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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 (OS) Kaplan–Meier curves for IL8 2767A>T (rs1126647) genotype in confirmation study 2 (from COMPARZ) for (A) pazopanib-treated patients and (B) sunitinib-treated patients. 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. AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.
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fig3: Overall survival (OS) Kaplan–Meier curves for IL8 2767A>T (rs1126647) genotype in confirmation study 2 (from COMPARZ) for (A) pazopanib-treated patients and (B) sunitinib-treated patients. 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. AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.

Mentions: In study 2 (pazopanib- or sunitinib-treated, N=729), rs1126647 was significantly associated with OS (N=690; 287 events; P=0.018, HR=1.23, 95% CI: 1.04–1.46, with adjustment for treatment; 10 patients had missing genotype data and 29 patients had missing data for baseline factors). The effect size estimate was similar when baseline factors were not adjusted for (N=719; 299 events; P=0.014, HR=1.24, 95% CI: 1.04–1.46) (Figure 1B). The HRs for association between rs1126647 and OS were not significantly different between pazopanib-treated patients (N=353; 146 events; P=0.53, HR=1.08, 95% CI: 0.84–1.40) and sunitinib-treated patients (N=337; 141 events; P=0.008, HR=1.39, 95% CI: 1.09–1.77) in study 2 (Figure 2), with overlapping CIs (Figure 3) and no significant genotype by treatment interaction effect (P=0.23). The lack of a nominally significant association in pazopanib-treated patients in study 2 (P=0.53) precludes straightforward interpretation of these results, which is an issue we discuss further.


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 (OS) Kaplan–Meier curves for IL8 2767A>T (rs1126647) genotype in confirmation study 2 (from COMPARZ) for (A) pazopanib-treated patients and (B) sunitinib-treated patients. 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. 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

fig3: Overall survival (OS) Kaplan–Meier curves for IL8 2767A>T (rs1126647) genotype in confirmation study 2 (from COMPARZ) for (A) pazopanib-treated patients and (B) sunitinib-treated patients. 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. AA, reference genotype; AT, variant heterozygote genotype; TT, variant homozygote genotype.
Mentions: In study 2 (pazopanib- or sunitinib-treated, N=729), rs1126647 was significantly associated with OS (N=690; 287 events; P=0.018, HR=1.23, 95% CI: 1.04–1.46, with adjustment for treatment; 10 patients had missing genotype data and 29 patients had missing data for baseline factors). The effect size estimate was similar when baseline factors were not adjusted for (N=719; 299 events; P=0.014, HR=1.24, 95% CI: 1.04–1.46) (Figure 1B). The HRs for association between rs1126647 and OS were not significantly different between pazopanib-treated patients (N=353; 146 events; P=0.53, HR=1.08, 95% CI: 0.84–1.40) and sunitinib-treated patients (N=337; 141 events; P=0.008, HR=1.39, 95% CI: 1.09–1.77) in study 2 (Figure 2), with overlapping CIs (Figure 3) and no significant genotype by treatment interaction effect (P=0.23). The lack of a nominally significant association in pazopanib-treated patients in study 2 (P=0.53) precludes straightforward interpretation of these results, which is an issue we discuss further.

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