FINAL DIAGNOSIS
Right renal pelvis urothelial carcinoma with FGFR3 alteration.
FOLLOW UP: Based on the results of the Oncomine NGS, patient was started on Erdafitinib.
DISCUSSION
The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including embryonic development, proliferation, survival, migration, tissue development, angiogenesis, and tissue regeneration.
FGFR3 (fibroblast growth factor receptor 3) is a member of the transmembrane receptor tyrosine kinases (RTK) family that binds fibroblast growth factors (FGFs). It consists of three extracellular immunoglobulin-like domains, transmembrane domain, and one intracellular tyrosine kinase domain. Alternative splicing events of FGFR allow the generation of multiple isoforms, resulting in a dramatically variable FGF-binding specificity. FGF-FGFR interaction is stabilized by the extracellular matrix and the cell surface heparin sulfate proteoglycans (HSPG). Physiologically it has role in bone development through regulating ossification. The binding of FGF ligand leads to receptor dimerization and transphosphorylation of cytoplasmic tyrosine kinase domains. The activated receptor signals via RAS/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K/AKT) and STAT-dependent pathways.
In the context of cancer, FGFR3 acts as an oncogene and its aberrant signaling results in neoplastic cell proliferation and survival, neoangiogenesis, and resistance to anticancer agents. Molecular alterations of FGFR3 in cancer include FGFR3 gene fusions, FGFR3-activating mutations, and FGFR overexpression. Fusions involving FGFR3 and TACC3 (transforming acidic coiled-coil containing protein 3) are found in 3-7% of glioblastomas and 3-6% of urothelial bladder carcinomas, and are sensitive to FGFR inhibitors. Activating mutations in FGFR3 result in aberrant FGFR signaling through multiple mechanisms, including: (i) enhanced activation of the kinase domain; (ii) ligand-independent dimerization of the receptors; and (iii) altered affinity for FGF ligands. FGFR overexpression is caused by focal amplifications and has been shown to be associated with maintenance of tumor-initiating stem cells, poorer prognosis, and high sensitivity to FGFR inhibitors. The aberrant FGFR3 signaling in cancer is potentiated by positive feedback loop mediated by MYC protein that upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3.
FGFR3, a driver oncogene, is the most frequent alteration in urothelial carcinoma, agnostic of grade. Approximately 60-70% of non-muscle invasive urothelial carcinoma and up to 20% of muscle invasive high-grade urothelial carcinoma harbor activating point mutations in FGFR3 gene. FGFR3 p. S249C alteration affects extracellular immunoglobulin-like domain and leads to cysteine bridge formation and constitutive activation the molecular pathway.
Erdafitinib, an FGFR tyrosine kinase inhibitor, is an FDA approved drug for the treatment of advanced urothelial carcinoma with certain FGFR3 mutations, including FGFR3 p.S249C alteration.
Use of Erdafitinib is associated with objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations, with overall survival of 13.8 months (versus 7-9 months chemotherapy alone).
REFERENCES
Contributed by Armen Kasyan, MD, John M. Skaugen, MD
  |
