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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.

Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer