title: Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan.
abstract: OBJECTIVE
  To examine the predictive value of gene polymorphisms potentially linked to toxicity, clinical response, time to progression and overall survival, following cetuximab-tegafur-uracil (UFT)-irinotecan therapy.
  
  
  METHODS
  Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial. Treatment consisted of 21 day cycles of cetuximab (day 1-day 8-day 15, 250 mg m(-2) week(-1) following a 400 mg m(-2) initial dose) together with irinotecan (day 1, 250 mg m(-2)) and UFT-folinic acid (days 1-14, 250 mg m(-2) day(-1) UFT, 90 mg day(-1) folinic acid). Analysed gene polymorphisms (blood DNA) were as follows: EGFR (CA repeats in intron 1, -216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UDP-glycosyltransferase1-polypeptide A1 (TA repeats), TYMS (28 bp repeats, including the G>C mutation on the 3R allele, 6 bp deletion in 3' UTR) and MTHFR (677C>T, 1298A>C).
  
  
  RESULTS
  Maximum toxicity grade was linked to EGFR-191C>A polymorphism, with 71.1% grade 3-4 toxicity in CC patients vs. 28.6% in other patients (P= 0.010). A tendency to a better response was observed in patients bearing the TYMS 3RG allele (P= 0.029) and those bearing the FCGR3A 158Val genotype (P= 0.020). The greater the score of favourable TYMS and FCGR3A genotypes, the better the response rate (P= 0.009) and the longer the overall survival (P= 0.007). In multivariate analysis, the score of favourable genotypes was a stronger survival predictor than the performance status.
  
  
  CONCLUSIONS
  Present data suggest the importance of FCGR3A 158Phe>Val and TYMS 5' UTR polymorphisms in responsiveness and survival of patients receiving cetuximab-fluoropyrimidine-based therapy.
authors.affiliation: Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice cedex 2, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Formento
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Mireille
authors.initials: M
authors.lastname: Francoual
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hennebelle
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Eric
authors.initials: E
authors.lastname: Francois
authors.forename: Roger
authors.initials: R
authors.lastname: Faroux
authors.forename: Chaza
authors.initials: C
authors.lastname: El Hannani
authors.forename: Jacques-Henri
authors.initials: JH
authors.lastname: Jacob
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004815:Epidermal Growth Factor; D000077146:Irinotecan; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D066246:ErbB Receptors; D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin