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

Abstract

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.

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…With regard to pazopanib, SNPs in UGT1A1, CYP1A2, and HFE were associated with either bilirubin levels or ALT levels, and SNPs in IL8, HIF1A, NR1I2, and VEGFA were associated with efficacy outcomes on pazopanib. The association of rs1126647 in IL8 with OS was confirmed in two independent data sets including patients treated with either sunitinib or pazopanib [40,42]. Sorafenib toxicity and efficacy were related to genetic polymorphisms in ABCC2, HLA-A, and the only large study (n > 300) available on sorafenib treatment showed rs2071559 in VEGF-R2 was related to efficacy.…”

“…However, the effects on total drug exposure resulting from changes in CYP enzyme activity may be very different for sunitinib and pazopanib. Including both sunitinib-and pazopanib-treated patients in this type of analyses is not very reasonable [41,42], since sunitinib is converted to an active metabolite with similar activity and potency and a longer half-life, while pazopanib only has less active metabolites. In addition, the extent of absorption for pazopanib and sunitinib may be very different (due to substrate specificity, for example), and its role in the total PK of the TKI is unclear.…”

“…Only two pharmacogenetic studies on sorafenib were found in which genetic polymorphisms in ABCC2 and HLA-A were associated with high-grade skin rash and rs2071559 in VEGF-R2 was associated with PFS and OS. For axitinib, no associations were reported [40][41][42][43][44].…”

“…The variant T allele of SNP rs1126647 in IL8 was associated with an inferior OS in every separate cohort (P < 0.05). In a metaanalysis of the association results in the combined data set of 964 patients, this SNP was also associated with a worse OS [42].…”

“…None of the UGT1A1 SNPs showed an association with elevated ALT levels [41]. More recently, Xu et al [42] examined three separate patient cohorts of 186 patients on pazopanib in the first cohort, 690 patients using either pazopanib (n = 353) or sunitinib (n = 337) in the second cohort, and the third cohort comprised 88 patients on sunitinib. The variant T allele of SNP rs1126647 in IL8 was associated with an inferior OS in every separate cohort (P < 0.05).…”