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

1] Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Herestraat 49, 3000 Leuven, Belgium [2] Inserm U674 Génomique fonctionnelle des tumeurs solides, Université Paris-5 René Descartes, Rue Juliette Dodu 27, 75010 Paris, France.
British Journal of Cancer (Impact Factor: 4.84). 03/2013; 108(4):887-900. DOI: 10.1038/bjc.2012.548
Source: PubMed


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.

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.

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).

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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    • "Van der Veldt et al. (2011) studied polymorphisms of genes involved in sunitinib pharmacokinetics, and variations in the drug-converting enzyme CYP3A5 and efflux transporter ABCB1 were associated with enhanced progression-free survival in sunitinib-treated patients with metastatic renal cell cancer. In this study, no effects of SNPs in genes involved in pharmacodynamics of sunitinib, including its different targets, were found, whereas others do report a predictive value of VEGF and VEGFR3 (Beuselinck et al., 2013; Scartozzi et al., 2013). These studies show the complexity of linking SNPs to resistance to therapy, because multiple SNPs can be involved, exerting their effects on different levels of disease progression. "
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    • "Accumulating data suggests an influence of germline polymorphisms on RCC patient efficacy and safety when receiving targeted anti-VEGF or VEGFR2 tyrosine kinase inhibitor therapies. Specifically, publications have cited polymorphisms in the VEGF-A gene [48] or VEGFR-3 as associating with clinical outcome [49]. However, the absence of concordance of findings, different SNPs assayed and endpoints measured preclude use of germline polymorphism data for patient selection at the current time. "
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    • "Single nucleotide polymorphisms (SNP) are the most common source of genetic variations in the human genome (Feuk et al., 2009). Some SNP are considerate molecular markers for complex human diseases such as obesity (Frayling et al., 2007) and cancer (Beuselinck et al., 2013; Zienolddiny and Skaug, 2012) since individuals that carry a particular SNP allele may carry specific alleles at nearby sites that may predispose them to a pathological phenotype (The International HapMap Consortium, 2005). "
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