359 Background: There are no established biomarkers predicting outcome of SUN treatment in mRCC.
METHODS
We assessed 30 single nucleotide polymorphisms (SNPs) in 10 genes on fresh frozen clear cell RCC nephrectomy specimens originating from pts who developed metastatic disease.
RESULTS
We processed 79 samples. In 49 pts, normal kidney tissue adjacent to the tumor was used, in 30 pts only tumoral tissue was available. After nephrectomy and in presence of synchronous or metachronous metastasis, all pts received SUN as 1st line treatment. We observed associations between several SNPs and mTTP: In the promotor region of the gene encoding for IL-8 (proangiogenic growth factor): rs4073: TT or TA versus (vs) AA variant: mTTP 12 mo vs not reached (NR) (p=0.02). In ABCB1 (involved in drug transport): rs2032582: TA or TT vs GT/GA or GG: 9 vs 16 mo (p=0.03). rs1128503: TT vs CT or CC: 9 vs 16 mo (p=0.02). In VEGFR3 (a target of SUN): rs307826 : GA vs AA: 9.3 vs 18 mo (p=0.01). rs307821 : GT vs GG: 10 vs 16 mo (p=0.08). rs448012 : CC/CG vs GG: 12 mo vs NR (p=0.02). In NR1/2 (promotor leading to increased CYP3A4 expression): rs3814055: TT vs CC/CT: 13 vs 18 mo (p=0.02). rs1054190: CC vs CT: 14 vs 20 mo (p=0.14). In PDGFR-alpha (another SUN target): rs1800812: TT vs GG/GT: 3.5 vs 16 mo (p<0.0001). A scoring system combining 7 non-overlapping SNPs was build and pts were classified in a favorable, intermediate and unfavorable SNP profile group. A link with mTTP and response rate was found, but not with established clinical prognostic scores (MSKCC).
CONCLUSIONS
SNPs in genes linked to the pharmacokinetics and -dynamics of SUN can probably predict outcome of SUN treatment in mRCC. Our results confirm in part previous observations made by other groups in pazopanib or SUN (in IL-8, VEGFR3 and NR1/2) and highlight the potential role of other SNPs (in ABCB1, NR1/2 and PDGFR). Extension of the series and univariate/multivariate validation are ongoing. [Table: see text].