Sunitinib, used in the treatment of metastatic renal cell carcinoma. (mRCC), is characterized by a wide inter-individual variability. â« For sunitinib, dose reductions ...
A multicenter validation study of genetic polymorphisms associated with toxicity and efficacy of sunitinib in patients with metastatic renal cell carcinoma Meta H.M. Diekstra1,2, Jesse J. Swen1,2, Epie Boven2,3, D Castellano4,5, R. Ganapathi6, Hans Gelderblom2,7, Ron H.J. Mathijssen2,8, Cristina Rodríguez-Antona9,10, Jesus García-Donas5,11, Brian I. Rini6, Henk-Jan Guchelaar1,2. 1Leiden
University Medical Center, Dept. of Clinical Pharmacy and Toxicology, Leiden, Netherlands; 2Dutch SUTOX consortium, 3VU University Medical Center, Dept. of Medical Oncology, Amsterdam, The Netherlands; 4Hospital Universitario 12 de Octubre, Oncology Department, Madrid, Spain; Oncology Genitourinary Group (SOGUG), Madrid, Spain; 6Cleveland Clinic Taussig Cancer Institute (CCF), Dept. of Solid Tumor Oncology, Cleveland, Ohio, USA; 7Leiden University Medical Center, Dept. of Clinical Oncology, Leiden, Netherlands; 8Erasmus MC Cancer Institute, Dept. of Medical Oncology, Rotterdam, Netherlands; 9Spanish National Cancer Research Centre (CNIO), Hereditary Endocrine Cancer Group, Madrid, Spain; 10ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain; 11Clara Campal Comprehensive Cancer Center, Oncology Unit. 5Spanish
Introduction
Sunitinib, used in the treatment of metastatic renal cell carcinoma (mRCC), is characterized by a wide inter-individual variability For sunitinib, dose reductions are needed in 32% of mRCC patients because of toxicities. In our exploratory studies we have associated single nucleotide polymorphisms (SNPs) in candidate genes with efficacy and toxicities of sunitinib in mRCC (Table 1). These SNPs are potential predictive biomarkers and may enable individualized treatment regimens.
SNPs PK gene CYP1A1 CYP3A5 ABCB1
ABCG2
NR1I3
0bjective
To test these SNPs for association with sunitinib treatment outcome in the largest patient cohort to date.
rs number rs1048943 rs776746 rs1128503 rs2032582 rs1045642 rs2231142 rs55930652 rs2622604 rs2307424 rs2307418 rs4073054
SNPs PD gene VEGFA
NOS3 VEGFR2 VEGFR3 FLT3
rs number rs699947 rs833061 rs2010963 rs1570360 rs3025039 rs2070744 rs2305948 rs1870377 rs307826 rs307821 rs1933437
Table 1: 22 SNPs and 5 haplotypes in 10 genes related to PK or PD of sunitinib were selected because of reported associations (p
