UTUC underwent NU from December 2003 to 2014 at our institution. The median age at diagnosis was 73 years (41-89). poCK19 had been measured in 112 patients within 8 weeks after NU. Patients were divided into two groups, a high-group and a low-group based on poCK19 levels (a cut-off value of 3.5 ng/mL). CSS and progression-free survival (PFS) were measured by Kaplan–Meier curves and log–rank test. Multivariate analysis was carried out using the Cox hazards model. Results: Of 112 patients ≤pT1 was 39 (34%), pT2 in 26 (23%), pT3 in 40 (35%), and pT4 in 7 (8%). The 5-year (5y) CSS rate was 86% and the 5yPFS rate was 60%. There were 24 (21%) patients in the high-group and 88 (79%) in the low-group. During the median follow-up period of 34.0 (1-152) months, 39 patients (35%) died. The 5yCSS rate of the high-group was 51%, which is significantly lower than the low-group (86%) (p<0.001). The 1yPFS of the high-group was 66%, which was significantly lower than that of the low-group (86%) (p<0.001). On univariate analysis, positive margin (HR4.0, p<0.001) and poCK19 (HR3.9, p<0.001) were the significant factors for 1yPFS. On multivariate analysis, poCK19 (HR5.3 95%CI (1.8-15.7), p=0.002) and positive margin (HR 4.6 95%CI (1.1-18.9), p=0.032) were also independent factors for 1yPFS. Conclusions: Our study suggests that postoperative sCK19 could predict early progression in patients with UTUC who received NU. Adjuvant chemotherapy might be indicated for patients with high postoperative sCK19 levels independent of pathological findings.
Response to immunotherapy, platinum-based chemotherapy or their combination in metastatic urothelial carcinoma (MUC) with or without FGFR-3 alterations: Single cohort experience.
Authors: Ferrer-Mileo Laura , Rodriguez Adela , González Nuria , Orrillo Mayra , Jiménez Natalia , Marín-Aguilera Mercedes , Rodriguez-Carunchio Leonardo , Prat Aleix , Mellado Begona , Reig Oscar 
Published: February 2020

560 Background: Fibroblast growth factor receptor-3 (FGFR-3) is a promising target therapy in metastatic urothelial carcinoma. Its role in patient’s clinical outcome and treatment response is unclear. We present data for overall survival (OS) and response to platinum-based treatment, immunotherapy and combination (platinum plus immunotherapy) in MUC. Methods: Enrolled patients were diagnosed with muscle-invasive urothelial cancer (MIUC) between 2/2009-6/2019 at Clinic Hospital of Barcelona, Spain. All have been screened for FGFR-3 alterations using next-generation sequencing or qualitative real-time polymerase chain reaction-based assays in tumour or blood. Demographic, pathology, treatments and treatment response were collected retrospectively. Results: 101 patients with MIUC were screened, 99% had progressed to metastatic stage. At diagnosis 32.67% were metastatic. 77% were man and median age was 68y (38-85y). Median follow-up (FU) since metastatic disease was 16.25 months (1.2-89.72m) with 69.31% of patients had died at cut-off. 32% presented FGFR-3 alteration (fusion =1 and mutation=31). FGFR-3 altered more frequently had papillary histology than FGFR-3 wild type tumours (69 vs 26%, p<0.05). No statistical differences were detected between both groups for gender, age, stage at diagnosis, median FU, primary tumour site (upper vs lower tract) or previous history of non-invasive urothelial carcinoma. 58% patients received 1st line platinum-based chemotherapy, 25% immunotherapy and 8% the combination of both (9% with other therapies). FGFR-3 altered tended to present more benefit (complete, partial response or stable disease) with platinum-based chemotherapy than FGFR-3 wild type (81% vs 62%) but without reach statistical significance. No differences were detected for immunotherapy or combination therapies. Moreover, OS was similar for FGFR-3 altered (median 14.6m) and FGFR-3 wild- type (median 17.1 m) (HR 0.76, p=0.3). Conclusions: In our series, no significant differences related to response to first line therapy or survival was observed.
FGFR2/3 genomic alterations (GA) in cell-free (cf)DNA from patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Kiedrowski Lesli Ann , Thomas Roby Antony , Vogelzang Nicholas J. , Sonpavde Guru , Gupta Sumati , Gourdin Theodore Stewart , Faltas Bishoy Morris , Nagy Rebecca , Lanman Richard B. , Grivas Petros 
Published: February 2020

