107 results on '"Bishoy Faltas"'
Search Results
2. Validation of a Circulating Tumor <scp>DNA</scp>-Based <scp>Next-Generation</scp> Sequencing Assay in a Cohort of Patients with Solid tumors: A Proposed Solution for Decentralized Plasma Testing
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Kenneth Wha Eng, Ellen L. Verner, David Wilkes, Kentaro Ohara, Shaham Beg, John K. Simmons, Erika Hissong, Juan Miguel Mosquera, Aanavi Karandikar, Troy Kane, Bishoy Faltas, Kevin Holcomb, Manish A. Shah, Scott T. Tagawa, Eniko Papp, Nasser K. Altorki, Michael Sigouros, Ana M. Molina, Hussein Alnajar, Emily Patchell, Wael Al Zoughbi, Cora N. Sternberg, Murtaza Malbari, Rohan Bareja, Andrea Sboner, Samuel V. Angiuoli, Yariv Houvras, Laurel Keefer, Violeta Beleva Guthrie, Noah Greco, Donna Nichol, David M. Nanus, Daniel Bockelman, Gustavo C. Cerqueira, Olivier Elemento, Jesse Fox, and Jyothi Manohar
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cancer Diagnostics and Molecular Pathology ,Concordance ,Microsatellite instability status ,Cancer immunotherapy ,DNA sequencing ,Neoplasms ,Internal medicine ,medicine ,Humans ,Liquid biopsy ,Retrospective Studies ,Circulating tumor DNA ,Molecular pathology ,business.industry ,High-Throughput Nucleotide Sequencing ,Microsatellite instability ,Cancer ,Retrospective cohort study ,medicine.disease ,Primary tumor ,Microsatellite Instability ,business - Abstract
Background Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on‐site plasma‐based next‐generation sequencing (NGS) assays still needs to be proved. Materials and Methods In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell‐free DNA (cfDNA). Results The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI‐high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer. Conclusion Our validation experience of a plasma‐based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in‐house method that minimizes the need for invasive procedures, on‐site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice. Implications for Practice This study proposes a solution for decentralized liquid biopsy testing based on validation of a next‐generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single‐site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on‐site plasma‐based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors., This report describes the concordance between circulating tumor DNA and matched tumor tissue molecular profiles, discusses interpretation of observed discordant data, and illustrates applications through clinical cases. It is the first known report to evaluate the performance of an on‐site plasma‐based next‐generation sequencing test to detect microsatellite instability status along with common sequence alterations in the context of its clinical utility and therapeutic applications in precision oncology.
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- 2021
3. Spectrum of FGFR2/3 Alterations in Cell-Free DNA of Patients with Advanced Urothelial Carcinoma
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Sumati Gupta, Theodore Stewart Gourdin, Aaron Hardin, Petros Grivas, Lesli A. Kiedrowski, Roby Antony Thomas, Nicholas J. Vogelzang, Guru Sonpavde, Kimberly M. Hamann, and Bishoy Faltas
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,business.industry ,030220 oncology & carcinogenesis ,Urology ,Cancer research ,Medicine ,business ,Free dna ,Urothelial carcinoma - Abstract
Detecting genomic alterations (GAs) in advanced urothelial carcinoma (aUC) can expand treatment options by identifying candidates for targeted therapies. Erdafitinib is FDA-approved for patients with platinum-refractory aUC with activating mutation or fusion in FGFR2/3. We explored the prevalence and spectrum of FGFR2/3 GAs identified with plasma cfDNA NGS testing (Guardant360) in 997 patients with aUC. FGFR2/3 GAs were detected in 201 patients (20%) with characterized activating GAs in 141 (14%). Our results indicate the Guardant360-based FGFR2/3 GA detection rate is similar to those described from previous studies employing tumor tissue testing, suggesting that plasma-based cfDNA NGS may non-invasively identify candidates for anti-FGFR targeted therapies.
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- 2021
4. Immune Checkpoint Inhibitors and Long-term Survival of Patients With Metastatic Urothelial Cancer
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Alec Zhu, Jorge Alberto Garcia, Bishoy Faltas, Petros Grivas, Pedro Barata, and Jonathan E. Shoag
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General Medicine - Abstract
This cohort study uses published clinical trial data to assess long-term survival of patients with metastatic urothelial carcinoma who are treated with immune checkpoint inhibitors.
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- 2023
5. The evolution of genomic, transcriptomic, and single-cell protein markers of metastatic upper tract urothelial carcinoma
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Bishoy Faltas, Shaham Beg, David Wilkes, Kenneth Wha Eng, Brian D. Robinson, André F. Rendeiro, Aram Vosoughi, Bhavneet Bhinder, Rohan Bareja, Kyrillus S. Shohdy, Jyothi Manohar, Kentaro Ohara, Juan Miguel Mosquera, Scott T. Tagawa, David J. Pisapia, Hiranmayi Ravichandran, Olivier Elemento, Francesca Khani, Andrea Sboner, and Evan Fernandez
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Transcriptome ,medicine.anatomical_structure ,Stromal cell ,Immune system ,Cell ,Cancer cell ,medicine ,Cancer research ,biology.protein ,Mass cytometry ,Biology ,Antibody ,Subtyping - Abstract
The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are unknown. The genomic and transcriptomic differences between primary and metastatic UTUC is not well described either. We combined whole-exome sequencing, RNA-sequencing, and Imaging Mass Cytometry™ (IMC™) of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. IMC enables spatially resolved single-cell analyses to examine the evolution of cancer cell, immune cell, and stromal cell markers using mass cytometry with lanthanide metal-conjugated antibodies. We discovered that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature were stable across primary and matched metastatic UTUC. Molecular and immune subtypes were consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single-cells. Molecular subtyping at the single cell level was highly conserved between primary and metastatic UTUC tumors within the same patient.
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- 2021
6. Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab
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Hussein, Alnajar, Hiranmayi, Ravichandran, André, Figueiredo Rendeiro, Kentaro, Ohara, Wael, Al Zoughbi, Jyothi, Manohar, Noah, Greco, Michael, Sigouros, Jesse, Fox, Emily, Muth, Samuel, Angiuoli, Bishoy, Faltas, Michael, Shusterman, Cora N, Sternberg, Olivier, Elemento, and Juan Miguel, Mosquera
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Male ,Carcinoma, Transitional Cell ,Antineoplastic Agents, Immunological ,Urinary Bladder Neoplasms ,Tumor Microenvironment ,Humans ,Female ,Sarcoma ,Soft Tissue Neoplasms ,Antibodies, Monoclonal, Humanized ,B7-H1 Antigen ,Image Cytometry - Abstract
Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.
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- 2021
7. Functional comparison of exome capture-based methods for transcriptomic profiling of formalin-fixed paraffin-embedded tumors
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Juan Miguel Mosquera, Jyothi Manohar, Andrea Sboner, Michael Sigouros, Rob Kim, Bishoy Faltas, David Wilkes, Kentaro Ohara, Kenneth Eng, Princesca Dorsaint, Rohan Bareja, Olivier Elemento, Jenny Xiang, Daniel Bockelman, Alicia Alonso, and Kyrillus S. Shohdy
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Oncology ,medicine.medical_specialty ,Formalin fixed paraffin embedded ,Molecular medicine ,business.industry ,Concordance ,QH426-470 ,Article ,Transcriptome ,Precision oncology ,Exome capture ,Internal medicine ,Genetics ,medicine ,Fresh frozen ,Cancer genomics ,Medicine ,business ,Molecular Biology ,Immune gene ,Exome ,Genetics (clinical) - Abstract
The availability of fresh frozen (FF) tissue is a barrier for implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture platforms have been developed for RNA-seq from FFPE samples. However, these methods have not been systematically compared. We performed transcriptomic analysis of 32 FFPE tumor samples from 11 patients using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to the TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features. The Spearman’s correlation coefficients between the global expression profiles of the three capture-based methods from FFPE and matched FF-TruSeq were high (rho = 0.72–0.9, p p ERBB2, MET, NTRK1, and PPARG. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtype concordance with FF-TruSeq (Cohen’s k = 0.7, p
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- 2021
8. Impact of Use of Antibiotics on Response to Immune Checkpoint Inhibitors and Tumor Microenvironment
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Kaylee Ho, Sarah Oh, Cristian Peña, Doron Betel, Katherine Hoffman, Erika Hissong, Uqba Khan, Arindam RoyChoudhury, Gregory F. Sonnenberg, Ashish Saxena, Manish A. Shah, Bishoy Faltas, Eun Kyeong Hwang, Kaitlin Eng Weisiger, and Julianna Brouwer
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Antibiotics ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Neoplasms ,medicine ,Tumor Microenvironment ,Humans ,030212 general & internal medicine ,Immune Checkpoint Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,Tumor microenvironment ,Univariate analysis ,business.industry ,Retrospective cohort study ,Odds ratio ,Immunotherapy ,Middle Aged ,medicine.disease ,Prognosis ,Immune checkpoint ,Anti-Bacterial Agents ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,business ,Follow-Up Studies - Abstract
BACKGROUND Antibiotic use can result in reduced efficacy of immune checkpoint blockade (ICB), presumably because of dysbiosis of the intestinal microbiome. We sought to determine the precise temporal relation between antibiotic therapy and its possible effects on ICB efficacy. We also investigated the histologic changes in the tumor microenvironment secondary to antibiotics use. METHODS AND OBJECTIVES This was a single institution retrospective study that evaluated the impact of antibiotics on outcomes of patients with advanced or metastatic malignancy who were treated with ICB. Use of antibiotics among patients treated with ICB was assessed during a 12-week period before and after initiation of ICB. The primary outcome was response to ICB. Histologic changes in the tumor microenvironment following antibiotics use were also examined. RESULTS Between January 1, 2011 and December 31, 2018, 414 patients were identified who received ICB, and 207 patients (50%) received antibiotics within 12 weeks (before/after) of initiation of ICB. In univariate analysis, antibiotic use following initiation of ICB was associated with a significantly reduced response (odds ratio [OR]: 0.33, 95% confidence interval [CI]: 0.2-0.52, P
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- 2021
9. Functional Comparison of Different Exome Capture-based Methods for Transcriptomic Profiling of Formalin-Fixed Paraffin-Embedded Tumor Samples
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Princesca Dorsaint, Robert Kim, Alicia Alonso, Olivier Elemento, Jyothi Manohar, Michael Sigouros, David Wilkes, Jenny Xiang, D. Bockelman, Andrea Sboner, Juan Miguel Mosquera, Rohan Bareja, Bishoy Faltas, and Kyrillus S. Shohdy
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Transcriptome ,Formalin fixed paraffin embedded ,Concordance ,Exome capture ,Fresh frozen ,Computational biology ,Biology ,Exome ,Immune gene ,Subtyping - Abstract
BackgroundThe need for fresh frozen (FF) tissue limits implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are processed in clinical laboratories and stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture has recently emerged as a promising approach for RNA-seq from FFPE samples. Multiple exome capture platforms are now available. However, their performances have not been systematically compared.MethodsTranscriptomic analysis of 32 FFPE tumor samples from 11 patients was performed using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features, including the expression of key immune genes, expression outliers often associated with actionable genes, gene expression-based subtypes, and fusions using each of these capture methods.ResultsThe Spearman’s correlation coefficients between global expression profiles of the three capture-based methods and matched FF tumor samples, analyzed using TruSeq RNA-seq, were high (rho = 0.72-0.9, p < 0.05). There was a significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88, p < 0.05). All three exome capture-based methods reliably detected the outlier expression of actionable genes, including ERBB2, MET, NTRK1, and PPARG, initially detected in FF-TruSeq. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtyping agreement with FF-TruSeq (Cohen’s k = 0.7, p < 0.01). Both Agilent and IDT detected all the clinically relevant fusions which were initially identified in FF-TruSeq.ConclusionAll exome capture-based methods had comparable performance and concordance with FF-TruSeq. These findings provide a path for the transcriptomic profiling of vast numbers of FFPE currently stored in biobanks. For specific applications such as fusion detection and gene expression-based subtyping, some methods performed better. By enabling the interrogation of FFPE tumor samples, our findings open the door for implementing RNA-seq in the clinic to guide precision oncology approaches.
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- 2021
10. Integration of whole-exome and anchored PCR-based next generation sequencing significantly increases detection of actionable alterations in precision oncology
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Michael Sigouros, Andrea Sboner, Olivier Elemento, Kenneth Wha Eng, Jyothi Manohar, Francesca Khani, Wael Al Zoughbi, Wei Zhang, Sarah Kudman, Jenny Xiang, Bishoy Faltas, Shaham Beg, David Wilkes, David J. Pisapia, Rema Rao, Cora N. Sternberg, Troy Kane, Himisha Beltran, Kentaro Ohara, Brian D. Robinson, Rohan Bareja, and Juan Miguel Mosquera
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0301 basic medicine ,Original article ,Cancer Research ,Computational biology ,Biology ,lcsh:RC254-282 ,DNA sequencing ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Anchored multiplex PCR-based next-generation sequencing ,Multiplex polymerase chain reaction ,Oncogenic ,medicine ,Exome ,Exome sequencing ,RNA Sequencing ,Novel fusion ,Cancer ,Precision medicine ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,Precision oncology ,030220 oncology & carcinogenesis ,Whole-exome sequencing - Abstract
Highlights • NGS-based clinical studies have reported detection of clinically relevant alterations in ∼30% of patients. • To increase the detection of potential targets, we integrated whole-exome sequencing with a multiplex PCR-based NGS assay for fusion detection. • The targeted transcriptome sequencing was performed using a very low RNA input from archival cancer tissues. • With this integrated approach, we demonstrate a significant increase in detection of targetable genomic alterations in cancer patients., Background Frequency of clinically relevant mutations in solid tumors by targeted and whole-exome sequencing is ∼30%. Transcriptome analysis complements detection of actionable gene fusions in advanced cancer patients. Goal of this study was to determine the added value of anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) assay to identify further potential drug targets, when coupled with whole-exome sequencing (WES). Methods Selected series of fifty-six samples from 55 patients enrolled in our precision medicine study were interrogated by WES and AMP-based NGS. RNA-seq was performed in 19 cases. Clinically relevant and actionable alterations detected by three methods were integrated and analyzed. Results AMP-based NGS detected 48 fusions in 31 samples (55.4%); 31.25% (15/48) were classified as targetable based on published literature. WES revealed 29 samples (51.8%) harbored targetable alterations. TMB-high and MSI-high status were observed in 12.7% and 1.8% of cases. RNA-seq from 19 samples identified 8 targetable fusions (42.1%), also captured by AMP-based NGS. When number of actionable fusions detected by AMP-based NGS were added to WES targetable alterations, 66.1% of samples had potential drug targets. When both WES and RNA-seq were analyzed, 57.8% of samples had targetable alterations. Conclusions This study highlights importance of an integrative genomic approach for precision oncology, including use of different NGS platforms with complementary features. Integrating RNA data (whole transcriptome or AMP-based NGS) significantly enhances detection of potential targets in cancer patients. In absence of fresh frozen tissue, AMP-based NGS is a robust method to detect actionable fusions using low-input RNA from archival tissue.
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- 2021
11. Common germline-somatic variant interactions in advanced urothelial cancer
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David Wilkes, Tuo Zhang, David M. Nanus, Olivier Elemento, Bishoy Faltas, Xiao Fan, Cora N. Sternberg, Bhavneet Bhinder, Himisha Beltran, Scott T. Tagawa, Jenny Xiang, Mark A. Rubin, Andrea Sboner, Ana M. Molina, Samaneh Motanagh, Aram Vosoughi, Panagiotis J. Vlachostergios, Kyrillus S. Shohdy, Wendy K. Chung, Juan Miguel Mosquera, and Brian D. Robinson
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0301 basic medicine ,Urologic Neoplasms ,Somatic cell ,Science ,Loss of Heterozygosity ,General Physics and Astronomy ,Disease ,Biology ,Genome ,Article ,General Biochemistry, Genetics and Molecular Biology ,Germline ,Cohort Studies ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Cancer genomics ,medicine ,Humans ,Urothelial cancer ,Germ-Line Mutation ,Neoplasm Staging ,Multidisciplinary ,Genome, Human ,Bladder cancer ,Proteins ,Cancer ,General Chemistry ,medicine.disease ,Biological Evolution ,030104 developmental biology ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research - Abstract
The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients., The role of germline variation in human cancers is not fully understood. Here, the authors define the landscape of putative deleterious germline variants that abrogate tumor suppressor proteins in advanced urothelial cancer patients.
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- 2020
12. Defining the transcriptional landscape of infiltrating immune cells in human and mouse bladder cancer
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David J. Mulholland, Li Wang, Matthew D. Galsky, Nina Bhardwaj, Bishoy Faltas, Jun Zhu, Olivier Elemento, Jorge Daza, Haocheng Yu, and John P. Sfakianos
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Cell type ,Immune system ,LAG3 ,Bladder cancer ,Tumor progression ,medicine.medical_treatment ,medicine ,Cancer research ,Cancer ,Immunotherapy ,Biology ,medicine.disease ,Immune checkpoint - Abstract
SummaryThe tumor immune cell landscape is composed of infiltrating myeloid cells (TIMs) and lymphocytes (TILs) that are important for regulating tumor progression and response to immune therapies. Since at least 70% of bladder cancer patients are poorly responsive to immune checkpoint blockade, there is a need for in depth analysis of the immune landscape both within individual tumor samples and between patients. To facilitate this, we have conducted single cell RNA sequencing (scRNA-seq) to map and transcriptionally define immune cells from 10 human bladder tumors. While all human tumors showed the of presence of major immune cell types, significant differences were observed in the relative numbers of these populations. To determine the translational utility of these findings we also performed scRNA-seq of TIMs-TILs isolated from mouse bladder tumors that were induced by the BBN carcinogen. In human and mouse comparison, we identified significant cross-species conservation in gene expression programs for NK, T, dendritic cells, monocytes and macrophages immune cell populations. Our data identified the conserved expression of key immunotherapy targets between human and mouse tumors including coordinately high gene expression of PD-1, CTLA and IDO1 while also noting species divergent expression of TIM3, LAG3 and CD274 (PDL-1). To identify predictive immune cell-tumor interactions we computed conserved ligand-receptor (cell-cell) interaction scores between immune cell subsets and the epithelial tumor compartment. Together, this study defines the transcriptional status of bladder cancer immune cells and provides the rationale for future studies related to treatment response and therapeutic resistance.
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- 2020
13. Epithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers
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David J. Mulholland, Matthew D. Galsky, Yang Hu, Harry Anastos, Olivier Elemento, Geoffrey Bryant, Jorge Daza, Bishoy Faltas, Rohan Bareja, Ketan K. Badani, and John P. Sfakianos
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0301 basic medicine ,Lineage (genetic) ,Science ,Cell Plasticity ,General Physics and Astronomy ,Tumor initiation ,Urological cancer ,Biology ,Integrin alpha6 ,General Biochemistry, Genetics and Molecular Biology ,Article ,Transcriptome ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Single-cell analysis ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Cell Lineage ,lcsh:Science ,Cancer ,Regulation of gene expression ,Multidisciplinary ,Bladder cancer ,Gene Expression Profiling ,General Chemistry ,medicine.disease ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cell Transformation, Neoplastic ,Phenotype ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Cancer research ,Keratin-5 ,lcsh:Q ,Single-Cell Analysis - Abstract
Tumor heterogeneity is common in cancer, however recent studies have applied single gene expression signatures to classify bladder cancers into distinct subtypes. Such stratification assumes that a predominant transcriptomic signature is sufficient to predict progression kinetics, patient survival and treatment response. We hypothesize that such static classification ignores intra-tumoral heterogeneity and the potential for cellular plasticity occurring during disease development. We have conducted single cell transcriptome analyses of mouse and human model systems of bladder cancer and show that tumor cells with multiple lineage subtypes not only cluster closely together at the transcriptional level but can maintain concomitant gene expression of at least one mRNA subtype. Functional studies reveal that tumor initiation and cellular plasticity can initiate from multiple lineage subtypes. Collectively, these data suggest that lineage plasticity may contribute to innate tumor heterogeneity, which in turn carry clinical implications regarding the classification and treatment of bladder cancer., Recent studies have utilized bulk tumour mRNA sequencing to classify bladder cancers into distinct subgroups. Here, the authors use single cell transcriptomic analysis and cell transplant studies to show that epithelial plasticity can generate basal, luminal and mesenchymal phenotypes in human and murine bladder cancers.
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- 2020
14. Molecular Characterization of Upper Tract Urothelial Carcinoma in the Era of Next-generation Sequencing: A Systematic Review of the Current Literature
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Bishoy Faltas, Shahrokh F. Shariat, John P. Sfakianos, Morgan Rouprêt, James W.F. Catto, Freddie Bray, Surena F. Matin, Arndt Hartmann, Melanie R. Hassler, Arthur P. Grollman, and Vitaly Margulis
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Carcinoma, Transitional Cell ,Bladder cancer ,business.industry ,Ureteral Neoplasms ,Urology ,030232 urology & nephrology ,Microsatellite instability ,High-Throughput Nucleotide Sequencing ,Context (language use) ,Genomics ,Computational biology ,Precision medicine ,medicine.disease ,Kidney Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Systematic review ,Molecular Diagnostic Techniques ,030220 oncology & carcinogenesis ,DNA methylation ,Medicine ,Humans ,business ,Epigenomics - Abstract
Context While upper tract urothelial carcinoma (UTUC) share histological appearance with bladder cancer (BC), the former has differences in etiology and clinical phenotype consistent with characteristic molecular alterations. Objective To systematically evaluate current genomic sequencing and proteomic data examining molecular alterations in UTUC. Evidence acquisition A systematic review using PubMed, Scopus, and Web of Science was performed in December 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Evidence synthesis A total of 46 publications were selected for inclusion in this report, including 13 studies assessing genome-wide alterations, 18 studies assessing gene expression or microRNA expression profiles, three studies assessing proteomics, one study assessing genome-wide DNA methylation, and 14 studies evaluating distinct pathway alteration patterns. Differences between sporadic and hereditary UTUC, and between UTUC and BC, as well as molecular profiles associated with exposure to aristolochic acid are highlighted. Molecular pathways relevant to UTUC biology, such as alterations in FGFR3, TP53, or microsatellite instability, are discussed. Our findings are limited by tumor and patient heterogeneity and different platforms used in the studies. Conclusions Molecular events in UTUC and BC can be shared or distinct. Consequently, molecular subtypes differ according to location. Further work is needed to define the epigenomic and proteomic features of UTUC, and understand the mechanisms by which they shape the clinical behavior of UTUC. Patient summary We report the current data on the molecular alterations specific to upper tract urothelial carcinoma (UTUC), resulting from novel genomic and proteomic technologies. Although UTUC biology is comparable with that of bladder cancer, the rates and UTUC-enriched alterations support its uniqueness and the need for precision medicine strategies for this rare tumor type.
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- 2020
15. Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes
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Emil Christensen, Lars Dyrskjøt, Hikmat Al-Ahmadie, Joshua J. Meeks, Bishoy Faltas, David J. DeGraff, David J. McConkey, Thomas W. Flaig, John A. Taylor, and Benjamin L. Woolbright
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0301 basic medicine ,Tumour heterogeneity ,Urology ,medicine.medical_treatment ,Drug resistance ,medicine.disease_cause ,Article ,Metastasis ,03 medical and health sciences ,Genetic Heterogeneity ,0302 clinical medicine ,Medicine ,Humans ,Chemotherapy ,Mutation ,Carcinoma, Transitional Cell ,Bladder cancer ,Genome ,business.industry ,Immunotherapy ,medicine.disease ,Clinical trial ,030104 developmental biology ,Treatment Outcome ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Cancer research ,business - Abstract
Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.
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- 2020
16. The emerging landscape of germline variants in urothelial carcinoma: Implications for genetic testing
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Guru Sonpavde, Amin Nassar, Bishoy Faltas, Sarah Abou Alaiwi, Panagiotis J. Vlachostergios, and Maria I. Carlo
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0301 basic medicine ,Cancer Research ,Genetic testing ,DNA repair ,Germline variants ,Disease ,Bioinformatics ,Germline ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Family history ,Gene ,RC254-282 ,Bladder cancer ,medicine.diagnostic_test ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Lynch syndrome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Urothelial carcinoma ,business - Abstract
Urothelial carcinoma (UC) of the bladder and upper tract (ureter, renal pelvis) is one of the most frequently occurring malignancies. While the majority of UC are chemically induced by smoking, accumulating evidence from genetic studies have demonstrated a small, but consistent impact of heritable gene variants and family history of UC on the development of the disease. Beyond the established association between upper tract UC and germline mismatch DNA repair defects as a defining feature of Lynch syndrome, newer investigations focusing on moderate- and high-risk cancer-related gene variants in DNA damage repair and other signaling pathways are expanding our knowledge on the heritable genetic basis of UC, opening new avenues in the breadth of genetic testing and in clinical counseling of these patients. Overcoming existing challenges in the interpretation of uncertain findings and family cascade testing may help expand our testing approach and guidelines. Following the paradigm of other tumor types, such as breast and ovarian cancers, germline genetic testing, particularly when combined with somatic testing, has the potential to directly benefit affected UC patients and their families in the future through therapeutic targeting (i.e. with poly(ADP-ribose)) polymerase inhibitors, immune checkpoint inhibitors) and genetically informed screening/surveillance, respectively.
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- 2019
17. Open label phase II trial of cabozantinib (cabo) in patients with metastatic castrate resistant prostate cancer (mCRPC) and known amplifications or activating mutations in gene targets who have received prior anti-androgen therapy
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Karla V. Ballman, Scott T. Tagawa, Ana M. Molina, Amie Patel, Bishoy Faltas, Jones T. Nauseef, Himisha Beltran, Brian D. Robinson, David M. Nanus, Mark N. Stein, Charles G. Drake, Sharon Singh, Francesca Khani, Emerson A. Lim, Elisabeth I. Heath, Angela Tan, and Cora N. Sternberg
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Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Cabozantinib ,Gene targets ,business.industry ,Population ,Anti-Androgen ,Castrate-resistant prostate cancer ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,In patient ,Open label ,business ,education - Abstract
TPS5095 Background: Despite a variety of therapy classes extending survival in mCRPC – and excepting select population eligible for PARP inhibitors – no molecularly selected drugs are FDA approved in mCRPC. Previously, cabo, an inhibitor of multiple tyrosine kinases ( e.g. MET, VEGFRs 1-3, RET, KIT, TRKB, FLT-3, AXL, TIE-2), was evaluated in phase III trials (COMET-1, COMET-2) in mCRPC. Despite initial promising results, particularly in bone scan responses and rPFS benefit, further application of cabo in mCRPC was halted after improvement in OS was not observed. It is unclear why prolonged rPFS in COMET-1 (vs. prednisone) did not translate into improved OS. Previous failures may reflect inclusion of relatively cabo-insensitive tumors due to an unselected population with regard to presumed cabo activity. Given that mCRPC specimens from our precision medicine cohort have increased expression of target genes MET and KIT, and qualifying genomic alterations (amplifications, activating mutations) are reported in ̃15% of a publicly-available mCRPC cohort, we developed this rationally-designed study. We predict a molecularly-defined mCRPC cohort will identify the population that most benefits from cabo therapy, as reflected by prolonged rPFS and OS, and more frequent PSA declines and CTC conversions. Methods: We have activated a phase II non-randomized, open label trial designed to evaluate treatment response and survival of patients with mCRPC who harbor evidence of increased signaling of the targets of cabo. Study population will have progressed on an ARSI; prior taxane therapy in castration-sensitive PC or CRPC (beyond 12 mos) will be eligible. Molecular eligibility: DNA (tumor or cfDNA) evidence of amplification or activating mutation in selected targets of cabo. Alternatively, IHC confirming high expression (2 or 3+) via CLIA-approved assay is allowed. Overexpression via RNAseq, validated by CLIA-approved IHC, is permitted. All patients will receive 40 mg/d of cabo, with dose-reductions allowed (to 20 mg/d, then 20 mg EOD). Repeat biopsy after 3 weeks on treatment is mandated. Primary endpoint is rPFS. Using median of 5.6 mos (COMET-1) to guide our H0 (50% rPFS rate at 6 mo), the H1 is ≥75% rPFS at 6 mo. Sample size (30) provides 90% power with one-sided alpha of 0.05 via chi-square test. Secondary endpoints include PSA decline by PCWG3, objective radiographic response proportion, OS, and CTC response rate. Exploratory studies will include serial evaluation of cfDNA (via PCF-SELECT); immune tumor microenvironment response via on-treatment biopsy and collection of plasma for circulating immune markers; and exploration of baseline and on-treatment tumor genomic alterations. This trial is multicentered via the Prostate Cancer Clinical Trials Consortium (PCCTC c20-254). Clinical trial information: NCT04631744.
