Genetic variants alter chance of sunitinib dose reduction

By Lynda Williams, Senior medwireNews Reporter

Scientists have identified genetic variants that reduce the likelihood of sunitinib dose reduction in patients with metastatic renal cell carcinoma (mRCC).

“We hypothesized that patients carrying genotypes that reduce absorption of sunitinib or increase metabolism of sunitinib – through lower sunitinib plasma levels and less frequent adverse events – less frequently require dose reductions”, explain Benoit Beuselinck, from University Hospitals Leuven in Belgium, and colleagues.

They studied germ-line DNA from 96 patients receiving first-line sunitinib treatment and found two single nucleotide polymorphisms (SNPs) in the efflux transporter ABC1B gene, already known to alter tyrosine kinase inhibitor (TKI) pharmacokinetics.

As reported in Acta Oncologica, the time to dose reduction (TTDR) was significantly longer in patients carrying the TT genotype of ABCB1 rs1125803 compared with CC or CT carriers, at 19 versus seven cycles.

TTDR was also significantly longer in patients carrying the TT or TA genotype of ABCB1 rs2032582 compared with their counterparts carrying GG or GT/GA variants, again at 19 versus seven cycles.

A third SNP in the ligand-activated nuclear receptor NR1/2 rs2776707 was also found to increase TTDR for patients with the TT genotype versus CC or CT genotypes, at 41.5 versus seven cycles.

These SNPs were confirmed to influence TTDR in multivariate analysis adjusting for gender, age at start of sunitinib treatment and International Metastatic Renal Cell Carcinoma Database Consortium prognostic score.

“[A] patient whose disease is primarily or secondarily resistant to sunitinib 50 mg/day, who has few side effects and who has the ABCB1 rs1128503 TT-variant, the rs2032582 TT-variant or the NR1 /2 rs2776707 TT-variant, could be a good candidate for a trial with sunitinib dose escalation to 62.5 mg/day or even 75 mg/day”, suggest Beuselinck et al.

By contrast, no significant correlation was uncovered between TTDR and SNPs in the NR1/3 or CYP3A5 genes linked to sunitinib pharmacokinetics or between the sunitinib pharmacodynamic regulators VEGFR1 and VEGFR3.

Further analysis of 81 patients suggested an inverse correlation between efficacy and dose reduction, with poorer overall survival and progression-free survival for patients with the TT versus CC or CT genotypes for ABCB1 rs1125803. A similar relationship was also found for carriers of the TT/TA versus GA/GT genotype of ABCB1 rs2032582 and the TT versus CC or CT genotypes of NR1/2.

“With the lack of a placebo-treated control group, we cannot define if these SNPs have a prognostic or a predictive value for outcome”, the researchers say. But “the fact that these genes are involved in sunitinib pharmacokinetics points toward a predictive value”, they note.

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