The impact of FGFR1 and FRS2 expression on sorafenib treatment in metastatic renal cell carcinoma.
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BACKGROUND: Angiogenesis plays a role in tumor growth and is partly mediated by factors in both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) pathways. Durable clinical responses with VEGF tyrosine kinase inhibitors (TKIs) may be limited by intrinsic tumor resistance. We hypothesized that FGF signaling may impact clinical responses to sorafenib. METHODS: Nephrectomy material was available from 40 patients with metastatic renal cell carcinoma (RCC) enrolled in a phase II clinical trial of sorafenibinterferon (ClinicalTrials.gov Identifier NCT00126594). Fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor substrate 2 alpha (FRS2) expression was assessed by in situ hybridization and immunofluorescence, respectively. The relationship between fibroblast growth factor pathway marker levels and progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: Univariate analysis indicated that more intense FGFR1 staining was associated with shorter PFS (log-rank P=0.0452), but FRS2 staining was not significantly associated with PFS (log-rank P=0.2610). Multivariate Cox proportional hazards regression models were constructed for FGFR1 and FRS2 individually, adjusting for baseline Eastern Cooperative Oncology Group performance status, treatment arm and anemia status. When adjusted for each of these variables, the highest intensity level of FGFR1 (level 3 or 4) had increased progression risk relative to the lowest intensity level of FGFR1 (level 1) (P=0.0115). The highest intensity level of FRS2 (level 3 or 4) had increased progression risk relative to the lowest intensity level of FRS2 (level 1) (P=0.0126). CONCLUSIONS: Increased expression of FGFR1 and FRS2 was associated with decreased PFS among patients with metastatic RCC treated with sorafenib. The results suggest that FGF pathway activation may impact intrinsic resistance to VEGF receptor inhibition.