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- 2021
18. Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer
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Howard A. Fine, Alessandro Romanel, Juan Miguel Mosquera, Marc H. Schiffman, Tuo Zhang, David S. Rickman, Mark A. Rubin, Rohan Bareja, Andrea Sboner, Wei Song, Mirjam Blattner-Johnson, Samaneh Motanagh, Shaham Beg, Kenneth Eng, Bhavneet Bhinder, Scott T. Tagawa, Christopher E. Barbieri, Olivier Elemento, Eleni Andreopoulou, Jenny Xiang, Terra J. McNary, Ana M. Molina, Joanna Cyrta, Himisha Beltran, Verena Sailer, Hanna Rennert, Theresa Y. MacDonald, Douglas S. Scherr, Chantal Pauli, Bishoy Faltas, Loredana Puca, Jeffrey P. Greenfield, Alexandros Sigaras, Manish A. Shah, Myriam Kossai, David Wilkes, Linda T. Vahdat, Qiulu Pan, David M. Nanus, Rob Kim, Koen van Besien, Francesca Demichelis, Allyson J. Ocean, Jacqueline Fontunge, Noah Greco, Rema Rao, Evan Sticca, Brian D. Robinson, David J. Pisapia, Sheena Sahota, and Kevin Holcomb
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,MEDLINE ,Cancer ,medicine.disease ,Precision medicine ,Advanced cancer ,Article ,Molecular analysis ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business - Abstract
PURPOSE We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. PATIENTS AND METHODS Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated. RESULTS Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant. CONCLUSION Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.
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- 2019
19. Proteomic and genomic signatures of repeat instability in cancer and adjacent normal tissues
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Francesca Demichelis, Georgina D. Barnabas, Paola Gasperini, Erez Persi, Yuri I. Wolf, David Horn, Davide Prandi, Christopher E. Barbieri, Himisha Beltran, Eugene V. Koonin, Tamar Geiger, Yair Pozniak, Keren Levanon, Mark A. Rubin, Iris Barshack, and Bishoy Faltas
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0301 basic medicine ,Genome instability ,Proteomics ,Somatic cell ,Normal tissue ,Computational biology ,Biology ,Instability ,Genome ,Models, Biological ,Genomic Instability ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Databases, Genetic ,Humans ,610 Medicine & health ,Multidisciplinary ,Point mutation ,Biological Sciences ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Proteome ,Microsatellite - Abstract
Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in proteomes and genomes directly from proteomic and genomic raw data. This method was applied to a wide range of tumors and normal tissues. We identify high similarity between repeat instability patterns in tumors and their patient-matched adjacent normal tissues. Nonetheless, tumor-specific signatures both in protein expression and in the genome strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We observe an inverse relationship between repeat instability and point mutation load within and across patients independent of other somatic aberrations. Thus, repeat instability is a distinct, transient, and compensatory adaptive mechanism in tumor evolution and a potential signal for early detection.
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- 2019
20. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling
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Mark A. Rubin, Surena F. Matin, Scott T. Tagawa, Ana M. Molina, Himisha Beltran, Tyler J. Moss, Joanna Cyrta, Panagiotis J. Vlachostergios, Juan Miguel Mosquera, Bishoy Faltas, Rohan Bareja, Francesca Khani, Douglas S. Scherr, Kyung Park, Kailyn Li, Olivier Elemento, Evanguelos Xylinas, Shahrokh F. Shariat, Weisi Liu, Brian D. Robinson, David M. Nanus, Bhavneet Bhinder, Seth P. Lerner, and Peyman Tavassoli
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Male ,0301 basic medicine ,T-Lymphocytes ,DNA Mutational Analysis ,General Physics and Astronomy ,02 engineering and technology ,Urologic Neoplasms ,Fibroblast growth factor ,Tumor Microenvironment ,Cancer genomics ,Receptor ,610 Medicine & health ,lcsh:Science ,Exome sequencing ,Urothelial carcinoma ,Aged, 80 and over ,Multidisciplinary ,Molecular medicine ,Bladder cancer ,Middle Aged ,021001 nanoscience & nanotechnology ,Phenotype ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Transitional Cell ,Female ,Microsatellite Instability ,0210 nano-technology ,Signal Transduction ,Science ,Urology ,T cell ,Down-Regulation ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Immune system ,Downregulation and upregulation ,Exome Sequencing ,Carcinoma ,medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Aged ,Carcinoma, Transitional Cell ,Sequence Analysis, RNA ,Ureteral Neoplasms ,business.industry ,Gene Expression Profiling ,Microsatellite instability ,General Chemistry ,medicine.disease ,Gene expression profiling ,030104 developmental biology ,Upper tract ,Mutation ,Cancer research ,lcsh:Q ,Urothelium ,business - Abstract
Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies., Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.
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- 2019
21. Clinical features of neuroendocrine prostate cancer
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Karla V. Ballman, Clara Oromendia, Scott T. Tagawa, Bishoy Faltas, Ana M. Molina, David M. Nanus, Rohan Bareja, Juan Miguel Mosquera, Olivier Elemento, Kenneth Eng, Vincenza Conteduca, Andrea Sboner, Michael Sigouros, and Himisha Beltran
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Biopsy ,Adenocarcinoma ,Small-cell carcinoma ,Article ,Cohort Studies ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,medicine ,Carcinoma ,Humans ,Carcinoma, Small Cell ,Neoplasm Metastasis ,Lymph node ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Prostatic Neoplasms ,Histology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Carcinoma, Neuroendocrine ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cohort ,Disease Progression ,business - Abstract
BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. Despite being important to recognise, the clinical features of NEPC are poorly defined and could help guide when to perform a biopsy to look for NEPC histologic transformation. METHODS: We reviewed baseline, treatment and outcome data of 87 patients with metastatic prostate cancer and tumour biopsy confirming NEPC histology. Forty-seven (54.0%) NEPC cases presented de novo, and 40 (46.0%) were therapy-related (t-NEPC). Thirty-six (41.4%) were classified as pure small-cell carcinoma, and 51 (58.6%) demonstrated mixed features with both small-cell carcinoma and adenocarcinoma present. Genomic data were available for 47 patients. RESULTS: The median age at time of NEPC was 68.1 years, median prostate-specific antigen (PSA) was 1.20 ng/ml (0.14 ng/mL small-cell carcinoma, 1.55 ng/mL mixed carcinoma) and sites of metastases included bone (72.6%), lymph node (47.0%), and viscera (65.5%). Median time from adenocarcinoma to t-NEPC diagnosis was 39.7 months (range, 24.5–93.8) with a median of two lines of prior systemic therapy. Platinum chemotherapy was used to treat 57.5% of patients, with a median progression-free survival of 3.9 months. Small-cell carcinoma was associated with worse overall survival (OS) than mixed histology (8.9 months from NEPC diagnosis versus 26.1 months, P < 0.001). Median OS of de novo NEPC was shorter than that of t-NEPC (16.8 months from prostate cancer diagnosis versus 53.5 months, P = 0.043). An average PSA rise per month of ≤0.7 ng/ml before t-NEPC; elevated lactate dehydrogenase levels, RB1 and TP53 loss and liver metastases were poor prognostic features. CONCLUSIONS: We describe the clinical features of a cohort of patients with NEPC. These characteristics may inform future diagnostic strategies.
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- 2019
22. MP57-01 MULTI LINEAGE PLASTICITY AND HETEROGENEITY IN MUSCLE INVASIVE BLADDER CANCER
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Harry Anastos, Olivier Elemento, Geoffrey Bryant, Jorge Daza, David J. Mulholland, Matthew D. Galsky, John P. Sfakianos, Bishoy Faltas, Rohan Bareja, and Ketan K. Badani
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Lineage (genetic) ,Bladder cancer ,business.industry ,Urology ,Gene expression ,Cancer research ,Muscle invasive ,Medicine ,Cancer ,business ,medicine.disease ,Tumor heterogeneity - Abstract
INTRODUCTION AND OBJECTIVES:Tumor heterogeneity occurs in most cancer types including those of urothelial in origin. Despite this, studies have increasingly applied gene expression signatures to cl...
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- 2019
23. PD11-08 A 30-GENE HEREDITARY CANCER MUTATION ANALYSIS PREDICTS TIME TO BIOCHEMICAL RECURRENCE IN CLINICALLY LOCALIZED PROSTATE CANCER
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Michael Sun, Bishoy Faltas, Himisha Beltran, Aileen Lee, Scott T. Tagawa, Ana M. Molina, Dario Martin Villamar, Ariel Schapp, Panagiotis J. Vlachostergios, and David M. Nanus
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Biochemical recurrence ,Prostate cancer ,business.industry ,Urology ,Cancer research ,Mutation testing ,Medicine ,Hereditary Cancer ,business ,medicine.disease ,Gene ,Germline - Abstract
INTRODUCTION AND OBJECTIVES:Pathogenic germline DNA repair mutations are enriched in men with advanced prostate cancer (PC) and are harbingers of an aggressive, lethal course. Though guidelines rec...
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- 2019
24. Circulating Tumor DNA Alterations in Advanced Urothelial Carcinoma and Association with Clinical Outcomes: A Pilot Study
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Gregory R. Pond, Dharmesh Gopalakrishnan, Sumati Gupta, Aly-Khan A. Lalani, Bradley Alexander McGregor, Bishoy Faltas, Alexandra Drakaki, Lesli A. Kiedrowski, Guru Sonpavde, Jue Wang, Petros Grivas, Rebecca J. Nagy, Gurudatta Naik, Pedro C. Barata, Richard B. Lanman, Ulka N. Vaishampayan, and Neeraj Agarwal
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Oncology ,Adult ,medicine.medical_specialty ,ARID1A ,DNA damage ,Urology ,030232 urology & nephrology ,Pilot Projects ,Circulating Tumor DNA ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Gene ,Urothelial carcinoma ,Aged ,Retrospective Studies ,Aged, 80 and over ,Carcinoma, Transitional Cell ,Taxane ,Bladder cancer ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Cell-free fetal DNA ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Surgery ,business - Abstract
Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.
