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

摘要

Aim To examine the predictive value of gene polymorphisms potentially linked to toxicity, clinical response, time to progression and overall survival, following cetuximab-tegafur-uracil (UFT)-irinotecan therapy. 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, 250mgm -2 week -1 following a 400mgm -2 initial dose) together with irinotecan (day 1, 250mgm -2) and UFT-folinic acid (days 1-14, 250mgm -2 day -1 UFT, 90mg day -1 folinic acid). Analysed gene polymorphisms (blood DNA) were as follows: EGFR (CA repeats in intron 1, -216GT, -191CA), EGF (61AG), FCGR2A (131ArgHis), FCGR3A (158PheVal), UDP-glycosyltransferase1-polypeptide A1 (TA repeats), TYMS (28bp repeats, including the GC mutation on the 3R allele, 6bp deletion in 3′UTR) and MTHFR (677CT, 1298AC). Results: Maximum toxicity grade was linked to EGFR-191CA 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 of FCGR3A 158PheVal and TYMS 5′UTR polymorphisms in responsiveness and survival of patients receiving cetuximab-fluoropyrimidine-based therapy.