bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravesical gemcitabine and docetaxel in the treatment of BCG-naïve non–muscle invasive urothelial carcinoma of the bladder: Updates from a phase 2 trial.
Authors: Patel Sunil H. , Gabrielson Andrew , Collins Connie , Singla Nirmish , Bivalacqua Trinity , Hahn Noah M. , Kates Max R. 
Published: March 2023

507 Background: Combination intravesical Gemcitabine and Docetaxel (GEMDOCE) has demonstrated benefit for bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) in retrospective series and is now being widely utilized as salvage therapy. BCG therapy is fraught with frequent drug shortages and some patients are unable to tolerate BCG due to side effects. Given ongoing BCG shortages as well as the promising efficacy and tolerability of GEMDOCE as a salvage therapy, our objective was to investigate the safety and efficacy of intravesical GEMDOCE for high-risk (HR) BCG-naïve NMIBC in a prospective manner. Methods: This study is an IRB-approved prospective single-arm open-label phase II trial for patients with BCG-naïve HR NMIBC. Intravesical gemcitabine (1,000 mg)/docetaxel (40 mg) in 100mL normal saline is given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary endpoint was 3-month complete response (CR), defined as a negative bladder biopsy 6 weeks after induction treatment. Secondary endpoints included adverse events (AE) and 12-month CR. Results: To date, the study has fully accrued with 25 patients enrolled from July 2020-August 2022. The pre-trial pathologic stages in our cohort were as follows: HGT1 with CIS (n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3) (Table). All 25 patients who completed induction therapy demonstrated CR at 3 months. Eight out of 9 (89%) patients with at least 12 months of follow-up demonstrated continued CR. One patient with HGT1 + CIS on enrollment developed a recurrence at 9 months with HGTa. No enrolled patients have undergone radical cystectomy. Grade 1 AEs were common (19/25 patients, 76%) including hematuria, urinary frequency, urgency, and fatigue. Two patients (8%) experienced a Grade 3 AE including urinary retention and UTI requiring hospitalization and intravenous antibiotics. Conclusions: In this ongoing single-arm phase II trial, GEMDOCE appears to be well-tolerated with promising short-term efficacy for patients with BCG-naïve HR NMIBC. [Table: see text]
Preliminary clinical outcomes of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in patients with advanced urothelial cancer.
Authors: Aggen David H , Hong David S. , Clarke Jeffrey Melson , Asch Adam Steven , Calvo Emiliano , Zugazagoitia Jon , Butler Marcus O. , Moreno Victor , Cervantes Andres , Van Tine Brian Andrew , Lawrence Donald P. , Johnson Melissa Lynne , Brophy Francine Elizabeth , Broad Robyn , Isabelle Martin , Gunn Alasdair , Navenot Jean-Marc , Saro Jose , Norry Elliot , Charlson John A. 
Published: March 2023

517 Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated an acceptable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients with unresectable or metastatic tumors positive for MAGE-A4.1 Here we report updated clinical outcomes in patients with urothelial cancer (UC). Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the patients as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: At ESMO 2022, we reported promising results from SURPASS in several tumour types.2 In the 43 evaluable patients, the overall response rate was 28%, including 1 complete response and 11 partial responses (PR), and an additional 2 unconfirmed PRs awaiting confirmatory scans (as of August 1, 2022). Data from the 7 evaluable patients in the UC subset (updated September 6, 2022) showed that 3 (43%) had a best overall response of PR, and 1 (14%) had an unconfirmed PR. Disease control rate was 100% (3 PR + 1 unconfirmed PR + 3 stable disease). Adverse events have been consistent with those typically observed with lymphodepletion chemotherapy or cellular therapy. This trial is ongoing; data from additional patients with UC treated by January 2023 and updated translational data will be presented. Conclusions: ADP-A2M4CD8 continues to show an acceptable benefit to risk profile in multiple MAGE-A4+ unresectable or metastatic tumors, and preliminary encouraging evidence of efficacy in UC. An additional treatment cohort has been included in the updated trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. 1. Hong DS, et al. E-poster 540P: ESMO 2021; Virtual. 2. Hong DS, et al. Ann Oncol 33(suppl_7); S331-S355, Abstract 735MO. ESMO 2022. Clinical trial information: NCT04044859 .
A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis).
Authors: Kulkarni Girish S. , Richards Kyle A , Black Peter C. , Rendon Ricardo A. , Chin Joseph , Shore Neal D. , Jayram Gautam , Kramolowsky Eugene V. , Saltzstein Daniel , Agarwal Piyush K. , Belkoff Laurence , O'Donnell Michael A. , Kamat Ashish M. , Jewett Michael A.S. , Lamm Donald L. , DeGruttola Victor , Mandel Arkady , Dumoulin-White Roger , Kassouf Wassim 
Published: March 2023

528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]
Prognostic value of integrated liquid biopsies in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Stahlfeld Charlotte , Emamekhoo Hamid , Kaufmann Katherine , Grivas Petros , Ornstein Moshe Chaim , Sheng Iris Yeong- Fung , Burkey Caroline , Sperger Jamie , Bade Rory M. , Schehr Jennifer L. , Taylor Amy K , Shi Yue , Zhao Shuang , Lang Joshua Michael 
Published: March 2023

547 Background: Despite recent therapeutic advancements for patients with mUC, including checkpoint inhibitors (CPIs), anti-FGFR and antibody-drug conjugates (ADCs), biomarker data to predict therapeutic response and identify mechanisms of resistance remain limited. Ongoing randomized clinical trials evaluating the combination of CPIs and ADCs in these pts underscore the need to develop biomarkers to better understand who might best respond to these therapies. Here, we employ a liquid biopsy approach to molecularly characterize circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), including those isolated with Trop-2, the target of the novel drug Sacituzumab Govitecan and Datopotamab Deruxtecan. Methods: 104 blood samples serially collected from pts being treated for mUC were used for CTC collection using anti-EpCAM and Trop-2 antibodies in parallel. CTCs were isolated and stained for immune markers PD-L1 and HLA I using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. Plasma was isolated for paired analysis of CTC and ctDNA content. CTCs were analyzed for enumeration and single-cell protein analysis. Overall survival (OS) was defined from time of sample collection, and survival analyses were performed using the Kaplan-Meier method. Results: We observed significantly shorter OS in pts with higher CTC burden (≥ 20 CTCs/7.5 mL blood) in samples captured with either EpCAM (median 34.1 vs 3.1 mo, P < 0.01) or Trop-2 (median 34.1 vs 6.2 months, P < 0.01). Furthermore, EpCAM and Trop-2 CTC burdens were higher at progression timepoints relative to responding or stable timepoints, when stratified according to treatment modality (table). Inter and intra-patient heterogeneous PD-L1 and HLA I expression and co-expression was observed on CTCs although no significant differences were seen globally between EpCAM and Trop-2 CTCs. In a cohort of pts treated with CPIs, we observed dynamic phenotypic changes in the ratio of HLA:PD-L1 that differed between EpCAM and Trop-2 CTCs. ctDNA analysis identified concordant increases in tumor fraction and acquired genomic mutations. When examined longitudinally across individual pts, these findings in tandem with changes in enumeration, suggest the emergence of different CTC subpopulations that may serve as biomarkers of resistance. Conclusions: We identify the prognostic significance of CTC enumeration with parallel EpCAM and Trop-2 CTC isolation and demonstrate the utility of a liquid biopsy assay that can detect pharmacodynamic changes in CTC burden and immune marker expression throughout the course of treatment. [Table: see text]
Systematic literature review and testing of HER2 status in urothelial carcinoma (UC).