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- 2019
25. Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-based Tumor Mutational Burden Distribution
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Bishoy Faltas, Shaham Beg, Rema Rao, Manish A. Shah, Olivier Elemento, Andrea Sboner, David J. Pisapia, Mark A. Rubin, Kenneth Eng, Wei Song, Juan Miguel Mosquera, Himisha Beltran, Evan Fernandez, Brian D. Robinson, and David M. Nanus
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0301 basic medicine ,Cancer Research ,Cancer ,Context (language use) ,Computational biology ,Biology ,medicine.disease ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Distribution (pharmacology) ,610 Medicine & health ,Exome sequencing - Abstract
PURPOSE To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. MATERIALS AND METHODS Using whole exome sequencing data from primary tumors in The Cancer Genome Atlas (n = 3,534) and advanced and/or metastatic tumors from Weill Cornell Medicine Advanced (n = 696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. RESULTS The distribution of TMB varied dramatically among cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, whereas the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared with the static pan-cancer threshold. In addition, no significant difference in survival outcomes was found with the cancer-specific threshold compared with the pan-cancer threshold. Furthermore, the cancer-specific threshold maintained higher predicted neoantigen load for the TMB-high samples compared with the TMB-low samples, even when the threshold was lower than the pan-cancer threshold. CONCLUSION TMB is determined within the context of cancer type, metastatic state, and disease stage. Compared with a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that are not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Because of the potential impact in the care of patients with cancer, TMB status should be determined in a cancer-specific manner.
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- 2019
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26. Rationale for co-targeting CDK4/6 and FGFR pathways in urothelial carcinoma
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Bishoy Faltas, Raafat Abdel-Malek, Kyrillus S. Shohdy, and Panagiotis J. Vlachostergios
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0301 basic medicine ,Pharmacology ,High prevalence ,business.industry ,Clinical Biochemistry ,Cyclin-Dependent Kinase 4 ,Antineoplastic Agents ,Cyclin-Dependent Kinase 6 ,Small molecule ,Receptors, Fibroblast Growth Factor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Urinary Bladder Neoplasms ,Fibroblast growth factor receptor ,030220 oncology & carcinogenesis ,Drug Discovery ,Cancer research ,Molecular Medicine ,Medicine ,Humans ,Molecular Targeted Therapy ,business ,Urothelial carcinoma - Abstract
Despite the high prevalence of multiple targetable molecular alterations in urothelial carcinoma (UC), there are currently no approved small molecule inhibitors for UC patients [1]. The standard of...
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- 2018
27. Proteomic and Genomic Signatures of Repeat-instability in Cancer and Adjacent Normal Tissues
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Francesca Demichelis, Eugene V. Koonin, Christopher E. Barbieri, Bishoy Faltas, Mark A. Rubin, Erez Persi, David Horn, Paola Gasperini, Davide Prandi, Himisha Beltran, Tamar Geiger, Yair Pozniak, and Yuri I. Wolf
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Data sequences ,Somatic cell ,Point mutation ,Proteome ,Normal tissue ,Computational biology ,Biology ,Genome ,Instability ,Protein expression - Abstract
SummaryRepetitive sequences are hotspots of evolution at multiple levels. However, due to technical difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content of proteomes and genomes, directly from proteomic and genomic raw sequence data, and applied it to analyze a wide range of tumors and normal tissues. We identify high similarity between the repeat-instability in tumors and their patient-matched normal tissues, but also tumor-specific signatures, both in protein expression and in the genome, that strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We find an inverse relationship between repeat-instability and point mutation load, within and across patients, and independently of other somatic aberrations. Thus, repeat-instability is a distinct, transient and compensatory adaptive mechanism in tumor evolution.
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- 2018
28. Single-cell DNA targeted sequencing (scDNA-seq) to test therapeutic vulnerabilities in urothelial cancer (UC) patient-derived organoids (PDO)
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M. Laura Martin, Alicia Alonso, Bishoy Faltas, Olivier Elemento, Kyrillus S. Shohdy, Jenny Xiang, and Weisi Liu
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Cancer Research ,business.industry ,Cell ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,chemistry ,CDKN2A ,030220 oncology & carcinogenesis ,Organoid ,Cancer research ,Medicine ,Urothelial cancer ,business ,DNA ,030215 immunology - Abstract
464 Background: Genomic alterations in FGFR3, PIK3CA, and CDKN2A are common actionable targets in urothelial cancer (UC). We aimed to determine the efficacy of alpelisib, a PIK3CA inhibitor, and abemaciclib, a CDK4/6 inhibitor in bladder cancer patient-derived organoid using single-cell targeted DNA sequencing. Methods: We established a patient-derived UC organoid (PDO) harboring the FGFR3 mutation (p.Y375C), the PIK3CA (p. E452K) mutation, and CDKN2A deletion, which we characterized using whole-genome sequencing. We generated dose-response curves of alpelisib, abemaciclib, and erdafitinib (an FGFR3 inhibitor) in PDO cells to determine the IC50 concentrations. The scDNA-seq (Tapsteri) platform was used to measure changes in the variant allele frequencies (VAF) and clonal fractions post-treatment. The Chi-square test for trend was used to test for linear trend across ordered categories. Results: scDNA-seq was performed after treating PDO cells with 3uM erdafitinib or DMSO. A total of 7000 single cells were obtained (4179 cells treated with erdafitinib vs. 2821 cells treated with DMSO). After removing variants mutated in
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- 2021
29. Common deleterious germline variants shape the urothelial cancer genome
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Mark A. Rubin, SM Nanus, Tuo Zhang, WK Chung, Samaneh Motanagh, Scott T. Tagawa, Olivier Elemento, Aram Vosoughi, Kyrillus S. Shohdy, Ana M. Molina, Cora N. Sternberg, Jenny Xiang, David Wilkes, Juan Miguel Mosquera, Bishoy Faltas, Andrea Sboner, Brian D. Robinson, Panagiotis J. Vlachostergios, and Himisha Beltran
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Oncology ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Urology ,Population ,Disease ,Genome ,Germline ,Internal medicine ,Cohort ,medicine ,Urothelial cancer ,1000 Genomes Project ,education ,business ,Gene - Abstract
Introduction The prevalence and biological consequences of deleterious germline variants (DGVs) in urothelial cancer (UC) are unknown. Methods We performed whole-exome sequencing (WES) of 158 tumors and corresponding germline DNA from 80 UC patients at Weill-Cornell Medicine (WCM). We developed a novel computational framework (DGVar) to detect DGVs from germline WES data and predict their biological functions. We used strict criteria to identify truncating variants in 1604 tumor suppressor genes (TSGs) from germline WES data. We assessed germline-somatic interactions over the lifetime of each tumor. We confirmed our findings by applying DGVar to germline WES from 398 patients from the Cancer Genome Atlas (TCGA). We performed extensive validation of our results in other UC cohorts and whole-exome sequencing data from more than 13,000 non-cancer subjects. Results DGVs were identified in 45/80 patients (56%) of the WCM UC cohort and 315 DGVs in 48% (190/398) of patients in the TCGA UC cohort. DGVs were significantly more common in UC patients of WCM and TCGA compared to 2,504 subjects from the 1000 genome project (1KGP) population (p Conclusions We show that close half of UC patients harbor DGVs, which potentially play a critical role in UC initiation and progression. Our results redefine the landscape of germline variants in urothelial cancer and provide a pivotal new understanding of their unique role in the biology of the disease.
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- 2020
30. Application of next-generation sequencing in gastrointestinal and liver tumors
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Bishoy Faltas, Tanios Bekaii-Saab, Mohamed E. Salem, and Sameh Mikhail
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0301 basic medicine ,Cancer Research ,Liver Neoplasms ,Cancer therapy ,High-Throughput Nucleotide Sequencing ,Biology ,medicine.disease ,Precision medicine ,Bioinformatics ,DNA sequencing ,Clinical Practice ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Humans ,Gastrointestinal cancer ,Treatment decision making ,Gastrointestinal Neoplasms - Abstract
Malignant transformation of normal cells is associated with the evolution of genomic alterations. This concept has led to the development of molecular testing platforms to identify genomic alterations that can be targeted with novel therapies. Next generation sequencing (NGS) has heralded a new era in precision medicine in which tumor genes can be studied efficiently. Recent developments in NGS have allowed investigators to identify genomic predictive makers and hereditary mutations to guide treatment decision. The application of NGS in gastrointestinal cancers is being extensively studied but continues to face substantial challenges. In our review, we discuss various NGS platforms and highlight their role in identifying familial mutations and markers of response or resistance to cancer therapy. We also provide a balanced discussion of the challenges that limit the routine use of NGS in clinical practice.
