Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes.

Détails

ID Serval
serval:BIB_588474150457
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes.
Périodique
Journal of Clinical Oncology
Auteur(s)
Xu C.F., Bing N.X., Ball H.A., Rajagopalan D., Sternberg C.N., Hutson T.E., de Souza P., Xue Z.G., McCann L., King K.S., Ragone L.J., Whittaker J.C., Spraggs C.F., Cardon L.R., Mooser V.E., Pandite L.N.
ISSN
1527-7755 (Electronic)
ISSN-L
0732-183X
Statut éditorial
Publié
Date de publication
2011
Volume
29
Numéro
18
Pages
2557-2564
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
PURPOSE: Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways.¦PATIENTS AND METHODS: Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively.¦RESULTS: Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%).¦CONCLUSION: Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
Mots-clé
Angiogenesis Inhibitors/pharmacology, Angiogenesis Inhibitors/therapeutic use, Carcinoma, Renal Cell/drug therapy, Carcinoma, Renal Cell/genetics, Clinical Trials, Phase II as Topic/statistics & numerical data, Cross-Over Studies, DNA Mutational Analysis, Disease-Free Survival, Genetic Markers, Genotype, Germ-Line Mutation, Humans, Kidney Neoplasms/drug therapy, Kidney Neoplasms/genetics, Multicenter Studies as Topic/statistics & numerical data, Neoplasm Proteins/genetics, Neovascularization, Physiologic/genetics, Polymorphism, Single Nucleotide, Proportional Hazards Models, Pyrimidines/pharmacology, Pyrimidines/therapeutic use, Randomized Controlled Trials as Topic/statistics & numerical data, Receptor Protein-Tyrosine Kinases/antagonists & inhibitors, Sulfonamides/pharmacology, Sulfonamides/therapeutic use
Pubmed
Web of science
Création de la notice
22/03/2012 10:44
Dernière modification de la notice
20/08/2019 15:12
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