Authors: Koshkin Vadim S , Boyiddle Christine , Schwartz Naomi , Yu Judy , Yu Kristina S. , Kang Ashley , Bloudek Lisa , Fang Qijun , Schafer Johanna M. , Baker Amanda F. , Sayedian Farzaneh H. , Scherrer Emilie 
Published: March 2023

556 Background: Recent clinical trials suggest an emerging role for HER2-targeted therapy in locally advanced and metastatic UC (LA/mUC). The prevalence of HER2 expression and gene amplification (encoded by ERBB2) in LA/mUC has not been well defined, as testing for HER2 expression in LA/mUC is not part of current routine practice and is not standardized. We report (1) findings of a systematic literature review (SLR) of HER2 status in LA/mUC and (2) preliminary results of an ongoing evaluation of HER2 status in UC assaying HER2 protein expression by immunohistochemistry (IHC) and gene amplification by in situ hybridization (ISH). Methods: (1) The SLR used databases PubMed and EMBASE to identify English-language studies of LA/mUC HER2 status published Jan2000 – Oct2021. We used the following definitions: HER2-positive (HER2+) was defined as IHC 3+, or IHC 2+ with HER2 gene amplification (Amp+). HER2-low was defined as IHC 2+/Amp–, or as IHC 1+. HER2-zero was defined as IHC 0. Weighted averages were calculated to estimate population prevalence. (2) Commercially sourced, formalin-fixed paraffin-embedded surgical resections of primary UC were evaluated by trained readers for HER2 protein expression using the VENTANA HER2/neu (4B5) Rabbit Monoclonal Primary Antibody IHC assay and for HER2 gene amplification using the VENTANA HER2 Dual ISH DNA Probe Cocktail that detects both ERBB2 and its residing chromosome, chromosome 17 (Chr17), using a two-color chromogenic stain. HER2 IHC staining was scored based on an established scoring algorithm for gastric cancer. HER2 gene amplification was defined by a HER2/Chr17 ratio ≥2.0. Results: (1) Of 744 records screened for the SLR, 45 studies reported HER2 status, including 10,602 patients (pts) with LA/mUC. A variety of assays and scoring guidelines were used. In the 4 studies (862 pts) reporting data applicable to our predefined criteria for HER2 status, the percentage of HER2+ ranged from 6.7% to 37.5% (weighted average, 13.1%; 95% CI, 7.3%–18.8%). (2) Of 252 UC samples evaluated, 38 were HER2+ (15.1%; 95% CI, 11.2%–20.0%), 74 were HER2-low (29.4%; 95% CI, 24.1%–35.3%), and 140 were HER2-zero (55.5%; 95% CI: 49.4%–61.6%; Table). The HER2 gene was amplified in 31 (12.3%), among them 24 (77.4%) at stage III or IV muscle-invasive UC (MIUC). Conclusions: The SLR revealed wide variability of HER2 status in LA/mUC, highlighting a lack of standardized methods for assessing and defining HER2 status. In our large study using standardized laboratory methods, 44% of UC samples were HER2+ or HER2-low, and HER2 status distribution was consistent with that reported for pts with LA/mUC. Results suggest a potentially important role for HER2-targeted therapy for UC. [Table: see text]
Evaluating technical feasibility of a urine cell-free DNA (cfDNA) NGS assay for identifying biomarkers in bladder cancer.