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- 2016
31. Abstract 859: Deep learning predicts expression-based molecular subtypes and immune status of urothelial cancer using digital pathology slides
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Iman Hajirasouliha, Emily Tse, Pegah Khosravi, Kyrillus S. Shohdy, Bishoy Faltas, Bhavneet Bhinder, Matthew Brendel, Rohan Bareja, Olivier Elemento, and Lilly Gu
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Oncology ,Cancer Research ,Treatment response ,medicine.medical_specialty ,Immune status ,business.industry ,Deep learning ,H&E stain ,Class activation mapping ,Digital pathology ,Internal medicine ,medicine ,Urothelial cancer ,Artificial intelligence ,business ,Urothelial carcinoma - Abstract
RNA-sequencing (RNA-seq) has revealed intrinsic subtypes of urothelial carcinoma (UC). We have recently developed a molecular classifier to separate UC tumors to ‘hot' and ‘cold' based on the expression of immune-related genes. Both molecular subtype and immune-status correlate with response to different treatments, however, RNA-seq data is not readily available for all tumors thus limiting our ability to predict treatment response. We hypothesized that a deep learning approach can predict urothelial cancer molecular subtype and classify immune cell levels from pathology tissue slides. To test this hypothesis, we developed a deep learning model to classify urothelial carcinoma subtypes from hematoxylin and eosin (H&E) stained tissue sections using BASE47 luminal-basal classification and our immune-status classifiers based on RNA-seq data from patients in the TCGA dataset as ground truth. Patches of 2048x2048 pixels were generated from 446 whole slide images (WSIs) resulting in a total of 79,053 images. 70% of the patients were used for training, and 15% are being used as a validation set. The remaining 15% of the data will be a blind test set. We used the Resnet-18 architecture, which performed best based on empirical testing (high accuracy while minimizing overfitting). We performed a color normalization step based on the Vahadane algorithm (IEEE Trans Med Imaging. 2016;35(8):1962 71) to analyze the predictive performance and generalizability of the model compared to non-normalized slides. We also used gradient-weighted class activation mapping to highlight the regions of the tissue that may be important for classification. After 20 epochs of training, we achieved a 74% patch prediction accuracy on the validation set with a ROC-AUC of 0.80 for non-normalized immune cell classification. For normalized images, we achieved a 70% patch prediction accuracy on the validation set with a ROC-AUC of 0.75. For the luminal-basal subtype classification task, we achieved a 68% patch wise accuracy on the validation set with a ROC-AUC of 0.76 for normalized data and 68% patch-wise accuracy with a ROC-AUC of 0.74 for non-normalized data. We are currently testing the model on an internal urothelial cancer cohort at Weill Cornell Medicine. Our data demonstrates the utility of deep learning methods in predicting UC molecular subtype and immune status from digital pathology slides. This data has important implications for predicting prognosis and treatment response in UC patients. Citation Format: Matthew Bryan Brendel, Pegah Khosravi, Emily Tse, Lilly Gu, Kyrillus Shohdy, Rohan Bareja, Bhavneet Bhinder, Olivier Elemento, Bishoy Faltas, Iman Hajirasouliha. Deep learning predicts expression-based molecular subtypes and immune status of urothelial cancer using digital pathology slides [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 859.
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- 2020
32. Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients
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M. Laura Martin, Douglas S. Scherr, Scott T. Tagawa, Ana M. Molina, Jones T. Nauseef, Cora N. Sternberg, David M. Nanus, Timothy D. McClure, Panagiotis J. Vlachostergios, Olivier Elemento, Giorgio Inghirami, and Bishoy Faltas
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Oncology ,medicine.medical_specialty ,Window of opportunity ,Cancer Research ,Bladder cancer ,Cell Cycle Inhibition ,business.industry ,medicine.medical_treatment ,Muscle invasive ,Combination chemotherapy ,medicine.disease ,Cystectomy ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,Open label ,business ,Abemaciclib - Abstract
TPS5096 Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trials information: NCT03837821. Clinical trial information: NCT03837821 .
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- 2020
33. Serial circulating tumor DNA (ctDNA) measurement to predict progression in patients (pts) with advanced urothelial carcinoma (aUC)
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Petros Grivas, Guru Sonpavde, Yen Cao, Scott T. Tagawa, Dario Martin Villamar, Bishoy Faltas, Ana M. Molina, Kristin Price, Kyrillus S. Shohdy, Cora N. Sternberg, Janson Trieu, Rebecca Nagy, Nicholas J. Vogelzang, and David M. Nanus
- Subjects
Cancer Research ,Oncology ,Somatic cell ,business.industry ,Circulating tumor DNA ,Cancer research ,Medicine ,In patient ,business ,Urothelial carcinoma - Abstract
558 Background: Next-generation sequencing (NGS) of plasma ctDNA is a promising non-invasive method to detect somatic genomic alterations (GAs). We investigated whether serial ctDNA measurements can predict disease progression and map the molecular evolution of advanced UC (aUC) through successive treatments. Methods: We analyzed cohorts from 2 academic centers, WCM and UNLV, with serial (≥2) ctDNA targeted NGS using the Guardant360 panel of 73 genes, ctDNA was collected within four weeks of restaging scans. Non-progressive disease (non-PD) was defined as stable disease or radiological response. Results: Our cohort included 176 individual ctDNA samples (median 3/patient) from 52 patients (38 men), the median age was 69 (range 38-88), 38 pts (73%) had metastatic disease, 20 pts (38.5%) had visceral metastases and 35 pts (67%) received first-line platinum-based combination chemotherapy for aUC. The median number of lines of therapy was 2. 49 pts (94%) had detectable GAs in at least one ctDNA sample. Most commonly identified GAs involved TP53 (67%), PIK3CA, EGFR, and ERBB2 (each in 19%). FGFR3 GAs were identified in 9 pts (17%, 2 FGFR3-TACC3 fusions, and 7 SNVs, including two novel mutations P250R and K650M). The mean variant allele fraction (VAF) significantly decreased in pts with non-PD (80 non-PD events) compared to pts with PD (45 PD events) with a mean VAF decrease of 2.06 % (p< 0.0001). This effect was consistent independent of the number of prior lines of therapy. The mean number of GAs per patient at each time point was significantly decreased in non-PD vs. PD group (2.8 vs. 4.4, p=0.004). Pts with detectable VAF in somatic alterations at any time point during the disease course had shorter overall survival (HR 1.18, 95% CI: 1.08 – 1.28, p
- Published
- 2020
34. INTACT: Phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer—SWOG/NRG1806
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Joshua J. Meeks, Bishoy Faltas, Ian M. Thompson, Sameer G. Jhavar, Parminder Singh, Seth P. Lerner, Nicholas J. Vogelzang, Srikala S. Sridhar, Richard Carlton Bangs, Amit Gupta, Ronald C. Chen, Weliang Du, Jason A. Efstathiou, Felix Y. Feng, Brian A. Costello, Kathryn Winter, Petros Grivas, Catherine M. Tangen, Noah M. Hahn, and Alicia K. Morgans
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Bladder cancer ,business.industry ,medicine.medical_treatment ,Muscle invasive ,Urology ,medicine.disease ,law.invention ,Cystectomy ,Radiation therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Randomized controlled trial ,Atezolizumab ,law ,030220 oncology & carcinogenesis ,medicine ,business ,Chemoradiotherapy ,030215 immunology - Abstract
TPS586 Background: Chemoradiotherapy(CRT) is a SOC for patients with muscle invasive bladder cancer (MIBC) who refuse or are not fit for radical cystectomy. Radiotherapy and chemotherapy are known to increases the PD-L1 expression in bladder cancer. Based on these observations, we hypothesized that addition of atezolizumab to CRT will increase its efficacy. Methods: This is a randomized phase III trial testing CRT with and without atezolizumab for 6 months in 475 patients with MIBC. Pts will be stratified on performance status (0-1 vs. 2); clinical stage (T2 vs T3/T4a, chemotherapy(cisplatin vs 5FU+mitomycin vs gemcitabine); and radiation field (bladder only vs small pelvis). Patients will undergo biopsy 18 week from registration. If they have residual disease they will be taken off protocol treatment and can proceed with alternative SOC option including radical cystectomy. Patients will be followed for 5 years. The primary end point of the study is bladder intact event –free survival (BIEFS). The event is comprised of: recurrence or residual muscle-invasive bladder cancer at 18 weeks or later, clinical evidence of nodal or metastatic disease, radical cystectomy, or death due to any cause. This composite endpoint is reflective of the intent of bladder preservation strategy with radical cystectomy included as one of the outcomes. Secondary end points include overall survival, modified event free survival, pathologic response at 18 weeks, metastasis free survival, cancer specific survival, rate of salvage cystectomy, rate of adverse event and QOL & PRO end points. The expected 3 year BIEFS for the control arm is 52%. The study leadership concluded that a 12% improvement in this endpoint is meaningful for this patient population. With a sample size of 475 patients the study has 85% power to detect the improvement from 52% to 64% in the BIEFS at 3 years (hazard ratio=0.68). The study team will perform translational studies evaluating tumor tissue, whole blood and urine for molecular and immunologic markers of immune response and response to RT. Successful completion of this trial could lead to a new treatment paradigm for patients with muscle invasive bladder cancer. Clinical trial information: NCT03775265.
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- 2020
35. Oncogenic Addiction to ERBB2 Signaling Predicts Response to Trastuzumab in Urothelial Cancer
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Olivier Elemento, Scott T. Tagawa, Ana M. Molina, Panagiotis J. Vlachostergios, Brian D. Robinson, Francesca Khani, Bishoy Faltas, Andrea Sboner, Juan Miguel Mosquera, Michael Karass, Ethan Shelkey, Rohan Bareja, Douglas S. Scherr, and David M. Nanus
- Subjects
Genotype ,Receptor, ErbB-2 ,Oncogenic Addiction ,Antineoplastic Agents, Immunological ,Trastuzumab ,Cell Line, Tumor ,Exome Sequencing ,Oncogene Addiction ,Medicine ,Urothelial cancer ,Humans ,RNA, Messenger ,skin and connective tissue diseases ,Urothelial carcinoma ,Aged ,Neoplasm Staging ,Urethral Neoplasms ,business.industry ,RNA ,Cancer ,Sequence Analysis, DNA ,medicine.disease ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Oncology ,Sustained response ,Cancer research ,Female ,Signal transduction ,business ,Tomography, X-Ray Computed ,medicine.drug ,Signal Transduction - Abstract
Urothelial carcinoma (UC) is a common and frequently lethal cancer. Despite the presence of genomic alterations creating dependency on particular signaling pathways, the use of targeted therapies in advanced and metastatic UC has been limited. We performed an integrated analysis of whole-exome and RNA sequencing of primary and metastatic tumors in a patient with platinum-resistant UC. We found a strikingly high ERBB2 mRNA expression and enrichment of downstream oncogenic ERBB2 signaling in this patient’s tumors compared with tumors from an unselected group of patients with UC (N=17). This patient had an exceptional sustained response to trastuzumab. Our findings show that oncogenic addiction to ERBB2 signaling potentially predicts response to ERBB2-directed therapy of UC.
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- 2018
36. The molecular limitations of biomarker research in bladder cancer
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Bishoy Faltas and Panagiotis J. Vlachostergios
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Oncology ,medicine.medical_specialty ,DNA repair ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Antineoplastic Agents ,Disease ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,medicine ,Humans ,Neoplasm Invasiveness ,Molecular Targeted Therapy ,Cisplatin ,Tumor microenvironment ,Carcinoma, Transitional Cell ,Bladder cancer ,business.industry ,Liquid Biopsy ,Muscle, Smooth ,Immunotherapy ,medicine.disease ,Prognosis ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,business ,Biomarkers ,medicine.drug - Abstract
Urothelial carcinoma of the bladder (UCB) is a common malignancy with limited systemic treatment options in advanced stages. Despite recent advances in immunotherapy, the majority of patients do not respond to these treatments. There is an unmet need for developing robust biomarkers to inform treatment decisions and identify patients who are likely to respond. A MEDLINE/PubMed literature search was performed, focusing on tissue-based and circulating biomarkers, and their potential in muscle-invasive UCB. UCB is a heterogeneous disease that consists of several clonal and subclonal populations, each with a mix of truncal and private genomic alterations. This inter- and intra-tumoral heterogeneous landscape results in the development of treatment resistance. Tumor heterogeneity also constitutes a barrier to the development of robust markers of response and resistance to chemotherapy and immunotherapy. Defects in DNA repair genes and a high tumor mutational burden independently confer sensitivity to cisplatin-based chemotherapy and checkpoint inhibitors. Oncogenic alterations such as FGFR3 mutations and fusions are associated with response to FGFR3 inhibitors. Several emerging potential biomarkers, including gene expression-based molecular subtypes, T-cell receptor clonality, and tissue- or blood-based immune-gene profiling, require prospective testing and validation. Tissue-based biomarkers such as PD-L1 immunohistochemistry have several limitations due to discordance in assay methodology and trial designs. Novel liquid-biopsy techniques are promising as potential biomarkers. Validated biomarkers that capture the complexity of the biology of both the tumor and the tumor microenvironment are needed in muscle-invasive UCB. Standardization of methods is critical to developing reliable biomarkers to guide clinical management.
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- 2018
37. Novel molecular targets for urothelial carcinoma
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Scott T. Tagawa, Bishoy Faltas, Jonathan E. Rosenberg, and Beerinder S. Karir
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medicine.medical_treatment ,Clinical Biochemistry ,Antineoplastic Agents ,Genomics ,Disease ,Computational biology ,Biology ,Bioinformatics ,Article ,Targeted therapy ,Platinum resistance ,Drug Discovery ,medicine ,Animals ,Humans ,Urothelial cancer ,Molecular Targeted Therapy ,Drug Approval ,Urothelial carcinoma ,Pharmacology ,Carcinoma, Transitional Cell ,United States Food and Drug Administration ,United States ,Clinical trial ,Drug Resistance, Neoplasm ,Drug Design ,Molecular targets ,Molecular Medicine ,Urothelium - Abstract
Urothelial cancer (UC) remains a significant public health problem, with no new second-line agents FDA-approved in the US. Next-generation sequencing technologies are starting to generate a molecular landscape of UC thus revealing novel molecular targets.In this review, the authors provide a detailed review of novel molecular targets in UC based on published genomic analyses of urothelial tumors. We provide an overview of each molecular target with a brief discussion of therapeutic strategies and clinical trials targeting each pathway.UC continues to be a lethal disease with no FDA-approved effective second-line therapies. Platinum resistance continues to be a daunting clinical problem. Next-generation sequencing methods have led to the elucidation of numerous molecular targets in UC, including PI3K, to the elucidation of numerous molecular targets in UC, including PI3K, ERBB2 and FGFR3, among many others. These molecular perturbations can be exploited therapeutically with targeted therapies in patient populations enriched for these molecular alterations, thus paving the way for precision medicine in UC management.
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- 2015
38. Precision Medicine in Prostate Cancer: Approach to the Patient
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Scott T. Tagawa, Bishoy Faltas, and Beerinder S. Karir
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medicine.medical_specialty ,business.industry ,Cancer ,Treatment options ,Precision medicine ,medicine.disease ,Patient preference ,Patient care ,Prostate cancer ,Informed consent ,Medicine ,Medical physics ,Personalized medicine ,business - Abstract
The advent of genomic discoveries and decreasing cost of next-generation sequencing (NGS) technologies has ushered in a new era of precision medicine. The early effects of this paradigm shift in oncology are beginning to impact patient care and thus increase the relevance of a discussion on the approach to patients with prostate cancer (PC). Bringing the application of precision medicine to the clinic raises new challenges related to informed consent prior to testing, effectively communicating the results of cancer genomic testing to the patient, understanding and managing the patient’s expectations, and working with the patient to select the best treatment options based on genomic tests (or not). This introductory chapter will cover the approach to men with PC undergoing genomic testing of their tumors.
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- 2017
39. MP48-18 GERMLINE DNA REPAIR SINGLE NUCLEOTIDE POLYMORPHISMS IN UROTHELIAL CANCER PATIENTS
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Panagiotis J. Vlachostergios, Linda Lam, Bishoy Faltas, Tuo Zhang, Olivier Elemento, and Mark A. Rubin
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Genetics ,03 medical and health sciences ,0302 clinical medicine ,business.industry ,Urology ,030232 urology & nephrology ,Urothelial cancer ,Medicine ,Single-nucleotide polymorphism ,business ,Germline - Published
- 2017
40. Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine
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Lewis C. Cantley, Verena Sailer, Davide Prandi, Bishoy Faltas, Juan Miguel Mosquera, Mark A. Rubin, Brian D. Robinson, Terra J. McNary, Himisha Beltran, Reid Shaw, Andrea Sboner, Tarcisio Fedrizzi, Brooke E Emerling, Vijayakrishna K. Gadi, Cynthia Cheung, Rema Rao, David J. Pisapia, Joanna Triscott, Francesca Demichelis, Olivier Elemento, Christopher J. Kemp, Loredana Puca, Yelena Churakova, Chantal Pauli, Michael A. Augello, Rachele Rosati, Brady Bernard, Benjamin D. Hopkins, Carla Grandori, University of Zurich, and Rubin, Mark A
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0301 basic medicine ,Drug ,media_common.quotation_subject ,MEDLINE ,Cancer ,610 Medicine & health ,Precision medicine ,Bioinformatics ,medicine.disease ,Biobank ,3. Good health ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,Oncology ,In vivo ,10049 Institute of Pathology and Molecular Pathology ,medicine ,2730 Oncology ,Exome sequencing ,media_common - Abstract
Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board–approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted. Significance: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 462–77. ©2017 AACR. See related commentary by Picco and Garnett, p. 456. This article is highlighted in the In This Issue feature, p. 443
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- 2017
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41. Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models
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Francesca Demichelis, Scott T. Tagawa, Kyung Park, Nicolas Robine, Bishoy Faltas, Mark A. Rubin, Kenneth Eng, Anne-Katrin Emde, Danielle Pancirer, David J. Pisapia, Ana M. Molina, Rema Rao, Jeffrey P. Greenfield, Rohan Bareja, Prajwal Rajappa, Joanna Cyrta, Verena Sailer, Olivier Elemento, Himisha Beltran, Davide Prandi, Juan Miguel Mosquera, Andrea Sboner, Myriam Kossai, Erika Hissong, Brian D. Robinson, Robert Kim, David M. Nanus, Steven P. Salvatore, Jacqueline Fontugne, Mark M. Souweidane, Chantal Pauli, and Alexandros Sigaras
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Melanoma ,Cancer ,Autopsy ,medicine.disease ,Precision medicine ,Article ,3. Good health ,Metastatic carcinoma ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Glioma ,medicine ,Radiology ,Treatment resistance ,business - Abstract
Purpose Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types. Materials and Methods One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts. Results Three hundred forty-six frozen samples were procured in total. WES was performed on 113 samples and RNA-Seq on 72 samples. Successful cell strain, tumor organoid, and/or patient-derived xenograft development was achieved in four samples, including an inoperable pediatric glioma. WES data were used to assess clonal evolution and molecular heterogeneity of tumors in individual patients. Mutational profiles of primary tumors and metastases yielded candidate mediators of metastatic spread and organotropism including CUL9 and PIGM in metastatic ependymoma and ANKRD52 in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates. Conclusion A next-generation sequencing–based autopsy program in conjunction with a premortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.
