Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell-free DNA results.
BACKGROUND: Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings. METHODS: Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin-fixed, paraffin-embedded tissues. Blood was collected for cell-free DNA analysis using a 600-gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response [PR] plus complete response [CR]) and disease control rate (DCR; CR plus PR plus stable disease [SD]) were characterized. RESULTS: A total of 67 patients were enrolled; the majority (70.1%) had received >/=2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%). CONCLUSIONS: Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3-restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.
Last. Matthew D. Galsky(ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 63
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Abstract Prior studies have demonstrated that fibroblast receptor 3 (FGFR3)-mutant urothelial cancers (UCs) are associated with decreased T-cell infiltration. As FGFR3 mutations are enriched in luminal-like UC and luminal-like UC has been shown to be relatively less responsive to PD-1/PD-L1 inhibition (checkpoint inhibition [CPI]), these data have led to the speculation that FGFR3 mutations may be causally related to poor T-cell infiltration and that UC patients harboring FGFR3 mutations may be ...
Abstract Background Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions...
Last. Andrew C. Hsieh(UW: University of Washington)H-Index: 6
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BACKGROUND: Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease. METHODS: We performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatur...
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 immun...
: Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non-invasive test for detecting UTUC, but its sensitivity is low. A novel non-invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell-free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary...
Purpose of Review Since 2016, five new programmed cell death protein 1/ligand 1 (PD-1/L1) checkpoint inhibitors have been approved for metastatic urothelial carcinoma. This review will summarize the data supporting the widespread use of these agents and highlight areas of ongoing clinical development.
419Background: FGFR alterations have been shown to be associated with immunologically “cold” UC tumors with low immune marker expression and T cell infiltrate, a poorly receptive environment for im...
Last. Sumanta K. Pal(City of Hope National Medical Center)H-Index: 60
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409Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. About 20% of them usually respond to immune checkpoint inhibitors (ICI). Also, 20% of pts w...
Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors. Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess ...
: COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mut...
Abstract null null The development of rapid genome sequencing has greatly enhanced our understanding of the molecular biology underlying many malignancies. Whole exome sequencing has highlighted the individualistic nature of malignancies on a patient-to-patient basis and begun to revolutionize therapeutic approaches. In recent years, whole genome sequencing of urothelial malignancies has identified a host of somatic mutations which contribute to growth, progression, and metastasis of urothelial ...
#1Juanni Li(CSU: Central South University)H-Index: 9
#2Kuan Hu(CSU: Central South University)H-Index: 5
Last. Zhijie Xu(CSU: Central South University)H-Index: 18
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Fibroblast growth factor receptor 3 (FGFR3) alters frequently across various cancer types and is a common therapeutic target in bladder urothelial carcinoma (BLCA) with FGFR3 variants. Although emerging evidence supports the role of FGFR3 in individual cancer types, no pan-cancer analysis is available. In this work, we used the open comprehensive datasets, covering a total of 10,953 patients with 10,967 samples across 32 TCGA cancer types, to identify the full alteration spectrum of FGFR3. FGFR3...
Abstract Identification of reliable molecular biomarkers that can complement clinical practice represents a fascinating challenge in any cancer field. Urothelial carcinoma is a very heterogeneous disease and responses to systemic therapies, and outcomes after radical cystectomy are difficult to predict. Advances in molecular biology such as next generation sequencing and whole genome or transcriptomic analysis provide promising platforms to achieve a full understanding of the biology behind the ...
Last. Ashish M. Kamat(University of Texas MD Anderson Cancer Center)H-Index: 76
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Abstract Context Bladder and kidney cancers require invasive procedures for definitive diagnosis, and bladder cancer requires repeated procedures to monitor for disease recurrence. Given the recent work to identify molecular alterations in liquid biopsies to diagnose and monitor these diseases, a synthesis of the growing body of evidence is merited. Objective To review current data on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) and to synthesize their roles in the diagnosis, monitori...
Last. Joaquim Bellmunt(BIDMC: Beth Israel Deaconess Medical Center)H-Index: 8
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Abstract Context To improve the prognosis of upper tract urothelial carcinoma (UTUC), clinicians have used neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) before or after radical nephroureterectomy (RNU). Despite some new data, the evidence remains mixed on their efficacy. Objective To update the current evidence on the role of NAC and AC for UTUC. Evidence acquisition We searched for all studies investigating NAC or AC for UTUC in Medline, Embase, the Cochrane Central Register of C...
The hallmark of precision medicine involves tailoring the treatment to the patient and/or tumor-specific biomarkers. Candidate biomarkers in bladder cancer are abundant, but few have been validated in clinical practice. Significant obstacles to precision medicine in bladder cancer include the limited predictive value of candidate biomarkers, lack of standardization in biomarker assessment, heterogeneity in biomarker expression and function, and limited insight into the biologic factors that infl...
Bladder cancer (BC) is among the most frequent cancer types in the world and is the most lethal urological malignancy. Presently, diagnostic and follow-up methods for BC are expensive and invasive. Thus, the identification of novel predictive biomarkers for diagnosis, progression, and prognosis of BC is of paramount importance. To date, several studies have evidenced that cell-free DNA (cfDNA) found in liquid biopsies such as blood and urine may play a role in the particular scenario of urologic...
Dysregulation of fibroblast growth factor receptors (FGFRs) has been implicated in several human malignancies, including urothelial carcinoma. In urothelial carcinoma, the oncogenic role of mutated FGFR is mediated by the RAS-mitogen-activated protein kinase pathway, resembling the effects observed with activated HRAS Activating somatic mutations of FGFR3 are clustered in three hotspots in exons 7, 10 and 15, and are almost always missense mutations leading to amino acid substitution in the exte...
Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemoth...
#2Vitaly Margulis(UTSW: University of Texas Southwestern Medical Center)H-Index: 40
Last. Shahrokh F. Shariat(MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 132
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Abstract To evaluate the oncologic prognostic value of fibroblast growth factor receptor (FGFR) and to assess the safety and efficacy of its inhibitors in patients with urothelial bladder carcinoma. A literature search using PubMed, Scopus, and Cochrane Library was conducted on June 2020 to identify relevant studies according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The pooled recurrence-free survival (RFS), progression-free survival (PFS), and cancer-...