SNPs predict sunitinib outcome in mRCC

Research has confirmed that single nucleotide polymorphisms (SNPs) in genes related to the processing of sunitinib influence the outcome of treatment for metastatic renal cell carcinoma (mRCC).

Of 22 SNPs previously associated with the efficacy or toxicity of sunitinib in exploratory studies, two were found to have a significant effect on treatment outcome. The first, CYP3A5*1 was associated with a twofold increased odds of dose reduction. The second, CGT in ABCB1, was significantly associated with increased progression-free survival (PFS), with a hazard ratio of 1.9.

An additional two SNPs previously associated with adverse effects from sunitinib also showed similar magnitudes of effect as in exploratory studies, but these did not reach statistical significance.

The study, involving 333 patients, used data from three exploratory studies. Patients were enrolled between 2004 and 2010 and treated with sunitinib at doses of up to 50 mg for a minimum of 4 cycles.

Overall, 115 (35%) patients received a dose reduction in the first four cycles of sunitinib treatment and, this was due to toxicity in the 53% of patients for whom data were available. The median PFS and overall survival (OS) were 16 and 26 months, respectively.

Writing in European Urology, Henk-Jan Guchelaar (Leiden University Medical Centre, the Netherlands) and colleagues explain that the CYP3A5*1 allele results in CYP3A5 expression, which has previously been associated with increased sunitinib conversion to the SU12662 metabolite. This has a longer half-life than sunitinib, resulting in increased exposure, and could explain why the polymorphism was associated with dose reductions.

However, the team notes that they were unable to confirm all previous findings regarding SNPs in genes related to the pharmacodynamics pathway of sunitinib. In particular, the associations between VEGF and VEGFR-3 and increased PFS and OS were not confirmed by this study. The researchers say this is probably due to a more robust methodology, including their large sample size. Additionally, unlike the earlier research, they looked at VEGF expression in germline DNA and not tumour DNA, which can differ.

“Pharmacogenetic testing for CYP3A5 and ABCB1 may help make better informed decisions regarding [tyrosine kinase inhibitor] selection for individual patients and limit toxicity while increasing efficacy”, the authors comment.

“A prospective validation study is needed to confirm our findings”, they add.

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