According to the results of a study published early online in the Lancet Oncology, polymorphisms in the VEGFR3 and CYP3A5*1 genes may be able to define a subset of patients with renal-cell carcinoma (RCC) who have a decreased response to and tolerability of sunitinib.

The authors note that there are no validated molecular predictors of response or toxicity to sunitinib, a tyrosine kinase inhibitor used in the treatment of RCC.  They therefore conducted a prospective, observational study to identify genetic markers predictive of outcome and toxic effects in this patient group. 

The study enrolled 101 adults with clear cell RCC who received sunitinib as a first-line treatment at one of 15 institutions in Spain.  They assessed response (according to RECIST criteria), progression-free survival (PFS), overall survival, and toxicity of sunitinib, in association with 16 key polymorphisms in nine different genes. 

The authors report that two missense polymorphisms of the VEGFR3 gene were associated with reduced PFS with sunitinib - rs307826 (hazard ratio [HR] per allele 3.57, 95% CI 1.75-7.30; adjusted p=0.0079) and rs307821 (3.31, 1.64-6.68; adjusted p=0.014).  In addition, the CYP3A5*1 high metabolising allele was associated with an increased risk of dose reductions due to toxicity (3.75, 1.67-8.41; adjusted p=0.022). No other single nucleotide polymorphisms were were associated with sunitinib response or toxicity.

The authors comment that their results, if confirmed, ‘should promote interventional studies testing alternative therapeutic approaches for patients with such variants’.