Fibroblast Growth Factor Receptor 3 Alterations and Response to Immune Checkpoint Inhibition in Metastatic Urothelial Cancer: A Real World Experience
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PROVIDER: PRJNA735749 | ENA |
REPOSITORIES: ENA
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Project description:Prospective pharmacotyping of urothelial carcinoma organoids for drug sensitivity prediction – feasibility and real world experience
| PRJNA1180454 | ENA
Project description:Purpose: We evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance Methods: 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014-2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3 alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients Results: Our findings from this dataset confirm that FGFR3-altered (n=17) and wild type (n=86) bladder cancers are equally responsive to ICB (12 vs 19%, p=0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumors have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response Conclusions: Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumors have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.
2021-06-08 | GSE176307 | GEO
Project description:Urothelial carcinoma (UC) of the urinary bladder has significant challenges in treatment due to its diverse genetic landscape and variable response to systemic therapy. In recent years, patient-derived organoids (PDOs) emerged as a novel tool to model primary tumors with higher resemblance than conventional 2D cell culture approaches. However, the potential of organoids to predict therapy response in a clinical setting remains to be evaluated. This study explores the clinical feasibility of PDOs for pharmacotyping in UC. Initially, we subjected tumor tissue specimens from 50 patients undergoing transurethral resection or radical cystectomy to organoid propagation, of whom 19 (38%) yielded PDOs suitable for drug sensitivity assessment. Notably, whole transcriptome-based analysis indicated that PDOs may show phenotypes distinct from their parental tumor tissue. Pharmacotyping within a clinically relevant timeframe [mean of 35.44 and 55 days for non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), respectively] was achieved. Drug sensitivity analyses revealed marked differences between NMIBC and MIBC, with MIBC-derived organoids demonstrating higher chemosensitivity toward clinically relevant drugs. A case study correlating organoid response with patient treatment outcome illustrated the complexity of predicting chemotherapy efficacy, especially considering the rapid acquisition of drug resistance. We propose a workflow of prospective organoid-based pharmacotyping in UC, enabling further translational research and integration of this approach into clinical practice.
2024-11-03 | GSE280749 | GEO
Project description:BackgroundFGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance.Methods103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients.ResultsOur findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response.ConclusionsOur work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.
| S-EPMC8548561 | biostudies-literature
Project description:Urothelial cancer is a challenging disease with a wide tumor-biological spec-trum. Most molecular classification attempts are transcriptome-based and re-late only indirectly to the therapeutically relevant protein level. We improve preanalytical preparation of clinical samples for proteome analyses and char-acterize a comprehensive cohort of 434 samples with 242 tumors and 192 paired normal mucosae. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify five tumor clusters that add prog-nostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both, in silico as well as in vitro data, indicate predictive value of the proteo-mic clusters for these drugs. Comparative validation on external transcriptom-ic data confirms prognostic relevance and contextualizes proteomic and tran-scriptomic classifications. A real-world diagnostic approach based on im-munohistochemistry further validates our proteomic data but underlines the necessity of omics scale molecular analyses for personalized oncology.
2024-06-16 | PXD041733 | Pride
Project description:Urothelial cancer is a challenging disease with a wide tumor-biological spectrum. Most molecular classification attempts are transcriptome-based and relate only indirectly to the therapeutically relevant protein level. We improve preanalytical preparation of clinical samples for proteome analyses and characterize a comprehensive cohort of 434 samples with 242 tumors and 192 paired normal mucosae. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify five tumor clusters that add prognostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both, in silico as well as in vitro data, indicate predictive value of the proteomic clusters for these drugs. Comparative validation on external transcriptomic data confirms prognostic relevance and contextualizes proteomic and transcriptomic classifications. A real-world diagnostic approach based on immunohistochemistry further validates our proteomic data but underlines the necessity of omics scale molecular analyses for personalized oncology.
2024-06-16 | PXD041268 | Pride
Project description:Expression profiling of a panel of urothelial cancer cells. The goal of the study is to exam the genome wide expression profile in each of the 30 urothelial cancer cells tested in our laboratory Each of the 30 cell lines was DNA fingerprinted to confirm its real identity. Total RNA was obtained from each cell line and subjected to illumina expression profiling microarray
2014-05-01 | E-GEOD-47992 | biostudies-arrayexpress
Project description:The Treatment Choices, Duration and Outcomes in Patients with Ras Wild Type (RAS WT) Metastatic Colorectal Cancer (mCRC). Retrospective, Multi-Center, Real-World Data Analysis
| 2367583 | ecrin-mdr-crc
Project description:Real-World Effectiveness of Regorafenib in the Treatment of Patients with Metastatic Colorectal Cancer- A Retrospective, Observational Study
| 2388058 | ecrin-mdr-crc
Project description:PurposeErdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution.Experimental designProspectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment.ResultsFGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2).ConclusionsFGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.
| S-EPMC11233068 | biostudies-literature