The impact of FGFR1 and FRS2α expression on sorafenib treatment in metastatic renal cell carcinoma

Thai H Ho, Xian-De Liu, Yanqing Huang, Carla L Warneke, Marcella M Johnson, Anh Hoang, Pheroze Tamboli, Fen Wang, Eric Jonasch, Thai H Ho, Xian-De Liu, Yanqing Huang, Carla L Warneke, Marcella M Johnson, Anh Hoang, Pheroze Tamboli, Fen Wang, Eric Jonasch

Abstract

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 sorafenib ± interferon (ClinicalTrials.gov Identifier NCT00126594). Fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor substrate 2 alpha (FRS2α) 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 FRS2α staining was not significantly associated with PFS (log-rank P = 0.2610). Multivariate Cox proportional hazards regression models were constructed for FGFR1 and FRS2α 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 FRS2α (level 3 or 4) had increased progression risk relative to the lowest intensity level of FRS2α (level 1) (P = 0.0126).

Conclusions: Increased expression of FGFR1 and FRS2α 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.

Figures

Figure 1
Figure 1
Fibroblast growth factor receptor 1 and fibroblast growth factor receptor substrate 2 alpha expression. Intensity levels were stratified using the Ariol imaging platform (higher number corresponds to higher intensity) in renal cell carcinoma. Non-tumor tissue was excluded from analysis. (A)In situ hybridization for localization of FGFR1 message. (B) FRS2α immunofluorescence.
Figure 2
Figure 2
Progression-free survival curves (PFS) with number at risk stratified by FGFR1 intensity. The Ariol imaging platform was used to stratify the specimens based on intensity of in situ hybridization staining for FGFR1. Non-tumor tissue was excluded from analysis. The differences across FGFR1 intensity strata were statistically significant with better progression-free survival among those patients with the lowest FGFR1 intensity (level 1) in univariate analysis; P = 0.0452.
Figure 3
Figure 3
Progression-free survival curves (PFS) with number at risk stratified by FRS2α intensity. The Ariol imaging platform was used to stratify the specimens based on intensity of immunofluorescence staining for FRS2α. Non-tumor tissue was excluded from analysis. The differences across FRS2α intensity strata were not statistically significant in univariate analysis; P = 0.2610.

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