Abstract
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.
Highlights
The treatment options of metastatic renal cell cancer have been limited and systemic treatment primarily consisted of immunotherapy with cyto-Authors' Affiliations: 1Department of Medical Oncology, VU University Medical Center, Amsterdam; 2Department of Medical Oncology, Erasmus University Medical Center – Daniel den Hoed Cancer Center, Rotterdam; Departments of 3Clinical Oncology and 4Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden; 5Department of Medical Oncology, University Medical Center Groningen, Groningen; and 6Department of Medical Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, the NetherlandsNote: Supplementary data for this article are available at Clinical Cancer Research Online.Note: This study was presented at the 2010 ASCO Annual Meeting, Chicago, IL, June 4–8, 2010, #4521.A.A.M. van der Veldt and K
Multivariate analysis showed that progression-free survival (PFS) was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P 1⁄4 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; Hazard ratios (HR), 1.76; P 1⁄4 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P 1⁄4 0.033)
This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in metastatic renal cell cancer (mRCC) patients treated with this drug
Summary
The treatment options of metastatic renal cell cancer (mRCC) have been limited and systemic treatment primarily consisted of immunotherapy with cyto-Authors' Affiliations: 1Department of Medical Oncology, VU University Medical Center, Amsterdam; 2Department of Medical Oncology, Erasmus University Medical Center – Daniel den Hoed Cancer Center, Rotterdam; Departments of 3Clinical Oncology and 4Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden; 5Department of Medical Oncology, University Medical Center Groningen, Groningen; and 6Department of Medical Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, the NetherlandsNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Note: This study was presented at the 2010 ASCO Annual Meeting, Chicago, IL, June 4–8, 2010, #4521.A.A.M. van der Veldt and K. The treatment options of metastatic renal cell cancer (mRCC) have been limited and systemic treatment primarily consisted of immunotherapy with cyto-. Authors' Affiliations: 1Department of Medical Oncology, VU University Medical Center, Amsterdam; 2Department of Medical Oncology, Erasmus University Medical Center – Daniel den Hoed Cancer Center, Rotterdam; Departments of 3Clinical Oncology and 4Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden; 5Department of Medical Oncology, University Medical Center Groningen, Groningen; and 6Department of Medical Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Increasing knowledge of the underlying biology of renal cell cancer (RCC), in particular the clear-cell subtype, has expanded the treatment options for patients with mRCC [1]. RCC is characterized by an inactivated von Hippel–Lindau (VHL) tumor suppressor gene. The development of targeted therapy against signaling of these proteins has significantly improved the perspectives of patients with mRCC
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