Author:

Abstract:

Background: SUN is an oral angiogenesis inhibitor targeting VEGFR-1, -2, and -3, PDGFR-α and -β, RET and c-Kit, approved for the treatment of advanced RCC. Reliable biomarkers predictive for SUN sensitivity or primary/secondary resistance to SUN are lacking. Methods: We analyzed 15 SNPs in 6 genes (VEGF-A, VEGFR-2, VEGFR-3, CA-9, ABCB-1 and NR-1/3) on 80 fresh frozen clear cell RCC nephrectomy specimens (in 49 patients (pts) on normal kidney tissue, in 31 pts on tumour). After nephrectomy, all the pts were treated in the metastatic setting with SUN as first line anti-angiogenic therapy. Results: Global median time-to-progression (TTP) was 13.5 months (mo) and global median overall survival (OS) 28.5mo. Pts with the TT/TA genotype of the missense rs2032582 SNP (2677G>T or G>A) in the ABCB-1 gene, responsible for drug transport, had a significantly worse outcome than pts with the GT/GA or GG genotypes. TTP was 9.0 versus 16.0mo (p=0.03) and OS 22.8 versus 31.0mo (p=0.02) respectively. The TT-variant of the synonymous rs1128503 SNP (1236T>C) was linked to a significantly worse outcome than the CT or CC genotypes. TTP was 9.0 versus 16.0mo (p=0.03) and OS 22.8 versus 31.0mo (p=0.05) respectively. No significant link with TTP/OS and the synonymous rs1045642 SNP (3435C>T) in ABCB-1 could be observed. Pts with the GA variant of the missense rs307826 SNP (1480A>G) in the VEGFR-3 gene, responsible for tumoral angiogenesis and blocked by SUN, had a TTP of 9.3mo (p=0.009) and an OS of 15.0mo (p=0.009) versus 18.5 and 31.0mo for pts with the wild type/wild type AA genotype. For pts with the GT variant of the missense rs307821 SNP (3971G>T), TTP was 10.0mo (p=0.08) and OS of 15.0mo (p=0.15) versus 16.0 and 30.7mo for pts with the wild type/wild type GG genotype. We did not observe any link between TTP/OS and SNPs in the following genes: VEGFR-2 (rs1870377, rs1870378, rs1870379), CA-9 (rs1538536, rs1934158, rs12553173, the latter a prognostic factor for OS in immunotherapy with interleukine-2), VEGF-A (rs699947, rs2010963) and NR-1/3 (rs4073054, rs2307424). Conclusions: We observed significant associations between SNPs in genes involved in drug transport (ABCB-1) and in tumoral angiogenesis (VEGFR-3) and response on SUN in advanced clear cell RCC pts.