Microvessel area as a predictor of sorafenib response in metastatic renal cell carcinoma

Abstract

Background: Sorafenib was the first Food and Drug Administration approved anti-angiogenic therapy for renal cell carcinoma (RCC). Currently, there are no validated predictive biomarkers for sorafenib. Our purpose was to determine if sorafenib target expression is predictive of sorafenib sensitivity.

Methods: We used an automated, quantitative immunofluorescence-based method to determine expression levels of sorafenib targets VEGF, VEGF-R1, VEGF-R2, VEGF-R3, c-RAF, B-RAF, c-Kit, and PDGFR-β in a cohort of 96 patients treated with sorafenib. To measure vasculature in the tumor samples, we measured microvessel area (MVA) by CD-34 staining.

Results: Of the markers studied, only high MVA was predictive of response (p = 0.005). High MVA was associated with smaller primary tumors (p = 0.005). None of the biomarkers studied was predictive of overall or progression-free survival. Using the Bonferroni adjustment correcting for 9 variables with an alpha of 0.05, MVA remained significantly associated with sorafenib response.

Conclusions: Our results suggest that high MVA in tumor specimens might be associated with a greater likelihood of response to therapy. Further studies are needed to confirm these results in additional patients and in patients receiving other VEGF-R2 inhibitors, as MVA might be useful to improve patient selection for VEGF-R2 inhibitors.

Figure 1

High (panel A) and low (panel B) microvessel area (MVA) by AQUA. We used a cocktail of anti-cytokeratin and anti-carbonic anhydrase-9 conjugated to Cy2 to create a tumor mask (green), and anti-CD-34 conjugated to Cy5 (red) to identify microvessels. An example of a patient with high MVA is shown in panel A, and an example of low MVA in panel B. The corresponding MVA scores were 28.37% and 3.31%.

Figure 2

Means plot analysis depicting differences in MVA between sorafenib non-responders (progressive disease and stable disease) and responders (partial and complete responders).