Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib

Abstract

PURPOSE Biomarkers that predict response or toxicity to antiangiogenic therapy are sought to favorably inform the risk/benefit ratio. This study evaluated the association of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) genetic polymorphisms with the development of hypertension (HTN) and clinical outcome in meta-static clear cell renal cell carcinoma (MCCRCC) patients treated with sunitinib. PATIENT AND METHODS Sixty-three MCCRCC patients receiving sunitinib (50 mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. A panel of candidate VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) were evaluated for associations with the development of hypertension and clinical outcome. RESULTS VEGF SNP −634 genotype was associated with the prevalence and duration of sunitinib-induced hypertension (as defined by systolic pressure ≥150 mmHg and/or diastolic pressure ≥90 mmHg) in both univariable analysis (P = .03 and .01, respectively) and multivariable analysis, which adjusted for baseline BP and use of antihypertension medication (P = .05 and .02, respectively). Patients with the GG genotype were estimated to have a greater likelihood of being hypertensive during treatment compared with patients with the CC genotype (odds ratio of 13.62, 95% confidence interval [CI] 3.71–50.04). No single VEGF or VEGFR SNPs were found to correlate with clinical outcome. However, the combination of VEGF SNP 936 and VEGFR2 SNP 889 were associated with overall survival after adjustment for prognostic risk group (P = .03). CONCLUSIONS In MCCRCC patients treated with sunitinib, VEGF SNP −634 is associated with hypertension and a combination of VEGF SNP 936 and VEGFR2 SNP 889 genotypes is associated with overall survival.

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“…Changes in genes encoding efflux transporters can, therefore, be more important for sunitinib than for pazopanib. Regarding pharmacodynamics of sunitinib, SNPs in eNOS, IL8, VEGF-A, and VEGF-R1,2,3 present promising biomarkers for toxicity or survival on sunitinib [19,20,25,26,32,34,35]. However, results on VEGF-A and VEGF-R1,2 or 3 genes are contradictory for both toxicity and efficacy outcomes since also negative associations were reported [30,33].…”

“…Similarly, Kim et al [26] evaluated 63 sunitinib-treated mRCC patients for the association of SNPs in VEGF or VEGF-R with hypertension and clinical outcome. The GG genotype of SNP rs2010963 in VEGF was associated with a greater chance for the occurrence and duration of hypertension [26].…”

“…Ultimately, a total of 54 articles was included in our systematic review. 1.3-2.6 P = 0.000275 The Netherlands, Spain, and the United States [19,20,25,26,31], resulting in a sample size of 333 mRCC patients. Data confirmed the association of CYP3A5*1 with the need for dose reductions (P < 0.05) as presented earlier by Garcia-Donas et al [20,30].…”

“…With regard to SNPs in VEGF and VEGF-R, Garcia-Donas et al reported SNPs rs307826 and rs307821 in VEGF-R3 to be associated with a decrease in PFS in a study of 89 mRCC patients [20]. Kim et al [26] showed that carriers of the combination of CC and GG genotypes of rs3025039 in VEGF-A and rs2305948 in VEGF-R2, respectively, showed a worse OS compared to noncarriers [26]. In another study of VEGF and VEGF-R SNPs in a group of 84 mRCC patients, Scartozzi et al [32] report that carriers of the favorable SNP genotypes of rs833061, rs6877011, rs2010963, and rs699947 showed a better overall response rate compared to the unfavorable genotype carriers [32].…”

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“…VEGF-A is highly polymorphic in the promoter and 5¢ untranslated region and single-nucleotide polymorphisms in this region have been reported to regulate VEGF expression via alternative initiation of transcription and internal initiation of translation (Akiri et al, 1998;Huez et al, 1998). Polymorphisms of VEGF have been studied with disparate results in various diseases like type 2 diabetes (Awata et al, 2002;Buraczynska et al, 2007), giant cell arteritis (Rueda et al, 2005), renal complications in Henoch-Schonlein purpura (Rueda et al, 2006), hepatocellular carcinoma (HCC) (Kong et al, 2007), prostate cancer (Onen et al, 2008), familial endometriosis (Zhao et al, 2008), ectopic pregnancy (Elito et al, 2010), glomerulonephritides (Safrankova et al, 2011), hypertension (Kim et al, 2012), age-related macular degeneration (Lu et al, 2012), and breast cancer (Lu et al, 2005;Jacobs et al, 2006;Langsenlehner et al, 2008;Schneider et al, 2008;Rodrigues et al, 2012).…”