The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients.
We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2. 4, 95% confidence interval: 1. 1-5. 2, P=0. 021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib. The Pharmacogenomics Journal advance online publication, 26 January 2016; doi:10. 1038/tpj. 2015. 100.
The pharmacogenomics journal. 2016 Jan 26 [Epub ahead of print]
M H Diekstra, A Belaustegui, J J Swen, E Boven, D Castellano, H Gelderblom, R H Mathijssen, J García-Donas, C Rodríguez-Antona, B I Rini, H-J Guchelaar
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. , Department of Clinical Pharmacy, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain. , Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. , Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands. , Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. , Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands. , Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands. , Spanish Oncology Genitourinary Group, Madrid, Spain. , Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain. , Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA. , Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.