Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma

• Published in: European urology 2020-12, Vol.78 (6), p.907-915
• Main Authors: Teo, Min Yuen, Mota, Jose Mauricio, Whiting, Karissa A., Li, Han A., Funt, Samuel A., Lee, Chung-Han, Solit, David B., Al-Ahmadie, Hikmat, Milowsky, Matthew I., Balar, Arjun V., Pietzak, Eugene, Dalbagni, Guido, Bochner, Bernard H., Ostrovnaya, Irina, Bajorin, Dean F., Rosenberg, Jonathan E., Iyer, Gopa
• Format: Article
• Language: English
• Subjects: Aged; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - secondary; Chemotherapy; Female; FGFR3; Humans; Male; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Staging; Platinum; Platinum - therapeutic use; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Retrospective Studies; Treatment Outcome; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urothelial cancer
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2020.07.018

Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs). To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC. The authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA). Platinum-based chemotherapy. Pathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts. Nine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients. FGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers. Approximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers.