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

Abstract

Background: Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs).

Objective: To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC.

Design, setting, and participants: 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).

Intervention: Platinum-based chemotherapy.

Outcome measurements and statistical analysis: 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.

Results and limitations: 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.

Conclusions: 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.

Patient summary: 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.

Keywords: Chemotherapy; FGFR3; Platinum; Urothelial cancer.

Fig. 1 –

CONSORT diagrams for the analyzed cohorts: (A) patients with muscle-invasive bladder cancer treated with neoadjuvant cisplatin-based chemotherapy (NAC cohort); (B) patients with metastatic urothelial cancer treated with first-line platinum-based chemotherapy (M1 cohort); and (C) patients with muscle-invasive bladder cancer from The Cancer Genome Atlas (TCGA cohort). FGFR3 = fibroblast growth factor receptor 3; FGFR3alt = FGFR3 alteration; FGFR3wt = FGFR3 wild type; MSK-IMPACT = Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets; NAC = neoadjuvant chemotherapy; TCGA = The Cancer Genome Atlas.

Fig. 2 –

(A) Recurrence-free survival (RFS) and (B) overall survival by FGFR3 mutation status in the neoadjuvant cohort. FGFR3 = fibroblast growth factor receptor 3.

Fig. 3 –

(A) Recurrence-free survival and (B) overall survival by FGFR3 mutation status in the TCGA bladder cancer subset who received adjuvant chemotherapy; (C) recurrence-free survival and (D) overall survival in the TCGA bladder cancer subset who did not receive perioperative chemotherapy. All analyses are log-rank tests and not adjusted for other variables. FGFR3 = fibroblast growth factor receptor 3; TCGA = The Cancer Genome Atlas.