Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

<p>Abstract</p> <p>Background</p> <p>We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (<it>EGFR</it>, <it>EGF</it>, <it>CCND1</it>) or antibody-directed cell cytotoxicity (<it>FCGR2A </it>and <it>FCGR3A</it>) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy.</p> <p>Methods</p> <p>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: <it>EGFR </it>(CA repeats in intron 1, -216 G > T, -191C > A, R497K), <it>EGF </it>(A61G), <it>CCND1 </it>(A870G), <it>FCGR2A </it>(R131H), <it>FCGR3A </it>(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 <it>vs </it>wt/mut <it>vs </it>mut/mut), with the exception of -191C > A <it>EGFR </it>polymorphism (AA patient merged with CA patients).</p> <p>Results</p> <p>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). <it>CCND1 </it>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 <it>EGFR </it>-191C > A polymorphism with a longer TTP in CC patients as compared to others, and to <it>CCND1 </it>A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained <it>CCND1 </it>polymorphism. Overall survival was significantly related to <it>CCND1 </it>polymorphism with a shorter survival in patients bearing the G allele, and to <it>FCGR3A </it>F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). <it>FCGR3A </it>F158V and <it>CCND1 </it>A870G polymorphisms were significant independent predictors of overall survival.</p> <p>Conclusions</p> <p>Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that <it>CCND1 </it>A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, <it>FCGR3A </it>F158V polymorphism was a significant independent predictor of overall survival.</p

The role of the Beltrami parametrization of complex structures in 2-d Free Conformal Field Theory

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