Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib

Abstract

Background:There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients.Methods:We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates.Results:In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013).Conclusion:Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

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“…The authors previously published on a discovery cohort of patients with mRCC treated with sunitinib and found results consistent with the aforementioned exploratory studies; the CC-variant in rs9582036 was associated with worse response rate, progression-free survival (PFS), and overall survival (14 months vs 31 months; P = 0.008) on multivariate analysis [5,6]. This current study [7] represents their findings of a validation cohort of the potential predictive association of the VEGFR1 SNP rs9582036 in mRCC treated with sunitinib.…”

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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].…”

“…On PK, the results show that SNPs in genes coding for CYP enzymes, CYP regulators, and drug efflux transporters (ABCB1, ABCC2, and ABCG2) seem to play an important role in sunitinib treatment outcome, especially CYP3A5 and ABCB1 SNPs [19][20][21]29,31,34,37]. In some of the articles on sunitinib, the intermediate endpoints clearance and exposure were investigated and confirmed the hypotheses that SNPs in CYP3A4, CYP3A5, and ABCB1 influence drug exposure [22,29,36,37] (Figure 2).…”

“…For PFS only, rs2981582 in FGF-R2 and rs2276707 in NR1I2 showed an association. For OS only, rs2307424 in NR1I3 and rs307826 in VEGF-R3 were associated (P < 0.05) [34]. In a separate study on 91 subjects, the CC genotypes of rs9582036 in VEGF-R1 had a lower response rate and a decreased survival (PFS and OS) compared to A-allele carriers [35].…”

“…Beuselinck et al assessed 16 SNPs in 10 genes for their relation with efficacy endpoints in 88 mRCC patients treated with sunitinib [34]. SNP rs1128503 in ABCB1, rs4073054 in NR1I3, and rs307821 in VEGF-R3 were associated with PFS and OS.…”