The Role of FGFR3 in the Diagnosis and Treatment of Bladder Cancer: A Review
Bladder cancer is the most common malignant tumor of the urinary system. The muscle-invasive bladder cancer (MIBC) is associated with poor prognosis; therefore, new systemic treatment is urgently needed. Although the prognosis of non-muscle-invasive bladder cancer (NMIBC) is relatively good, it is highly recurrent and requires lifelong monitoring that brings huge burden to patients and medical services. Thus, improving the diagnosis and treatment of bladder cancer is still a very important milestone to achieve. Fibroblast growth factor receptor 3 (FGFR3) gene mutations frequently occur in bladder cancer. The mutations are related to the development, progression, and prognosis of bladder cancer and may serve as effective biomarkers and therapeutic targets. An increase in the understanding of FGFR3 in recent years is expected to lead to new insights into the diagnosis and treatment of bladder cancer, thereby prolonging the survival of patients. Combined with relevant clinical research and basic research, this article reviews the application of FGFR3 in the diagnosis and treatment of bladder cancer.
Helsten T, Elkin S, Arthur E, et al., 2016, The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin Cancer Res, 22:259–67. DOI: 10.1158/1078-0432.ccr-14-3212.
Di Martino E, Tomlinson DC, Williams SV, et al., 2016, A Place for Precision Medicine in Bladder Cancer: Targeting the FGFRs. Future Oncol, 12:2243–63. DOI: 10.2217/fon-2016-0042.
Homami A, Kachoei ZA, Asgarie M, et al., 2020, Analysis of FGFR3 and HRAS Genes in Patients with Bladder Cancer. Med J Islam Repub Iran, 34:108.
Neuzillet Y, Paoletti X, Ouerhani S, et al., 2012, A Meta-analysis of the Relationship between FGFR3 and TP53 Mutations in Bladder Cancer. PLoS One, 7:e48993. DOI: 10.1371/journal.pone.0048993.
Garcia-Perdomo HA, Usubillaga-Velasquez JP, Zapata-Copete JA, et al. 2019, Mutations in CDKN2A and the FGFR3 Genes on Bladder Cancer Diagnosis: A Systematic Review and Meta-analysis. World J Urol, 37:2001–7. DOI: 10.1007/s00345-019-02779-7.
Nakanishi Y, Akiyama N, Tsukaguchi T, et al., 2015, Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1. Mol Cancer Ther, 14:704–12. DOI: 10.1158/1535-7163.mct-14-0927-t.
Costa R, Carneiro BA, Taxter T, et al., 2016, FGFR3-TACC3 Fusion in Solid Tumors: Mini Review. Oncotarget, 7:55924–38. DOI: 10.18632/oncotarget.10482.
Kim YS, Kim K, Kwon GY, et al., 2018, Fibroblast Growth Factor Receptor 3 (FGFR3) Aberrations in Muscle-invasive Urothelial Carcinoma. BMC Urol, 18:68. DOI: 10.1186/s12894-018-0380-1
Babina IS, Turner NC, 2017, Advances and Challenges in Targeting FGFR Signalling in Cancer. Nat Rev Cancer, 17:318–32. DOI: 10.1038/nrc.2017.8.
Sarkar S, Ryan EL, Royle SJ, 2017, FGFR3-TACC3 Cancer Gene Fusions Cause Mitotic Defects by Removal of Endogenous TACC3 from the Mitotic Spindle. Open Biol, 7:170080. DOI: 10.1098/rsob.170080.
Amaral AF, Méndez-Pertuz M, Muñoz A, et al., 2012, Plasma 25-Hydroxyvitamin D(3) and Bladder Cancer Risk According to Tumor Stage and FGFR3 Status: A Mechanism-based Epidemiological Study. J Natl Cancer Inst, 104:1897–904. DOI: 10.1093/jnci/djs444.
Neuzillet Y, Van Rhijn BW, Prigoda NL, et al., 2014, FGFR3 Mutations, but not FGFR3 Expression and FGFR3 Copy-Number Variations, are Associated with Favourable Non-Muscle Invasive Bladder Cancer. Virchows Arch, 465:207–13. DOI: 10.1007/s00428-014-1596-4.
Mao W, Huang X, Wang L, et al., 2019, Circular RNA hsa_circ_0068871 Regulates FGFR3 Expression and Activates STAT3 by Targeting miR-181a-5p to Promote Bladder Cancer Progression. J Exp Clin Cancer Res, 38:169. DOI: 10.1186/s13046-019-1136-9.
Sethakorn N, O’donnell PH, 2016, Spectrum of Genomic Alterations in FGFR3: Current Appraisal of the Potential Role of FGFR3 in Advanced Urothelial Carcinoma. BJU Int, 118:681–91. DOI: 10.1111/bju.13552.
Critelli R, Fasanelli F, Oderda M, et al., 2016, Detection of Multiple Mutations in Urinary Exfoliated Cells from Male Bladder Cancer Patients at Diagnosis and During Follow-up. Oncotarget, 7:67435–48. DOI: 10.18632/oncotarget.11883.
Borkowska EM, Traczyk-Borszyńska M, Kutwin P, et al., 2019, Usefulness of Droplet Digital PCR and Sanger Sequencing for Detection of FGFR3 Mutation in Bladder Cancer. Urol Oncol, 37:907–15. DOI: 10.1016/j.urolonc.2019.06.010.
Roperch J P, Hennion C, 2020, A Novel Ultra-sensitive Method for the Detection of FGFR3 Mutations in Urine of Bladder Cancer Patients Design of the Urodiag® PCR Kit for Surveillance of Patients with Non-muscle-Invasive Bladder Cancer (NMIBC). BMC Med Genet, 21:112. DOI: 10.1186/s12881-020-01050-w.
