Germline single nucleotide polymorphisms influence survival status in patients with stage IV renal cell carcinoma receiving VEGF or mTOR inhibitor therapy
Percy, Andrew G
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Background: Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) targeted therapies are standard in patients (pts) with metastatic renal cell carcinoma (mRCC). Predictive biomarkers for response are lacking. Single nucleotide polymorphisms (SNPs) in critical signaling pathways may impact the outcome of mRCC pts treated with these targeted agents. This study sought to characterize outcome after VEGF or mTOR inhibition based on germline variation in critical genes in the respective pathways. Methods: Germline DNA was extracted from pts receiving VEGF (N=263) or mTOR (N=76) inhibitors. All pts were of European-American ancestry and enrolled in a prospective protocol with full baseline and follow up clinical data. A total of 113 common SNPs within 16 select genes involved in VEGF signaling were genotyped and associations sought with clinical outcome. A total of nine SNPs within two genes involved in mTOR signaling were genotyped and associated with clinical outcome. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Cox model tested for the association between SNPs with PFS and OS in univariate and multivariate models that adjusted for age, gender, type of VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was used to control for the number of tests performed. Results: All patients were treated with an approved VEGF targeted agent (bevacizumab, sunitinib, sorafenib or pazopanib) or an approved mTOR targeted agent (temsirolimus or everolimus). Mean follow up was 51.6 months for the VEGF group and 23.7 months for the mTOR group. Two SNPs, one in vascular endothelial growth factor receptor-2 (VEGFR2) and one in hypoxia inducible factor-2-alpha (HIF2α), showed a significant association with improved PFS. The analysis adjusted for age, gender, type of VEGF targeted therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate was less than 20% with both SNPs. In the mTOR group, two intronic SNPs in phosphatidylinositol 3-kinase (PIK3CA) were significantly associated with improved PFS and OS, and a SNP in the 5' untranslated region of mTOR was associated with diminished OS. Associations were maintained when adjusted for age, gender and MSKCC RCC risk categories using Cox PH model. Conclusions: Five inherited variants may influence the PFS and OS of pts with mRCC treated with VEGF or mTOR targeted agents. If the results are validated, prospective studies could explore the role of genotyping in treatment selection for pts with mRCC. Further work will be needed to identify causal alleles and define the mechanism underlying the associations.
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