Purpose: 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. Experimental design: 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. Results: 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). Conclusions: 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.

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Keywords adult, aged, allele, article, bone metastasis, brain metastasis, breast cancer resistance protein, cancer chemotherapy, cancer patient, cancer risk, cancer survival, controlled study, cytochrome P450 3A5, electrocorticography, female, gene dosage, genetic association, genetic variability, haplotype, human, kidney carcinoma, liver metastasis, lung metastasis, lymph node metastasis, major clinical study, male, metastasis, multidrug resistance protein 1, multiple cycle treatment, nuclear receptor coactivator 2, overall survival, priority journal, prognosis, progression free survival, retrospective study, single nucleotide polymorphism, sunitinib, treatment outcome
Persistent URL dx.doi.org/10.1158/1078-0432.CCR-10-1828, hdl.handle.net/1765/22879
Citation
van der Veldt, A.A.M., Eechoute, K., Gelderblom, A.J., Gietema, J.A., Guchelaar, H.J., Erp, N.P., … Wessels, J.A.M.. (2011). Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clinical Cancer Research, 17(3), 620–629. doi:10.1158/1078-0432.CCR-10-1828