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

Xu CF, Johnson T, Garcia-Donas J, Choueiri TK, Sternberg CN, Davis ID, Bing N, Deen KC, Xue Z, McCann L, Esteban E, Whittaker JC, Spraggs CF, Rodríguez-Antona C, Pandite LN, Motzer RJ - Br. J. Cancer (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.

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.

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Related in: MedlinePlus

Overall survival Kaplan–Meier curves for patients by each IL8 2767A>T (rs1126647) genotype. (A) Pazopanib-treated patients in discovery study 1 (from NCT00334282 and NCT00387764): of the 241 patients, 223 had IL8 genotype data and were included in this plot (including the 37 patients who had missing data for baseline factors). The remaining 18 patients had missing genotype data. (B) Pazopanib- or sunitinib-treated patients in confirmation study 2 (from COMPARZ): of the 729 patients, 719 had IL8 genotype data and were included in this plot (including the 29 patients who had missing data for baseline factors). Ten patients had missing genotype data. (C) Sunitinib-treated patients in confirmation study 3 (SOGUG study): 88 of the 89 patients had IL8 genotype data and were included in this plot; one patient had missing genotype data. The curves show the proportion of patients in each genotype group who survived (y axis) vs time in months (x axis). Vertical bars on the survival curves indicate censored observations. The HR was adjusted for covariates comparing each of the variant genotype (AT or TT) with the reference genotype (AA). AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.
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fig1: Overall survival Kaplan–Meier curves for patients by each IL8 2767A>T (rs1126647) genotype. (A) Pazopanib-treated patients in discovery study 1 (from NCT00334282 and NCT00387764): of the 241 patients, 223 had IL8 genotype data and were included in this plot (including the 37 patients who had missing data for baseline factors). The remaining 18 patients had missing genotype data. (B) Pazopanib- or sunitinib-treated patients in confirmation study 2 (from COMPARZ): of the 729 patients, 719 had IL8 genotype data and were included in this plot (including the 29 patients who had missing data for baseline factors). Ten patients had missing genotype data. (C) Sunitinib-treated patients in confirmation study 3 (SOGUG study): 88 of the 89 patients had IL8 genotype data and were included in this plot; one patient had missing genotype data. The curves show the proportion of patients in each genotype group who survived (y axis) vs time in months (x axis). Vertical bars on the survival curves indicate censored observations. The HR was adjusted for covariates comparing each of the variant genotype (AT or TT) with the reference genotype (AA). AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.

Mentions: We hypothesised that in patients with advanced RCC, genetic effects on OS could be similar for angiogenesis inhibitors in the same class (i.e., pazopanib and sunitinib). Therefore, for follow-up of the discovery findings, we tested the four SNPs in both the pazopanib and sunitinib arms of study 2. In analysis of all patients in study 2, adjusted for treatment received, two IL8 SNPs were associated with OS at P≤0.05 (rs1126647, Figure 1A; rs4073, Supplementary Figure S1). Genotypes at these two IL8 SNPs were strongly correlated with each other (study 1 r2=0.79; P<0.0001), with rs1126647 (IL8 2767A>T) showing stronger association in both study 1 and study 2. Therefore, we focused on this SNP for a detailed description of the results. Given the inclusion of sunitinib-treated patients in study 2 but not in study 1, and a lack of other available genetic data for pazopanib-treated patients with advanced RCC, we sought additional confirmation for the association of rs1126647 in study 3.


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

Xu CF, Johnson T, Garcia-Donas J, Choueiri TK, Sternberg CN, Davis ID, Bing N, Deen KC, Xue Z, McCann L, Esteban E, Whittaker JC, Spraggs CF, Rodríguez-Antona C, Pandite LN, Motzer RJ - Br. J. Cancer (2015)

Overall survival Kaplan–Meier curves for patients by each IL8 2767A>T (rs1126647) genotype. (A) Pazopanib-treated patients in discovery study 1 (from NCT00334282 and NCT00387764): of the 241 patients, 223 had IL8 genotype data and were included in this plot (including the 37 patients who had missing data for baseline factors). The remaining 18 patients had missing genotype data. (B) Pazopanib- or sunitinib-treated patients in confirmation study 2 (from COMPARZ): of the 729 patients, 719 had IL8 genotype data and were included in this plot (including the 29 patients who had missing data for baseline factors). Ten patients had missing genotype data. (C) Sunitinib-treated patients in confirmation study 3 (SOGUG study): 88 of the 89 patients had IL8 genotype data and were included in this plot; one patient had missing genotype data. The curves show the proportion of patients in each genotype group who survived (y axis) vs time in months (x axis). Vertical bars on the survival curves indicate censored observations. The HR was adjusted for covariates comparing each of the variant genotype (AT or TT) with the reference genotype (AA). AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385958&req=5

fig1: Overall survival Kaplan–Meier curves for patients by each IL8 2767A>T (rs1126647) genotype. (A) Pazopanib-treated patients in discovery study 1 (from NCT00334282 and NCT00387764): of the 241 patients, 223 had IL8 genotype data and were included in this plot (including the 37 patients who had missing data for baseline factors). The remaining 18 patients had missing genotype data. (B) Pazopanib- or sunitinib-treated patients in confirmation study 2 (from COMPARZ): of the 729 patients, 719 had IL8 genotype data and were included in this plot (including the 29 patients who had missing data for baseline factors). Ten patients had missing genotype data. (C) Sunitinib-treated patients in confirmation study 3 (SOGUG study): 88 of the 89 patients had IL8 genotype data and were included in this plot; one patient had missing genotype data. The curves show the proportion of patients in each genotype group who survived (y axis) vs time in months (x axis). Vertical bars on the survival curves indicate censored observations. The HR was adjusted for covariates comparing each of the variant genotype (AT or TT) with the reference genotype (AA). AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.
Mentions: We hypothesised that in patients with advanced RCC, genetic effects on OS could be similar for angiogenesis inhibitors in the same class (i.e., pazopanib and sunitinib). Therefore, for follow-up of the discovery findings, we tested the four SNPs in both the pazopanib and sunitinib arms of study 2. In analysis of all patients in study 2, adjusted for treatment received, two IL8 SNPs were associated with OS at P≤0.05 (rs1126647, Figure 1A; rs4073, Supplementary Figure S1). Genotypes at these two IL8 SNPs were strongly correlated with each other (study 1 r2=0.79; P<0.0001), with rs1126647 (IL8 2767A>T) showing stronger association in both study 1 and study 2. Therefore, we focused on this SNP for a detailed description of the results. Given the inclusion of sunitinib-treated patients in study 2 but not in study 1, and a lack of other available genetic data for pazopanib-treated patients with advanced RCC, we sought additional confirmation for the association of rs1126647 in study 3.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.

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.

Show MeSH
Related in: MedlinePlus