Association of germ-line SNPs with overall survival (OS) in pazopanib-treated patients (Pts) with advanced renal cell carcinoma (RCC).

Abstract

4558 Background: Pazopanib, an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit, has been approved for the treatment of advanced RCC. Variability in response, progression free survival (PFS), and OS is observed among pazopanib treated RCC pts. Our previous analyses showed that SNPs in IL8, HIF1A, VEGFA and NR1I2 genes may predict PFS and response to pazopanib (ASCO 2010 abstract 4520). We now test the hypothesis that differences in OS can be explained, at least in part, by germline genetic variants in angiogenesis and exposure related genes. Methods: Baseline factors and 27 functional polymorphisms within 13 genes were evaluated in 241 pazopanib treated pts with advanced RCC from a phase III study and its extension study (GU ASCO 2011 abstract 303). Association with OS was analyzed using the Cox proportional hazards model. Results: High neutrophil count (>ULN) and low BMI were independent predictors of poor OS (P≤0.05). Despite including these covariates in the PGx analyses,five SNPs in IL8, FGFR2, NR1I2and ABCB1showed nominally significant association with OS (P≤0.05). A median OS of 30 months was observed in pts carrying wild-type IL82767 AA genotype, compared to 15 months in those with the TT variant genotype [HR (95%CI) = 2.2 (1.3, 3.6) for TT vs. AA, P=0.003]. The median OS for pts who were heterozygous for this IL8 polymorphism was 24 months. The FGFR2IVS2 + 906C>T variant TT genotype associated with inferior OS compared with the wild-type CC genotype [median OS, 21.4 vs. 28.0 months, HR (95%CI) = 1.7 (1.1, 2.8), P=0.02]. Similarly, the variant NR1I2 -25385TT genotype (23 months) and variant ABCB11236TT genotypes (20 months) associated with reduced median OS compared with the respective wild-type CC genotypes (29 months, P=0.02; 28 months, P=0.009). A multivariate analysis including baseline factors and SNPs from the four genes showed that these SNPs are independent predictors for OS. Conclusions: Germline variants in angiogenesis and exposure related genes may be associated with survival outcome for pazopanib monotherapy in pts with advanced RCC. These associations are considered exploratory and require confirmation in an independent dataset.