Authors: Kim Il-Jin , Quiroz Michelle , Zhao Zhixin , Mo Wei , Zheng Tiantian , Wang Amy , Singh Usha , Beeharry Neil , Smirnov Denis , Wang Songbai , Tate Renee , Zhang Tom , Liu Fang , Hanumanthe Seema , Xiang Binggang , Luo Shujun , Kuklin Alexander , Wirtz Ralph M. , Du Pan , Jia Shidong 
Published: March 2023

565 Background: Bladder cancer is one of the most common cancers worldwide. In 2022, about 81,000 people were diagnosed with this disease and 17,000 died from it (www.cancer.org). Despite significant breakthroughs in targeted medicines (i.e., Erdafitinib, FGFR2/3 kinase inhibitor) and clinical care over the past decade, non-invasive molecular testing remains an unmet clinical need for the treatment of bladder cancer patients. By contrasting the results with those from the FDA-approved tissue-based CDx assay, we assess the clinical utility of a urine NGS assay for identifying biomarkers, including mutations from FGFR genes. Methods: Paired urine and tissue samples were collected from 107 (muscle and non-muscle invasive) bladder cancer patients from the Bladder BRIDGister clinical trial in Germany. Tissue specimens were analyzed using the FDA approved Qiagen therascreen FGFR RGQ RT-PCR kit while matched urine samples were processed using the PredicineCARE urine (cell-free DNA) cfDNA NGS assay with detection sensitivity of 0.3% (0.1% for hotspot mutations). One hundred seven bladder cancer urine cfDNA NGS and tissue RT-PCR results were analyzed to determine the concordance (PPA and NPA) between these two assays. A smaller sample set was also used to compare tissue NGS to therascreen RT-PCR and tissue NGS to urine cfDNA NGS. A subset of discordant mutations were additionally validated by ddPCR. Results: For the concordance analysis between PredicineCARE Urine cfDNA NGS and therascreen tissue RT-PCR assay of 107 samples, PPA was 100% (20/20, 95% CI: 83.2-100) and NPA was 94.1% (48/51, 95% CI: 83.8-98.8). Three discrepant samples (tissue FGFR negative but urine positive for FGFR genes) were further analyzed by independent orthogonal ddPCR (Bio-Rad ddPCR Mutation Detection Assay). All tissue FGFR negative but urine positive samples were confirmed positive by ddPCR. PPA and NPA between PredicineCARE Urine cfDNA and Tissue NGS were 100% (19/19, 95% CI: 82.4-100) and 94.2% (49/52, 95% CI: 84.1-98.8) respectively. PPA and NPA between PredicineCARE Tissue NGS and Therascreen FGFR RGQ RT-PCR kit were both > 95%. Conclusions: High concordance between FGFR alterations detected with an FDA approved tissue CDx and urine cfDNA NGS assay demonstrates that the PredicineCARE urine cfDNA NGS assay may represent a novel, accurate, and non-invasive clinical application for molecular diagnostic testing to identify biomarkers in bladder cancer.
Extracellular domain ERBB2 (ERBB2 ECD+) mutations in urothelial bladder cancer (UBC).
Authors: Basin Michael , Jacob Joseph M , Bratslavsky Gennady , Grivas Petros , Spiess Philippe E. , Li Roger , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Sokol Ethan , Sivakumar Smruthy , Ross Jeffrey S. 
Published: March 2023

566 Background: Given the recent approval in lung cancer for the first anti-HER2 targeted therapy directed against activating kinase domain exon 20 ERBB2 insertion mutations, considerable interest has arisen in targeting additional locations in the ERBB2 gene in other tumor types. Methods: 5,485 UBC samples were sequenced using a hybrid capture-based comprehensive genomic profiling (CGP) assay to assess all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), trinucleotide signatures and predominant genetic ancestry. Statistical comparisons utilized the Bonferroni correction. Results: 548 (10.0%) of UBC featured ERBB2 gene amplification (amp) and 219 (4.0%) featured an ERBB2 ECD+ sequence mutation (74% S310F and 26% S310Y). ERBB2 ECD+ mutations and ERBB2 amplification were mutually exclusive. 