title: Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.
abstract: OBJECTIVE
  The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped.
  
  
  RESULTS
  The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5'UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5'UTR genotypes, respectively. Conversely, patients with the TS-5'UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006).
  
  
  CONCLUSIONS
  A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.
authors.affiliation: Department of Medicine, Institut Gustave-Roussy, Villejuif, France. boige@igr.fr
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.forename: Jean
authors.initials: J
authors.lastname: Mendiboure
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
authors.forename: Marine
authors.initials: M
authors.lastname: Castaing
authors.forename: Michel
authors.initials: M
authors.lastname: Barrois
authors.forename: David
authors.initials: D
authors.lastname: Malka
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouché
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Corre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miran
authors.forename: Claire
authors.initials: C
authors.lastname: Mulot
authors.forename: Michel
authors.initials: M
authors.lastname: Ducreux
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin