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Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma.

ABSTRACT: Earlier, the association of single nucleotide polymorphisms (SNPs) with toxicity and efficacy of sunitinib has been explored in patients with metastatic renal cell carcinoma (mRCC). Recently, additional SNPs have been suggested as potential biomarkers. We investigated these novel SNPs for association with sunitinib treatment outcome in mRCC patients.In this exploratory study, we selected SNPs in genes CYP3A4, NR1I2, POR, IL8, IL13, IL4-R, HIF1A and MET that might possibly be associated with sunitinib treatment outcome. Each SNP was tested for association with progression-free survival (PFS) and overall survival (OS) by Cox-regression analysis and for clinical response and toxicity using logistic regression.We included 374 patients for toxicity analyses, of which 38 patients with non-clear cell renal cell cancer were excluded from efficacy analyses. The risk for hypertension was increased in the presence of the T allele in IL8 rs1126647 (OR?=?1.69, 95 % CI?=?1.07-2.67, P?=?0.024). The T allele in IL13 rs1800925 was associated with an increase in the risk of leukopenia (OR?=?6.76, 95 % CI?=?1.35-33.9, P?=?0.020) and increased prevalence of any toxicity > grade 2 (OR?=?1.75, 95 % CI?=?1.06-2.88, P?=?0.028). No significant associations were found with PFS, OS or clinical response.We show that polymorphisms in IL8 rs1126647 and IL13 rs1800925 are associated with sunitinib-induced toxicities. Validation in an independent cohort is required.

SUBMITTER: Diekstra MH

PROVIDER: S-EPMC4643117 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma.

Diekstra Meta H M MH Liu Xiaoyan X Swen Jesse J JJ Boven Epie E Castellano Daniel D Gelderblom Hans H Mathijssen Ron H J RH Rodríguez-Antona Cristina C García-Donas Jesus J Rini Brian I BI Guchelaar Henk-Jan HJ

European journal of clinical pharmacology 20150921 12

<h4>Purpose</h4>Earlier, the association of single nucleotide polymorphisms (SNPs) with toxicity and efficacy of sunitinib has been explored in patients with metastatic renal cell carcinoma (mRCC). Recently, additional SNPs have been suggested as potential biomarkers. We investigated these novel SNPs for association with sunitinib treatment outcome in mRCC patients.<h4>Methods</h4>In this exploratory study, we selected SNPs in genes CYP3A4, NR1I2, POR, IL8, IL13, IL4-R, HIF1A and MET that might ...[more]

PMID: 26387812

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Project description:Single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor receptor (VEGFR) may have effects on the MAPK/ERK/STAT3 signaling pathway, and the resulting phenotypes may influence the response to sunitinib-targeted therapy for renal cell carcinoma. In order to test this hypothesis patients with advanced renal cell carcinoma treated with sunitinib, were enrolled in our study. Peripheral blood samples were used to run a polymerase chain reaction-restriction fragment length polymorphism protocol to type candidate nucleotide polymorphism loci (VEGFR1, VEGFR2 and VEGFR3). The samples were also used in western blots to determine p-MAPK/ERK/STAT3 protein expression levels. The clinical responses to treatment were recorded and then a logistic regression method was applied to analyze the correlation between polymorphism of loci and effectiveness of sunitinib therapy. According to a follow-up visit (on average after 15 months of treatment) there were 16 complete responses (CR), 29 partial responses (PR) and 23 stable disease (SD) and progression of disease (PD) cases. Tests were carried out for 5 SNPs: VEGFR1 (rs664393), VEGFR2 (rsl870377 and rs7667298) and VEGFR3 (rs448012 and rs72816988). Mutation rates of rsl870377 and rs448012 loci in the CR+PR group were lower than those in the SD+PD group. No such differences were found for the other 3 loci. Relative expression levels of p-MAPk, p-ERK and p-STAT3 in the CR+PR group were significantly lower than those in the SD+PD group (P<0.05). The median progression-free survival and overall survival (OS) in the CR+PR group were higher than those in the SD+PD group (P<0.001). The median OS of the TT rsl870377 genotype was higher than that of the AA genotype, and the median OS of the GG rs448012 genotype was higher than that of the CC genotype (P<0.001). It was concluded through a logistic regression model that rsl870377 (AA) and rs448012 (GG) are independent risk factors closely associated with the effectiveness of sunitinib-targeted therapy on renal cell carcinoma. VEGFR SNPs are able to mediate the MAPK/ERK/STAT3 signaling pathway and therefore influence the effectiveness of sunitinib-targeted therapy, which makes them possible new therapeutic targets.

Project description:BackgroundMetastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr.ObjectiveTo analyze long-term safety with sunitinib in mRCC patients.Design, setting, and participantsData were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g., cytokine refractory or treatment-naïve).Outcome measurements and statistical analysisInterval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment.Results and limitationsAmong long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients.ConclusionsProlonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative.Patient summaryMore than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk.

Dataset Information

Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma.

Publications

Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma.

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