Pharmacogenetics as predictor of sunitinib and mTOR inhibitors toxicity in patients with metastatic renal cell carcinoma (mRCC).

Abstract

4570Background: Single nucleotide polymorphisms (SNPs) in major pharmacokinetics (PK) and pharmacodynamics (PD) pathways of targeted agents may affect the incidence of drug toxicities. Methods: Germline DNA was extracted fromwhole blood or normal kidney parenchyma frommRCC pts of European ancestry in two cohorts: those treated with VEGF-targeted therapy (sunitinib) (n=159) or with an mTOR inhibitor (everolimus or temsirolimus) (n=62). Ten SNPs in 6 candidate genes: CYP3A4 (rs2242480, rs4646437, rs2246709), CYP3A5 (rs15524), ABCB1 (rs2032582, rs1045642), VEGFR2 (rs2305948), NR1I3 (rs2307424, rs2307418), FLT3 (rs1933437) were genotyped using Sequenom iPlex Gold platform. Logistic regression model tested the association of genotype variants with adverse events of 1) grade 3/4 (G3/4) toxicity and G3/4 hypertension (for sunitinib cohort) and 2) grade 3/4 toxicity and all grade pneumonitis (for mTOR inhibitors cohort), adjusted for clinical factors associated with toxicity outcomes. Results: In the sunitinib cohort, median treatment duration was 7.7 months (IQR=3-15.5), 83 (52%) pts had grade 3/4 toxicities and 22 (14%) had grade 3/4 hypertension. Rare variant (AG) of CYP3A4 rs464637 was associated with the reduced risk of grade 3/4 toxicities (4 events/17 cases) vs. wild-type (GG, 73 events/134 cases), (Odds Ratio (OR) = 0.27, 95%CI: 0.08-0.88, p=0.03). No association between SNPs and hypertension was observed. In the mTOR inhibitor cohort, median treatment duration was 3.4 months (IQR=1.4-6), 21(34%) pts had G3/4 toxicities and 27 (43%) had all grade pneumonitis. No association between SNPs and G3/4 toxicities was observed. Rare homozygote (GG) of FLT3 SNP rs1933437 was associated with increased risk of all grade pneumonitis (7 events/ 9 cases) vs. wild-type (AA, 4 events/12 cases), however, given the very small variant group size, further investigation is required to verify the association. Conclusions: The minor allele of SNP rs464637 in the gene CYP3A4 may influence sunitinib toxicity. Further validation is needed to determine if the marker could be used for in targeted therapy dosing strategies and direct patient care. (IQR=Interquartile Range).