565 Background: Erdafitinib is approved in pts with aUC with relevant FGFR2/3 GA. BLC2001 trials in pts with activating FGFR2/3 mutations reported 40% ORR to erdafitinib (49% for those with single nucleotide variants [SNVs] and 16% with fusions), 39% stable disease rate, and potentially reduced response to anti-PD-L1. Genomic profiling with plasma cfDNA next-generation sequencing (NGS) is increasingly used to identify targetable GA in pts with advanced solid tumors and presents a minimally invasive option for identification of FGFR2/3 GA. Methods: Genomic data from the Guardant360 database were queried from clinical results released from 10/19/15 - 8/28/19 for clinical samples submitted with diagnoses of aUC or related diagnoses (e.g. bladder cancer, renal pelvis carcinoma). All assays included FGFR2/3 fusions and complete sequencing of all critical exons harboring sensitizing FGFR2/3 SNVs. Results: 1349 results from 1096 unique pts were identified. Somatic GA were identified in 1192 tests (88%) from 997 pts. Fusions and/or nonsynonymous SNVs in FGFR2/3 were identified in 201 pts (20%); 141 pts (14%) had at least one characterized activating FGFR2/3 GA. Of 34 pts (3.4%) with FGFR3 fusions, partners included TACC3 (32), JAKMIP1 (1), and TNIP2 (1). Overall, most SNVs identified in FGFR3 were predicted to be activating (103/125, 82%) whereas in FGFR2 most were variants of uncertain significance (VUS; 62/72, 86%). Of 89 unique variants (59 in FGFR2, 30 in FGFR3), 19 (21%) were activating mutations (7 in FGFR2, 12 in FGFR3). The most common activating SNVs in FGFR3 were S249C (58 pts), Y373C (20) and R248C (10), and in FGFR2 was N549K (4). VUS in both genes were individually uncommon (no VUS recurring in >3 pts). Median copy number-adjusted clonality of SNVs in FGFR3 was higher than those in FGFR2 (0.80 vs 0.20); this remained true when limiting to only characterized activating mutations (0.84 vs 0.17). Conclusions: cfDNA NGS analysis identifies fusions and a broad spectrum of SNVs in FGFR2/3, including heterogeneous subclonal mutations, at a rate similar to reported tissue testing. cfDNA is a minimally invasive option for pts with aUC to assess candidacy for erdafitinib and clinical trials.
Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score to differentiate between high-grade and low-grade transitional cell carcinoma of the bladder.
Authors: Alanee Shaheen Riadh , Roumayah Zade , Deebajah Musatafa , Peabody James O. , Mora Rodrigo , Guevara Jose , Francisco Brian , Patterson Bruce Kendrick 
Published: February 2020

572 Background: We previously showed that adaptive genetic algorithms (AGA), in combination with single-cell flow cytometry technology, can be used to develop a noninvasive urine-based score to detect bladder cancer with high accuracy. Our aim in this analysis was to investigate if that same score can differentiate between high grade (HG) and low grade (LG) transitional cell carcinoma of the bladder (BC). Methods: We collected urine samples from cystoscopy confirmed HG and LG superficial bladder cancer patients and healthy donors in an optimized urine collection media. We then examined these samples using an assay developed from AGA in combination with single-cell flow cytometry technology. Results: We examined 50 BC and 15 healthy donor urine samples. Patients were majorly White (59.2%), males (61.2%), and had HG BC (66.7%). AGA derived score of 1.1 differentiated between BCa and healthy patients with high precision (AUC 0.92). The median score was 2.8 for LG BC and 6 for LG BC. Mann-Whitney Rank Sum Test indicated that the difference between the median score of HG and LG BC was significant at P value = 0.003. The score performed well independent of patients’ sex or smoking history. Conclusions: Using single-cell technology and machine learning, we developed a new urine-based score that can potentially differentiate between HG and LG bladder cancer. Future studies are planned to validate this score.
Improving quality of health-related quality of life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate cancer (mPC).
Authors: Jiang Di Maria , Wong Bryan , Morgans Alicia K. , Sweeney Christopher , Fizazi Karim , Chi Kim N. , Powles Thomas , Perlis Nathan , Kulkarni Girish S. , Sridhar Srikala S. 
Published: February 2020

58 Background: HRQOL data are increasingly used to guide patient care and health policy. However, their utility can be compromised by inadequate quality of HRQOL reporting (QHR). We aimed to evaluate QHR in phase III RCTs of mPC. Methods: A systematic review following PRISMA guidelines identified published manuscripts of phase III RCTs of mPC assessing systemic therapies (excluding androgen deprivation therapy and bone targeting agents) between 1990 - 2019. Supplements, references and companion publications were reviewed. QHR was independently quantified using the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (MSC, range 0-11) by 2 investigators. QHR is “probably robust” if MSC score is ≥8 and all 3 mandatory items (baseline compliance, missing data, and psychometric properties) are reported; “limited” if score is 5-7; and “very limited” if score is ≤4. Results: HRQOL was the primary (11%), secondary (61%), explorative (21%), and unspecified (7%) endpoint in 57/76 (75%) RCTs, and reported in 46/57 (81%). Primary HRQOL endpoints were pain palliation only. MSC scores ranged 2 – 11. QHR was mostly limited (Table). Most RCTs did not report mode of administration (82%), rationale for selected instrument (65%), or missing data (59%). Other common limitations were: unreported baseline compliance (35%), lack of culturally validated measure (33%), clinical significance not discussed (33%), no hypotheses stated (28%), and inadequate coverage of HRQOL domains (26%). QHR has improved since 2015, with the median MSC score reaching 8 (Table). Conclusions: QHR has improved considerably over time, with many recent phase III RCTs in mPC reporting “probably robust” HRQOL data. Within existing resource constraints however, nonreporting and methodologic deficiencies still remain. The use of standard checklists may further enhance QHR and promote high quality HRQOL research.[Table: see text]
Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.
Authors: Nassar Amin , Agarwal Archana , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , McGregor Bradley Alexander , Talasaz AmirAli , Lanman Richard B. , Sonpavde Guru 
Published: February 2020

6 Background: Penile cancer is a rare disease associated with HPV infection and harbors recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. Among the entire cohort, 51 ctDNA alterations were detected (median=2, range 0-6) in 15/16 patients (94%) across 21 genes (table). Of the 51 alterations, 24 (47%) were actionable and had approved targeted therapies in other cancers. Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), and TERT promoter (5/16, 31%) (table). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected and appeared similar to previously described tumor tissue analyses. New alterations found on serial ctDNA assays shed light on patterns of tumor evolution and may inform drug development for this challenging orphan malignancy.[Table: see text]