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


Xu, CF; Bing, NX; Ball, HA; Rajagopalan, D; Sternberg, CN; Hutson, TE; de Souza, P; Xue, ZG; McCann, L; King, KS; Ragone, LJ; Whittaker, JC; Spraggs, CF; Cardon, LR; Mooser, VE; Pandite, LN; (2011) Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes. Journal of clinical oncology , 29 (18). pp. 2557-64. ISSN 0732-183X DOI: 10.1200/JCO.2010.32.9110

Full text not available from this repository.

Abstract

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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 21576632
Web of Science ID: 291684600033
URI: http://researchonline.lshtm.ac.uk/id/eprint/354882

Statistics


Download activity - last 12 months
Downloads since deposit
0Downloads
273Hits
Accesses by country - last 12 months
Accesses by referrer - last 12 months
Impact and interest
Additional statistics for this record are available via IRStats2

Actions (login required)

Edit Item Edit Item