title: Pharmacogenetics of ABC and SLC transporters in metastatic colorectal cancer patients receiving first-line FOLFIRI treatment.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: aExperimental and Clinical Pharmacology Unit bEpidemiology and Biostatistics Unit cMedical Oncology Unit, 'Centro di Riferimento Oncologico' - National Cancer Institute, Aviano dMedical Oncology Unit, 'San Filippo Neri Hospital', Rome eMedical Oncology Unit 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: De Mattia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
authors.forename: Jerry
authors.initials: J
authors.lastname: Polesel
authors.forename: Mario
authors.initials: M
authors.lastname: D'Andrea
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Corona
authors.forename: Vittorina
authors.initials: V
authors.lastname: Zagonel
authors.forename: Angela
authors.initials: A
authors.lastname: Buonadonna
authors.forename: Eva
authors.initials: E
authors.lastname: Dreussi
authors.forename: Erika
authors.initials: E
authors.lastname: Cecchin
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005472:Fluorouracil / Q000627:therapeutic use; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D027381:Liver-Specific Organic Anion Transporter 1; D009362:Neoplasm Metastasis; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D018528:ATP-Binding Cassette Transporters; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin