Friday, October 28, 2011
24 October 2011
Lancet Oncol 2011; Advance online publication
MedWire News: Polymorphisms in the genes encoding vascular endothelial growth factor receptor 3 (VEGFR3) and cytochrome P450 3A5 (CYP3A5) may partially account for the absence of response and low tolerability to sunitinib observed in some patients with renal-cell carcinoma (RCC), researchers report.
"These data suggest that alternative treatment approaches for patients with these genetic variants should be promoted," write Cristina Rodríguez-Antona (Spanish National Cancer Center, Madrid) and colleagues in The Lancet Oncology.
The researchers explain that sunitinib is a tyrosine kinase inhibitor with proven efficacy in RCC, but around 20% of patients do not respond, while around 32% need dose reductions due to toxicity.
In the present study, Rodríguez-Antona and team aimed to identify polymorphisms as potential markers of sunitinib outcome, focusing on genetic variants that could alter the pharmacokinetics and pharmacodynamics of this drug.
They genotyped 101 RCC patients for 16 single nucleotide polymorphisms (SNPs) in nine genes: VEGFR2, VEGFR3, platelet-derived growth factor receptor α (PDGFR-α), VEGF-A, interleukin 8 (IL-8), CYP3A4, CYP3A5, ATP-binding cassette B1 (ABCB1), and ABCB2.
The researchers then assessed associations between each SNP and efficacy and toxicity of sunitinib using multivariable analyses adjusted for clinical factors associated with survival or toxicity.
After a median follow-up period of 21.2 months, the median progression-free survival (PFS) among 89 patients included the efficacy analysis was 12.3 months.
Objective response was assessed in 78 patients with measurable disease; one (1%) patient had a complete response, 36 (46%) had a partial response, 26 (33%) had stable disease, and 15 (19%) had progressive disease.
The analysis showed that two VEGFR3 missense SNPs, rs307826 and rs307821, were significantly associated with reduced PFS with sunitinib. Indeed, median PFS for people with the wild-type (AA) allele at rs307826 was 13.7 months, compared with 3.6 months for heterozygous (AG) individuals. The corresponding values for the rs307821 wild-type (GG) and heterozygous (GT) alleles were 13.7 months and 6.7 months, respectively.
Although not statistically significant, SNPs in ABCB1, ABCG2, and VEGFR2(rs1128503, rs2231142, and rs1870377) also showed a tendency to have worse response to sunitinib in terms of PFS or overall survival.
In terms of toxicity, the CYP3A5*1 (rs776746) high-metabolizing genotype (AG) was significantly associated with a 3.75-fold increased risk for dose reductions due to toxicity.
The researchers conclude that if their findings are independently validated in further studies, "these genetic variants could provide the basis for individualized renal cancer treatment."
In a related commentary, Brian Rini (Cleveland Clinic Taussig Cancer Institute, Ohio, USA) said: "An ideal predictive biomarker is one that is easily and unambiguously measured and reliably separates patients who will benefit from a specific approach from patients who will benefit from an alternative approach. [The present data] thus represent a small but important step toward truly targeted therapy for patients with renal-cell carcinoma."
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