IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma

• Published in: British journal of cancer Vol. 112; no. 7; pp. 1190 - 1198
• Main Authors: Xu, C-F, Johnson, T, Garcia-Donas, J, Choueiri, T K, Sternberg, C N, Davis, I D, Bing, N, Deen, K C, Xue, Z, McCann, L, Esteban, E, Whittaker, J C, Spraggs, C F, Rodríguez-Antona, C, Pandite, L N, Motzer, R J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.03.2015; Nature Publishing Group
• Subjects: 692/699/67/1059/99; 692/699/67/589/1588/1351; 692/700/1750; 692/700/565/1436/434; Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Agents - therapeutic use; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Clinical Study; Clinical Trials, Phase III as Topic; Drug Resistance; Epidemiology; Female; Growth factors; Humans; Indazoles; Indoles - therapeutic use; Interleukin-8 - genetics; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Male; Medical prognosis; Medical research; Metastasis; Middle Aged; Molecular Medicine; Oncology; Polymorphism, Single Nucleotide; Pyrimidines - therapeutic use; Pyrroles - therapeutic use; Randomized Controlled Trials as Topic; Sulfonamides - therapeutic use; Sunitinib; Survival Analysis; Young Adult; United States > US; Spain; sunitinib; overall survival; renal cell carcinoma; pazopanib; IL8 polymorphism; pharmacogenetics
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.64

Background: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC). Methods: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial ( N =241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib ( N =729, study 2) and an observational study of sunitinib-treated patients ( N =89, study 3). Results: In study 1, four SNPs showed nominally significant association ( P ≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated ( P ≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association ( P ≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment ( P =8.8 × 10 −5 ; variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15–1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients. Conclusions: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.