Roperch JP, Grandchamp B, Desgrandchamps F, et al., 2016, Promoter Hypermethylation of HS3ST2, SEPTIN9 and SLIT2 Combined with FGFR3 Mutations as a Sensitive/Specific Urinary Assay for Diagnosis and Surveillance in Patients with Low or High-risk Non-muscle-invasive Bladder Cancer. BMC Cancer, 16:704. DOI: 10.1186/s12885-016-2748-5.
Blanca A, Requena MJ, Alvarez J, et al., 2016, FGFR3 and Cyclin D3 as Urine Biomarkers of Bladder Cancer Recurrence. Biomark Med, 10:243–53. DOI: 10.2217/bmm.15.120.
Cambier S, Sylvester RJ, Collette L, et al., 2016, EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin. Eur Urol, 69:60–9. DOI: 10.1016/j.eururo.2016.01.055.
Larsen ES, Joensen UN, Poulsen AM, et al., 2020, Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer: A Review of Immunological Aspects, Clinical Effects and BCG Infections. Apmis, 128:92–103. DOI: 10.1111/apm.13011.
Zhang N, Jiang G, Liu X, et al., 2016, Prediction of Bacillus Calmette-Guerin Response in Patients with Bladder Cancer after Transurethral Resection of Bladder Tumor by Using vGenetic Variation Based on Genomic Studies. Biomed Res Int, 2016:9859021. DOI: 10.1155/2016/9859021.
Babjuk M, Burger M, Compérat EM, et al., 2019, European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ)-2019 Update. Eur Urol, 76:639–57. DOI: 10.1016/j.eururo.2019.08.016.
Langle YV, Belgorosky D, Mccormick BP, et al., 2016, FGFR3 Down-Regulation is Involved in Bacillus Calmette-Guerin Induced Bladder Tumor Growth Inhibition. J Urol, 195:188–97. DOI: 10.1016/j.juro.2015.06.093.
Xie X, Lin J, Zhong Y, et al., 2019, FGFR(3S249C) Mutation Promotes Chemoresistance by Activating Akt Signaling in Bladder Cancer Cells. Exp Ther Med, 18:1226–34. DOI: 10.3892/etm.2019.7672.
Yang Z, Zhang R, Ge Y, et al., 2018, Somatic FGFR3 Mutations Distinguish a Subgroup of Muscle-Invasive Bladder Cancers with Response to Neoadjuvant Chemotherapy. EBioMedicine, 35:198–203. DOI: 10.1016/j.ebiom.2018.06.011.
Sung JY, Sun JM, Jeong BC, et al., 2014, FGFR3 Overexpression is Prognostic of Adverse Outcome for Muscle-invasive Bladder Carcinoma Treated with Adjuvant Chemotherapy. Urol Oncol, 32:49.e23–31.
Sharma P, Retz M, Siefker-Radtke A, et al., 2017, Nivolumab in Metastatic Urothelial Carcinoma after Platinum Therapy (CheckMate 275): A Multicentre, Single-arm, Phase 2 Trial. Lancet Oncol, 18:312–22. DOI: 10.1016/s1470-2045(17)30065-7.
Sweis RF, Spranger S, Bao R, et al., 2016, Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer. Cancer Immunol Res, 4:563–8. DOI: 10.1158/2326-6066.cir-15-0274.
Wang L, Gong Y, Saci A, et al., 2019, Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer. Eur Urol, 76:599–603. DOI: 10.1016/j.eururo.2019.06.025.
Bahleda R, Italiano A, Hierro C, et al., 2019, Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Clin Cancer Res, 25:4888–97. DOI: 10.1158/1078-0432.ccr-18-3334.
Nadal R, Bellmunt J, 2019, Management of metastatic bladder cancer. Cancer Treat Rev, 76:10–21.
Hahn NM, Bivalacqua TJ, Ross AE, et al., 2017, A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157. Clin Cancer Res, 23:3003–11. DOI: 10.1158/1078-0432.ccr-16-2267.
Milowsky MI, Dittrich C, Duran I, et al., 2014, Phase 2 Trial of Dovitinib in Patients with Progressive FGFR3-mutated or FGFR3 Wild-type Advanced Urothelial Carcinoma. Eur J Cancer, 50:3145–52. DOI: 10.1016/j.ejca.2014.10.013.
Nogova L, Sequist LV, Garcia JM, et al., 2017, Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol, 35:157–65. DOI: 10.1200/jco.2016.67.2048.
Van Rhijn BW, Mertens LS, Mayr R, et al., 2020, FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment?. Eur Urol, 78:682–7. DOI: 10.1158/1557-3265.bladder19-b23.
Han Y, Liu X, Ye H, et al., 2020, Lower Mutant-allele Tumor Heterogeneity is a Biomarker in FGFR3-mutant Bladder Cancer for Better Prognosis. World J Surg Oncol, 18:310. DOI: 10.21203/rs.3.rs-62350/v1.
Breyer J, Wirtz RM, Erben P, et al., 2018, High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma. Clin Genitourin Cancer, 16:248–56.e2. DOI: 10.1016/j.clgc.2018.01.009.
Kang HW, Kim YH, Jeong P, et al. 2017, Expression Levels of FGFR3 as a Prognostic Marker for the Progression of Primary pT1 Bladder Cancer and its Association with Mutation Status. Oncol Lett, 14:3817–24. DOI: 10.3892/ol.2017.6621.
Akanksha M, Sandhya S, 2019, Role of FGFR3 in Urothelial Carcinoma. Iran J Pathol, 14:148–55.