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- 2017
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42. Immune-checkpoint blockade in cisplatin-ineligible patients with urothelial cancer
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Bishoy Faltas and Scott T. Tagawa
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0301 basic medicine ,Cisplatin ,business.industry ,General Medicine ,Immune checkpoint ,Article ,Blockade ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Urothelial cancer ,Humans ,business ,medicine.drug - Published
- 2016
43. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study
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Emerson A. Lim, Daniel P. Petrylak, Kevin Kalinsky, Matthew D. Galsky, Pamela S. Simpson, Elaine T. Lam, William A. Wegener, Scott T. Tagawa, Bishoy Faltas, Julio Hajdenberg, Philip J. Saylor, Aditya Bardia, Alicia K. Morgans, and Trishna Goswam
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Cancer Research ,Chemotherapy ,business.industry ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Treatment options ,03 medical and health sciences ,0302 clinical medicine ,Phase i ii ,Oncology ,030220 oncology & carcinogenesis ,Sacituzumab govitecan ,Cancer research ,Medicine ,Urothelial cancer ,In patient ,business ,Previously treated ,030215 immunology - Abstract
354 Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing >2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.
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- 2019
44. Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration
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Hikmat Al-Ahmadie, Ashley Marie Regazzi, Dean F. Bajorin, Bishoy Faltas, Catharine Kline Cipolla, Min Yuen Teo, Samuel Funt, Chung-Han Lee, Mariel Elena Boyd, Gopa Iyer, Jonathan E. Rosenberg, Alexander Solovyov, and Benjamin Greenbaum
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Transcriptome ,Cancer Research ,Bladder cancer ,Immune system ,Oncology ,Cisplatin based chemotherapy ,business.industry ,Immune infiltration ,Muscle invasive ,medicine ,Cancer research ,medicine.disease ,business - Abstract
443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]
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- 2019
45. Preoperative radiotherapy for high-risk prostate cancer (PORT-PC) trial
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Silvia C. Formenti, David M. Nanus, Scott T. Tagawa, Jim C. Hu, Josephine Kang, Ana M. Molina, Christopher E. Barbieri, Brian D. Robinson, Daniel Margolis, Bishoy Faltas, Peter N. Schlegel, Douglas S. Scherr, Francesca Khani, and Himanshu Nagar
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Cancer Research ,medicine.medical_specialty ,Prostate cancer ,Port (medical) ,Oncology ,Preoperative radiotherapy ,business.industry ,Prostatectomy ,medicine.medical_treatment ,Medicine ,Radiology ,business ,medicine.disease - Abstract
TPS137 Background: Prostatectomy has become the most common treatment for high-risk prostate cancer. After prostatectomy, risk features for local recurrence include extra-capsular extension and/or seminal vesicle invasion (pT3 disease) and positive surgical margins. Post-operative radiotherapy is recommended for patients with pT3 disease, positive margins and/or Group Grade 4-5 and has been shown to reduce the risk of recurrence. In planning adjuvant radiotherapy, the clinical target volume is the prostate bed which is difficult to delineate once the prostate has been surgically removed and can be overestimated by following the location of surgical clips. As such, controversy exists as to the optimal target volume. Guidelines suggest including a significant portion of the posterior and inferior aspects of the bladder, and anterior aspect of the rectum exposing a significant amount of normal tissue to high dose radiation. Pre-operative radiotherapy potentially offers the following advantages: 1) reduced radiation dose to normal tissues; 2) ability to utilize stereotactic body radiotherapy (SBRT) with real-time MRI guidance 3) patient convenience with less fractions and 4) radiobiologic advantage of high dose per fraction treatment delivery. Methods: This is a modified dose escalation trial for patients with high-risk prostate cancer defined as cT3 on MRI or Group Grade 4-5 disease. Patients will sequentially undergo 1) placement of a rectal SpaceOAR, 2) SBRT on the ViewRay MRIdian linear accelerator and 3) prostatectomy. As a modified dose escalation study, patients will be accrued starting at 5 Gy x 5 (up to 8 Gy x 5) with 3 patients per cohort with Grade 4 or 5 gastrointestinal (GI) and/or genitourinary (GU) adverse event related to preoperative radiotherapy as an unacceptable dose limiting toxicity.The primary endpoint is that a patient can undergo a radical prostatectomy after SBRT without a post-operative GI or GU grade 4 or 5 toxicity within 30 days related to preoperative radiotherapy. Secondary objectives include assessment of acute toxicity and quality of life scores. Exploratory analyses include analysis of tumor and normal biopsied and resected tissue and serum markers and interpretation of pre- and post-SBRT MRIs. Clinical trial information: NCT03663218.
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- 2019
46. Phase I/II dose-escalation trial of fractionated dose 177Lu-J591 plus 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC)
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David M. Nanus, Bishoy Faltas, Himisha Beltran, Lauren C. Harshman, John W. Babich, Muhammad Junaid Niaz, Amy Hackett, Joseph R. Osborne, Shankar Vallabhajosula, Jyothi Sreekumar, Neil H. Bander, Scott T. Tagawa, Ana M. Molina, Lauren Gracey, and Karla V. Ballman
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Cancer Research ,177Lu-PSMA-617 ,business.industry ,Castration resistant ,urologic and male genital diseases ,medicine.disease ,Androgen receptor ,Prostate cancer ,Phase i ii ,Oncology ,Downregulation and upregulation ,medicine ,Cancer research ,Dose escalation ,business - Abstract
TPS339 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. Prior studies of beta-emitting radiolabeled anti-PSMA antibody J591 demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable dose-limiting myelosuppression. Recent prospective trials have shown efficacy and safety of 177Lu-PSMA-617 in mCRPC. Studies demonstrate different binding sites of J591 and PSMA-617 and co-administration leads to non-competitive additive binding and delivery of payloads to PSMA+ cells. As the pharmacokinetics and biodistribution of the 2 agents is mostly non-overlapping (other than tumor) and given our prior dose-response data, we hypothesize that delivery of the combination will yield higher tumor delivery with less off-target toxicity (i.e. better responses without increased toxicity). Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) with metastatic disease on CT/MRI or bone scan without limit of # prior therapies (excluding bone-targeted beta-emitting radioisotopes) provided adequate organ function will be enrolled. Pre-treatment 88Ga-PSMA-11 will be performed, but results are not used for eligibility. Treatment includes fractionated 177Lu-J591 at a fixed moderate dose with escalating doses of 177Lu-PSMA-617 (7.4 – 18.5 GBq per cycle, fractionated D1 and D15) in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade > 3 heme toxicity or grade > 2 non-heme toxicity. Following determination of recommended phase 2 dose (RP2D), the phase 2 portion will enroll in a 2-stage design. Primary endpoints: DLT and RP2D (ph 1) and PSA decline proportion (ph 2). Secondary endpoints include toxicity, radiographic response, PFS, rPFS, OS, CTC count changes. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu, tissue and circulating genomic assessment, immunologic assessment, and patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03545165.
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- 2019
47. The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) after treatment with systemic therapy
- Author
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Himisha Beltran, Johannes C. van der Mijn, Olivier Elemento, Sinan Ramazanoglu, Tuo Zhang, Clara Oromendia, Evan Fernandez, Andrea Sboner, Lorraine J. Gudas, David M. Nanus, Rohan Bareja, Kenneth Eng, Bishoy Faltas, Juan Miguel Mosquera, Scott T. Tagawa, Ana M. Molina, and Aram Vosoughi
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Systemic therapy ,Clear cell renal cell carcinoma ,Internal medicine ,Cohort ,Medicine ,In patient ,business ,After treatment - Abstract
675 Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.
- Published
- 2019
48. Serial ctDNA tracking reveals clonal evolution dynamics in advanced urothelial carcinoma (UC)
- Author
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Rebecca Nagy, Guru Sonpavde, Nicholas J. Vogelzang, Bishoy Faltas, Kristin Price, Petros Grivas, Scott T. Tagawa, Ana M. Molina, David M. Nanus, and Dario Martin Villamar
- Subjects
Cancer Research ,genomic DNA ,Metastatic lesions ,Oncology ,business.industry ,Circulating tumor DNA ,Dynamics (mechanics) ,Cancer research ,Medicine ,business ,Somatic evolution in cancer ,Urothelial carcinoma - Abstract
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.
- Published
- 2019
49. Sustained remission in a patient with myelodysplastic syndrome and a complex karyotype after erythropoiesis-stimulating therapy followed by colonic T-cell lymphoblastic lymphoma
- Author
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William Fricke, Steven D. Gore, Bishoy Faltas, Ronald L. Sham, Rhett P. Ketterling, and Amer M. Zeidan
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Cancer Research ,business.industry ,T cell ,Lymphoblastic lymphoma ,Hematology ,medicine.disease ,Text mining ,medicine.anatomical_structure ,Oncology ,Complex Karyotype ,medicine ,Cancer research ,Erythropoiesis ,Sustained remission ,business - Published
- 2012
50. Clonal evolution of chemotherapy-resistant urothelial carcinoma
- Author
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Francesca Demichelis, Scott T. Tagawa, Davide Prandi, Olivier Elemento, Andrea Sboner, Ana M. Molina, Mark A. Rubin, Juan Miguel Mosquera, Himisha Beltran, David M. Nanus, Bishoy Faltas, Brian D. Robinson, Cora N. Sternberg, and Jonathan E. Rosenberg
- Subjects
0301 basic medicine ,L1 ,medicine.medical_treatment ,APOBEC-1 Deaminase ,Antineoplastic Agents ,Neural Cell Adhesion Molecule L1 ,Biology ,Bioinformatics ,Somatic evolution in cancer ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Carcinoma ,Genetics ,Humans ,Exome ,Prospective Studies ,Urothelial carcinoma ,Chemotherapy ,Carcinoma, Transitional Cell ,Bladder cancer ,High-Throughput Nucleotide Sequencing ,medicine.disease ,3. Good health ,Clone Cells ,030104 developmental biology ,Urinary Bladder Neoplasms ,Drug Resistance, Neoplasm ,Mutagenesis ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Chemotherapy resistant - Abstract
Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.
- Published
- 2016
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