Diekstra M.H.M., Swen J.J., Boven E., Castellano D., Gelderblom H., Mathijssen R.H.J., Rodríguez-Antona C., García-Donas J., Rini B.I., Guchelaar H.-J.
European Urology 2015 68:4 (621-629)
Background: In our exploratory studies, we associated single nucleotide polymorphisms (SNPs) in candidate genes with the efficacy and toxicities of sunitinib in metastatic renal cell carcinoma (mRCC). Objective To see whether previously reported associations of SNPs with sunitinib-induced toxicities and efficacy in mRCC can be confirmed in a large cohort of patients. Design, setting, and participants The mRCC patients treated with sunitinib and a DNA sample available were pooled from three exploratory studies conducted in the United States, Spain, and the Netherlands. A total of 22 SNPs and 6 haplotypes in 10 candidate genes related to the pharmacokinetics and pharmacodynamics of sunitinib were selected for association testing. Outcome measurements and statistical analysis SNPs and haplotypes were tested for associations with toxicity, dose reductions, progression-free survival (PFS), overall survival (OS), and best objective response. Results and limitations A total of 333 patients were included. We confirmed 2 of the 22 previously reported SNP associations. The presence of CYP3A5?1 was associated with dose reductions (odds ratio: 2.0; 95% confidence interval [CI], 1.0-4.0, p = 0.039). The presence of CGT in the ABCB1 haplotype was associated with an increased PFS (hazard ratio: 1.9; 95% CI, 1.3-2.6; p < 0.001) and remained significant after Bonferroni correction. These associations are consistent with prior observations. Conclusions The confirmation of previously reported associations between polymorphisms in CYP3A5 and ABCB1 with sunitinib toxicity and efficacy, respectively, indicates that genotyping of these genetic variants will be useful for guiding sunitinib treatment. A prospective validation study is needed to confirm our findings on ABCB1 and CYP3A5 genetic polymorphisms. Patient summary We confirmed that variants in genes involved in processing sunitinib through the body have an effect on sunitinib treatment outcome. These findings confirm the potential of testing for these genetic variants to improve individual patient care for patients with metastatic renal cell carcinoma treated with sunitinib