Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan

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 1day 8day 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 UFTfolinic acid (days 114, 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). 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 mgm-2 week-1 following a 400 mgm-2 initial dose) together with irinotecan (day 1, 250 mgm-2) and UFT-folinic acid (days 1-14, 250 mgm-2 day-1 UFT, 90mg 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-glycosyltransferase1polypeptide 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