16.4% of ERBB2 ECD+ UBC had more than one E RBB2 sequence mutation. Central pathology review of the 219 ERBB2 ECD+ UBC revealed that 63 (28.8%) featured a micropapillary histologic appearance (MPUC). ERBB2 ECD+ UBC featured more patients with European ancestry than both ERBB2 WT (90.9% vs 84.2%; p=.03) and ERBB2 amp (90.9% vs 83.2%; p=.04). ECD mut+ UBC also featured lower association with African ancestry than ERBB2 amp (2.7% vs 7.8%; p=.04) and lower frequency of gLOH > 16% (9.3% vs 19.1%; p=.04). MSI-High status was similar and rare in all 3 groups (range 0 to 0.9%). ERBB2 ECD+ UBC had a higher frequency of APOBEC signature than ERBB2 amp (82.9% vs 72.4%; p=.03). TMB > 10 mut/mb was higher in ERBB2 amp (49.2% vs 31.4%; p<.0001) and ERBB2 ECD+ (59.8% vs 31.4%; p<.0001) compared to ERBB2 WT as was the mean TMB (11.8 and 17.4 mut/Mb respectively vs 8.9 mut/Mb, p<0.001 for both). Among important UBC individual genes, FGFR3 GA were significantly higher in ERBB2 WT than both ERBB2 amp (19.9% vs 6.2%; p<.0001) and ERBB2 ECD+ (19.9% vs 10.5%; p=.0002). CDKN2A GA were significantly higher in ERBB2 amp (39.1% vs 27.9% ERBB2 WT; p<.0001) only. The higher frequency of KMT2D GA in MPUC+ ECD+ and MPUC- ECD+ UBC (63.4% vs 27.6%; p=.02) was the only genomic difference between these cohorts. Conclusions: ERBB2 ECD mutation driven UBC is a unique form of UBC featuring enrichment of MPUC histology and a unique clinical and genomic landscape including genomic signatures and ancestry.
Identification of lineage-specific transcription factor defined subtypes in small cell/neuroendocrine bladder cancer.
Authors: Choi Woonyoung , Feng Mingxiao , Epstein Gabriel , Hoffman-Censits Jean H. , Kates Max R. , Czerniak Bogdan , Comperat Eva , Matoso Andres , Kim Seungchan , McConkey David James 
Published: March 2023

568 Background: Small cell/neuroendocrine bladder cancer (SCBC) is a rare and clinically aggressive disease. However, its molecular characteristics are poorly studied; hence, biology-based therapeutic options are not available. Strong pan-cancer similarity in gene expression signature of neuroendocrine (NE) tumors including SCBC and small cell lung cancer (SCLC) has been reported. Recent genomics studies discovered that SCLC can be grouped into lineage- specific transcription factor (TF)-defined subtypes. Therefore, we explored whether TF-defined molecular subtypes could also be observed in SCBC with the goal of developing subtype-specific therapeutic strategies. Methods: Whole transcriptome RNAseq on a cohort of n = 44 pure SCBCs collected at Johns Hopkins (n=20) and Tenon Hospital (Paris) (n=24) and DNA panel sequencing on subset of the tumors (n=24) were performed. Two expert genitourinary pathologists selected the cases for the analyses based on the histopathological characteristics of the tumor tissue. Results: SCBC tumors displayed overexpression of canonical NE markers and high mutation rates in TERT, TP53 and RB1 with 92%, 75% and 38%, respectively, confirming the concordance between genomic features and histopathologic characteristics.Lineage-specific TFs (ASCL1, NEUROD1, and POU2F3) defined three molecular subtypes of SCBC that resembled the previously reported SCLC subtypes. The three subtypes expressed variable levels of NE biomarkers and were heterogeneous with respect to distinct downstream therapeutic targets. The ASCL1 and NEUROD1 subtypes expressed the highest levels of NE lineage-specific gene expression and were associated with expression of known regulators of the neuroendocrine phenotype including FOXA2 and HES6, respectively. The ASCL1 subtype was also enriched with DLLs and other genes that control oncogenic Notch signaling, whereas tumors enriched with POU2F3, a master regulator of the NE-low SCBC subtype, expressed TRPM5, SOX9 and CHAT. Finally, an inverse association between NE lineage-specific gene expression and immune signatures associated with response to immunotherapy was observed. Conclusions: Three lineage-specific TFs (ASCL1, NEUROD1, and POU2F3) defined discrete molecular subtypes in SCBC. Each subtype was characterized by distinct therapeutic targets and gene expression signatures associated with response to immunotherapy. Future studies will be required to test the clinical relevance of these observations.