850P - Genetic polymorphisms and sunitinib toxicity in metastatic renal-cell carcinoma

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Anti-Cancer Agents & Biologic Therapy
Renal Cell Cancer
Complications of Treatment
Presenter Juan Sepulveda Sanchez
Authors J. Sepulveda Sanchez1, C. Farfan2, G. Velasco3, F. Villacampa4, J. Benitez5, C. Rodriguez6, M. Calderon2, I. Cañamares7, H. Cortes-Funes1, D.E. Castellano1
  • 1Servicio De Oncologia Medica, University Hosptial 12 De Octubre Medical oncology, 28041 - Madrid/ES
  • 2Medical Oncology, Hospital Universitario 12 de Octubre, 28041 - Madrid/ES
  • 3Medical Oncology, Hopital 12 de Octubre, 28005 - Madrid/ES
  • 4Urology- Urooncology Unit, Hospital Universitario 12 de Octubre, 28041 - Madrid/ES
  • 5Clinical Pharmacology & Pharmacogenetics, University of Extremadura Medical School & Infanta Cristina University Hospital, 06006 - Badajoz/ES
  • 6Biology, Centro Nacional de Investigaciones Científicas, 28029 - Madrid/ES
  • 7Pharmacy, Hospital Universitario 12 de Octubre, 28041 - Madrid/ES

Abstract

Background

Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor that is approved for the treatment of renal cell carcinoma (RCC). However, several patients either do not respond to treatment or they experience significant toxicity. Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system.

Methods

30 patients with newly diagnosed metastatic RCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU in repeated 6-wk cycles of 50 mg/day (4 wks on followed by 2 wks off treatment). A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode ® pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS.

Results

Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1. a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction: 2.33 months Vs NR; p < 0.006). Pts with CYP2C19*1/*1, wild type genotype, had an increased risk of dose reductions due to toxicity versus other genotypes (Median time to dose reduction: 2.8 months Vs 9.73 months; P < 0.021). No statistically significant associations were observed among drug metabolizing genes and PFS or OS. Catechol-O-methyltransferase (COMT) V158M polymorphism was associated with PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 months; OS = 17.2 months and Val/Val pts PFS = 3.3 months; OS= 4.4 months; p = 0.005 for PFS and P = 0.003 for OS).

Conclusions

This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if confirmed, these results could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011) and will be presented.

Disclosure

All authors have declared no conflicts of interest.