835P - Tissue Microarray (TMA) and VHL Mutations as Predictors of Outcome in Advanced Clear Cell Renal Cell Carcinoma (CCRCC) Treated with Firs Line Sunitinib

Abstract

ABSTRACT Introduction Sunitinib is a standard treatment for kidney cancer, however in some patients response is lacking. Molecular predictors of outcome could deeply impact patient care. Methods We conducted an observational, prospective study in 15 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Inclusion criteria were patients with confirmed advanced clear cell renal cell carcinoma with no prior treatment, planned to receive sunitinib according to local practice. From paraffin embedded tumor samples a Tissue MicroArray (TMA) was constructed and evaluated independently by two pathologists, also blinded to clinical data. Expression of Carbonic Anhydrase IX, P-glicoprotein, Vascular Endothelial Growth Factor (VEGF), VEGF-Receptor 1,2 and 3 (VEGFR1,2 and 3), Platelet-Derived Growth Factor Receptor (PDGFR-Beta), Hypoxia-Inducible Factor 2 alpha (HIF2α) and Von Hippel-Lindau protein (pVHL) was assessed. In addition the presence of VHL gene mutations was studied. Results 101 patients were recruited from 2007 to 2010. TMA was constructed from 69 tumor samples. In multivariable analysis, HIF2α (HR 0.17 (0.05-0.64) p = 0.0083) and PDGFRβ (HR 0.042 (0.003-0.70) p = 0.028) overexpression correlated with progressive disease (PD) as best response. A similar trend in PFS and OS was observed for HIF-alfa but did not reach statistical significance. Progression free survival (PFS) was longer in cases with high VEGFR3 expression (HR 0.42 (0.21-0.83) p = 0.013). Interestingly, low levels of this protein strongly correlated (r = -0.441 P = 0.0003) with the presence of a germline SNP (VEGFR3 rs307826) that has been previously identified as a sunitinib resistance predictor by our group. Finally overexpression of VEGF (HR 4.6 (1.5-13.6), p= 0.0063), and VEGFR1 (HR 6.2 (1.2-32.2) p = 0.031) were associated with poor overall survival (OS). VHL gene alterations could only be determined in 30 cases, with 20 (66%) presenting a pathological mutation. No association with outcome could be established. Conclusion Expression of some proteins involved in neoangiogenesis pathway could play a role in sunitinib sensitivity and resistance. A significant association between low expression of VEGFR3 and one SNP in such gene, both correlated with poor outcome, deserves further investigation. Disclosure All authors have declared no conflicts of interest.