OBJECTIVE: Membrane transporters are widely recognized as important determinants of drug disposition and response, generating increasing interest on the pharmacological implications of their genetic variations. The aim of this study was to elucidate the predictive/prognostic role of ATP-binding cassette (ABC) and solute carrier (SLC) protein polymorphisms on irinotecan (FOLFIRI regimen) outcome. PATIENTS AND METHODS: A total of 250 White metastatic colorectal cancer patients homogenously treated with a first-line FOLFIRI regimen were genotyped for a panel of variants in five transporter genes. The primary study endpoints were the response rate (partial or complete response), overall survival, and time to progression. Toxicity was considered a secondary endpoint. Irinotecan pharmacokinetic data of 71 patients were used for polymorphism functional analysis. RESULTS: Two variants of the ABCG2 (-15622C>T, rs7699188) gene were found to be predictive (P < 0.01) of the response rate. High-order relationships of ABC/SLC markers with previously investigated genetic (UGT1A1 polymorphisms) and nongenetic (primary tumor site) factors that helped determine the response rate were highlighted. A prognostic effect of the ABCB1 rs2032582 variant on patient overall survival emerged (P = 0.0074). The ABCG2 rs7699788 variant was also seen to be associated with grade 3-4 nonhematological toxicity (P = 0.0012). The ABCG2 (-15622C>T, rs7699188) and ABCB1 (rs2032582) polymorphisms were not found to be associated with pharmacokinetic parameters. CONCLUSION: This study showed that ABC/SLC polymorphisms have a crucial contribution toward the FOLFIRI outcome. This could represent a further step toward personalized therapy.
OBJECTIVE: Membrane transporters are widely recognized as important determinants of drug disposition and response, generating increasing interest on the pharmacological implications of their genetic variations. The aim of this study was to elucidate the predictive/prognostic role of ATP-binding cassette (ABC) and solute carrier (SLC) protein polymorphisms on irinotecan (FOLFIRI regimen) outcome. PATIENTS AND METHODS: A total of 250 White metastatic colorectal cancerpatients homogenously treated with a first-line FOLFIRI regimen were genotyped for a panel of variants in five transporter genes. The primary study endpoints were the response rate (partial or complete response), overall survival, and time to progression. Toxicity was considered a secondary endpoint. Irinotecan pharmacokinetic data of 71 patients were used for polymorphism functional analysis. RESULTS: Two variants of the ABCG2 (-15622C>T, rs7699188) gene were found to be predictive (P < 0.01) of the response rate. High-order relationships of ABC/SLC markers with previously investigated genetic (UGT1A1 polymorphisms) and nongenetic (primary tumor site) factors that helped determine the response rate were highlighted. A prognostic effect of the ABCB1rs2032582 variant on patient overall survival emerged (P = 0.0074). The ABCG2rs7699788 variant was also seen to be associated with grade 3-4 nonhematological toxicity (P = 0.0012). The ABCG2 (-15622C>T, rs7699188) and ABCB1 (rs2032582) polymorphisms were not found to be associated with pharmacokinetic parameters. CONCLUSION: This study showed that ABC/SLC polymorphisms have a crucial contribution toward the FOLFIRI outcome. This could represent a further step toward personalized therapy.
Authors: S Chen; I Laverdiere; A Tourancheau; D Jonker; F Couture; E Cecchin; L Villeneuve; M Harvey; M H Court; F Innocenti; G Toffoli; E Lévesque; C Guillemette Journal: Pharmacogenomics J Date: 2015-03-17 Impact factor: 3.550