title: Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma.
abstract: OBJECTIVE
  Earlier, the association of single nucleotide polymorphisms (SNPs) with toxicity and efficacy of sunitinib has been explored in patients with metastatic renal cell carcinoma (mRCC). Recently, additional SNPs have been suggested as potential biomarkers. We investigated these novel SNPs for association with sunitinib treatment outcome in mRCC patients.
  
  
  METHODS
  In this exploratory study, we selected SNPs in genes CYP3A4, NR1I2, POR, IL8, IL13, IL4-R, HIF1A and MET that might possibly be associated with sunitinib treatment outcome. Each SNP was tested for association with progression-free survival (PFS) and overall survival (OS) by Cox-regression analysis and for clinical response and toxicity using logistic regression.
  
  
  RESULTS
  We included 374 patients for toxicity analyses, of which 38 patients with non-clear cell renal cell cancer were excluded from efficacy analyses. The risk for hypertension was increased in the presence of the T allele in IL8 rs1126647 (OR = 1.69, 95 % CI = 1.07-2.67, P = 0.024). The T allele in IL13 rs1800925 was associated with an increase in the risk of leukopenia (OR = 6.76, 95 % CI = 1.35-33.9, P = 0.020) and increased prevalence of any toxicity > grade 2 (OR = 1.75, 95 % CI = 1.06-2.88, P = 0.028). No significant associations were found with PFS, OS or clinical response.
  
  
  CONCLUSIONS
  We show that polymorphisms in IL8 rs1126647 and IL13 rs1800925 are associated with sunitinib-induced toxicities. Validation in an independent cohort is required.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333ZA, Netherlands.|Dutch SUTOX consortium, Leiden, Netherlands.
authors.forename: Meta H M
authors.initials: MH
authors.lastname: Diekstra
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333ZA, Netherlands.|Dutch SUTOX consortium, Leiden, Netherlands.|Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333ZA, Netherlands. j.j.swen@lumc.nl.|Dutch SUTOX consortium, Leiden, Netherlands. j.j.swen@lumc.nl.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Dutch SUTOX consortium, Leiden, Netherlands.|Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
authors.affiliation: Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.|Spanish Oncology Genitourinary Group (SOGUG), Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Dutch SUTOX consortium, Leiden, Netherlands.|Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Dutch SUTOX consortium, Leiden, Netherlands.|Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.affiliation: Spanish Oncology Genitourinary Group (SOGUG), Madrid, Spain.|Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: García-Donas
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute (CCF), Cleveland, OH, USA.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333ZA, Netherlands.|Dutch SUTOX consortium, Leiden, Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D018793:Interleukin-13 / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D000077210:Sunitinib; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D018793:Interleukin-13; D016209:Interleukin-8; D011758:Pyrroles; D000077210:Sunitinib
keywords: Metastatic renal cell carcinoma; Progression-free survival; Single nucleotide polymorphism; Sunitinib; Toxicity; Tyrosine kinase inhibitor