Major finding: VEGFR3 and CYP3A5 polymorphisms predict sunitinib response and toxicity.
Approach: An observational, prospective study was performed in previously untreated RCC patients.
Impact: Genetic markers may be used to predict efficacy and toxicity of sunitinib.
Renal cell carcinoma (RCC), the most common type of kidney cancer in adults, is resistant to both chemotherapy and radiation therapy. Sunitinib malate, an orally administered tyrosine kinase inhibitor with activity against VEGF receptor (VEGFR), has been shown to increase progression-free survival (PFS) in patients with advanced clear-cell RCC and is currently a standard treatment option. However, a subset of patients fails to respond to therapy or develops treatment-limiting toxicity. Garcia-Donas and colleagues hypothesized that genetic polymorphisms among patients may serve as biomarkers that can predict response or toxicity to sunitinib. Previously untreated patients with clear-cell RCC were enrolled in an observational, prospective study that assessed response, PFS, and toxicity to sunitinib in relation to single-nucleotide polymorphisms (SNP) in nine genes thought to be potentially involved in sunitinib action, metabolism, or transport. Interestingly, two VEGFR3 polymorphisms were associated with a shorter PFS, and one functional CYP3A5 polymorphism was associated with increased risk of sunitinib dose reduction secondary to toxic effects. These findings provide relevant insight into the pharmacodynamics and pharmacokinetics of sunitinib, as VEGFR3 is a direct target and CYP3A5 is a member of the cytochrome P450 family of enzymes involved in drug metabolism. Together, the data represent an important advance in personalized medicine, and with additional validation, potentially may be used to identify which RCC patients will benefit from treatment with sunitinib.
Garcia-Donas J, Esteban E, Leandro-García LJ, Castellano DE, del Alba AG, Climent MA, et al. 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. Lancet Oncol 2011;12:1143–50.
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