title: Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer.
abstract: BACKGROUND
  We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy.
  
  
  METHODS
  Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients).
  
  
  RESULTS
  Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival.
  
  
  CONCLUSIONS
  Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.
authors: Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Université de la Méditerranée, Marseille, France. laetitia.dahan@mail.ap-hm.fr
authors: Laetitia
authors: L
authors: Dahan
authors: Emmanuelle
authors: E
authors: Norguet
authors: Marie-Christine
authors: MC
authors: Etienne-Grimaldi
authors: Jean-Louis
authors: JL
authors: Formento
authors: Mohamed
authors: M
authors: Gasmi
authors: Isabelle
authors: I
authors: Nanni
authors: Jean
authors: J
authors: Gaudart
authors: Stéphane
authors: S
authors: Garcia
authors: L'Houcine
authors: L
authors: Ouafik
authors: Jean-François
authors: JF
authors: Seitz
authors: Gérard
authors: G
authors: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D019938:Cyclin D1 / Q000235:genetics; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics; D012871:Skin Diseases / Q000139:chemically induced; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C445323:FCGR2A protein, human; D017452:Receptors, IgG; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000068818:Cetuximab