Journal Article

Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study

Font, Albert, Leandro-García, Luis Javier, del Alba, Aranzazu González, Gallardo, Enrique, Garcia-Donas, Jesus, Puente, Javier, Robledo, Mercedes, Moreno, Fernando, Climent, Miguel Angel, Bellmunt, Joaquim, Martínez, Esther, Mellado, Begoña, Castellano, Daniel E, Esteban, Emilio, Rodríguez-Antona, Cristina, Arranz, José Angel

2011

Overview

Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. In our observational, prospective study we enrolled previously untreated adults (≥18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75–7·30; p unadjusted=0·00049, p adjusted=0·0079) and rs307821 (3·31, 1·64–6·68; p unadjusted=0·00085, p adjusted=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67–8·41; p unadjusted=0·0014, p adjusted=0·022). No other SNPs were associated with sunitinib response or toxicity. Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. Pfizer.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Aged / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - therapeutic use / Cancer / Carcinoma / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - pathology / Cytochrome P-450 CYP3A - genetics / Disease-Free Survival / Drug dosages / Female / Gene Frequency / Gene polymorphism / Genetic markers / Genetic Predisposition to Disease / Hematology, Oncology and Palliative Medicine / Heterozygote / Homozygote / Humans / Indoles - adverse effects / Indoles - therapeutic use / Interleukin 8 / Kaplan-Meier Estimate / Kidney Neoplasms - drug therapy / Kidney Neoplasms - genetics / Kidney Neoplasms - pathology / Kinases / Logistic Models / Male / Medical prognosis / Metabolism / Middle Aged / Oncology / Patient Selection / Phenotype / Polymorphism, Single Nucleotide / Precision Medicine / Predictive Value of Tests / Proportional Hazards Models / Prospective Studies / Protein Kinase Inhibitors - adverse effects / Protein Kinase Inhibitors - pharmacokinetics / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Pyrroles - adverse effects / Pyrroles - therapeutic use / Risk Assessment / Risk Factors / Single-nucleotide polymorphism / Spain / Sunitinib / Survival / Time Factors / Toxicity / Treatment Outcome / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular endothelial growth factor receptors