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      Fibroblast Growth Factor Receptor (FGFR) Inhibitors in Urothelial Cancer

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          Abstract

          Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns.

          Implications for Practice

          Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Most recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns.

          Abstract

          Focusing on urothelial malignancies, this review summarizes the oncogenic signaling of FGFR alterations, clinical trials of FGFR inhibitors, and resistance patterns.

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          Most cited references50

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          Cancer statistics, 2020

          Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)
          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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            AACR Project GENIE: Powering Precision Medicine through an International Consortium

            (2017)
            The AACR Project GENIE is an international data-sharing consortium focused on generating an evidence base for precision cancer medicine by integrating clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. In conjunction with the first public data release from approximately 19,000 samples, we describe the goals, structure, and data standards of the consortium and report conclusions from high-level analysis of the initial phase of genomic data. We also provide examples of the clinical utility of GENIE data, such as an estimate of clinical actionability across multiple cancer types (>30%) and prediction of accrual rates to the NCI-MATCH trial that accurately reflect recently reported actual match rates. The GENIE database is expected to grow to >100,000 samples within 5 years and should serve as a powerful tool for precision cancer medicine.Significance: The AACR Project GENIE aims to catalyze sharing of integrated genomic and clinical datasets across multiple institutions worldwide, and thereby enable precision cancer medicine research, including the identification of novel therapeutic targets, design of biomarker-driven clinical trials, and identification of genomic determinants of response to therapy. Cancer Discov; 7(8); 818-31. ©2017 AACR.See related commentary by Litchfield et al., p. 796This article is highlighted in the In This Issue feature, p. 783.
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              Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

              Nikolaus Schultz (2014)
              Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in miRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.
              Article 0 comments Cited 443 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Rohan Garje:
                ORCID: https://orcid.org/0000-0002-7244-5602
                rohan-garje@uiowa.edu
                Journal
                Journal ID (nlm-ta): Oncologist
                Journal ID (iso-abbrev): Oncologist
                Journal ID (doi): 10.1002/(ISSN)1549-490X
                Journal ID (publisher-id): ONCO
                Journal ID (hwp): theoncologist
                Title: The Oncologist
                Publisher: John Wiley & Sons, Inc. (Hoboken, USA )
                ISSN (Print): 1083-7159
                ISSN (Electronic): 1549-490X
                Publication date (Electronic): 15 September 2020
                Publication date (Print): November 2020
                Volume: 25
                Issue: 11 ( doiID: 10.1002/onco.v25.11 )
                Pages: e1711-e1719
                Affiliations
                [ 1 ] Division of Hematology, Oncology, Blood & Marrow Transplantation, University of Iowa Iowa City Iowa USA
                [ 2 ] Holden Comprehensive Cancer Center, University of Iowa Iowa City Iowa USA
                [ 3 ] Department of Pathology, University of Iowa Iowa City Iowa USA
                [ 4 ] Department of Pathology and Lab Medicine, AIIMS Rishikesh India
                Author notes
                [*] [* ] Correspondence: Rohan Garje, M.D., University of Iowa, Department of Internal Medicine, Division of Hematology, Oncology, Blood & Marrow Transplantation, 200 Hawkins Drive, C32 GH, Iowa City, Iowa 52242, USA. Telephone: 319‐356‐2353; e‐mail: rohan-garje@ 123456uiowa.edu

                Author information
                https://orcid.org/0000-0002-7244-5602
                Article
                Publisher ID: ONCO13482
                DOI: 10.1634/theoncologist.2020-0334
                PMC ID: 7648343
                PubMed ID: 32790011
                SO-VID: 9fdaf285-6311-45f0-8568-5f275a60f7f0
                Copyright © © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 20 April 2020
                Date accepted : 31 July 2020
                Page count
                Figures: 1, Tables: 2, Pages: 9, Words: 6546
                Categories
                Subject: 7
                Subject: Genitourinary Cancer
                Subject: Genitourinary Cancer
                Custom metadata
                source-schema-version-number 2.0
                cover-date November 2020
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:07.11.2020

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: urothelial cancer,fgfr alterations,fgfr inhibitors,erdafitinib,targeted therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: urothelial cancer, fgfr alterations, fgfr inhibitors, erdafitinib, targeted therapy

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