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Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

ABSTRACT: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients.We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates.In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013).Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

SUBMITTER: Beuselinck B

PROVIDER: S-EPMC3590652 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

Beuselinck B B Karadimou A A Lambrechts D D Claes B B Wolter P P Couchy G G Berkers J J Paridaens R R Schöffski P P Méjean A A Verkarre V V Lerut E E de la Taille A A Tourani J-M JM Bigot P P Linassier C C Négrier S S Berger J J Patard J-J JJ Zucman-Rossi J J Oudard S S

British journal of cancer 20130301 4

<h4>Background</h4>There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients.<h4>Methods</h4>We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis i ...[more]

PMID: 23462807

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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:PurposeWe identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes.Materials and methodsWe retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression.ResultsA total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05).ConclusionsSunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

Dataset Information

Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

Publications

Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

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