Abstract
BackgroundAngiogenesis 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.MethodsNephrectomy 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.ResultsUnivariate 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).ConclusionsIncreased 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1302-1) contains supplementary material, which is available to authorized users.
Highlights
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
We hypothesized that FGF signaling may impact response to sorafenib, a Tyrosine kinase inhibitor (TKI) whose targets include VEGFR2 and platelet-derived growth factor receptor (PDGFR) [12]
We investigated expression of FGF pathway components in patients with metastatic renal cell carcinoma (RCC) treated in a randomized phase II clinical trial that yielded no differences in progression-free survival (PFS) between sorafenib versus sorafenib + interferon α [13]
Summary
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. Over 13,000 patients die annually from RCC, making it one of the top 10 leading causes of Angiogenesis plays a key role in the growth of many tumors and is mediated by growth factors in both the fibroblast growth factor (FGF) and VEGF families [3,4]. Durable clinical responses with current VEGF tyrosine kinase inhibitors (TKIs) may be limited by acquired or intrinsic tumor resistance. Fibroblast growth factor-2 expression is increased in post-VEGF TKI treatment biopsies further supporting the role of FGF signaling in acquired resistance [7]. We hypothesized that FGF signaling may impact response to sorafenib, a TKI whose targets include VEGFR2 and platelet-derived growth factor receptor (PDGFR) [12]
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