Genetic Polymorphisms Associated with a Prolonged Progression-Free Survival in Patients with Metastatic Renal Cell Cancer Treated with Sunitinib

• Published in: Clinical cancer research 2011-02, Vol.17 (3), p.620-629
• Main Authors: VAN DER VELDT, Astrid A. M, EECHOUTE, Karel, GELDERBLOM, Hans, GIETEMA, Jourik, GUCHELAAR, Henk-Jan, VAN ERP, Nielka P, VAN DEN EERTWEGH, Alfons J. M, HAANEN, John B, MATHIJSSEN, Ron H. J, WESSELS, Judith A. M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Disease-Free Survival; Female; Humans; Indoles - pharmacokinetics; Indoles - therapeutic use; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Kidneys; Male; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Pyrroles - pharmacokinetics; Pyrroles - therapeutic use; Tumors of the urinary system
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-1828

The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib. A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model. Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001). This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy.