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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Previous pharmacogenetic studies have reported the potential predictive value of thymidylate synthase (TYMS) polymorphisms or methylenetetrahydrofolate reductase (MTHFR) polymorphisms for the efficacy of 5-fluorouracil-based therapy, even though they have not yet been fully validated. Also, functional polymorphisms of genes linked to the epidermal growth factor receptor pathway [epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR)], as well as polymorphisms of genes encoding for Fcγ receptors [Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)], which influence their affinity for the Fc fragment, have been reported to be linked to the pharmacodynamics of cetuximab in the clinical setting. WHAT THIS STUDY ADDS • This prospective study conducted on advanced colorectal cancer patients receiving first-line tegafur-uracil–irinotecan–cetuximab therapy suggests that a favourable genotype score, considering both the TYMS 3RG allele and any Val-containing FCGR3 allele, may be an indicator of better clinical response and longer overall survival. 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, 250 mg m−2 week−1 following a 400 mg m−2 initial dose) together with irinotecan (day 1, 250 mg m−2) and UFT–folinic acid (days 1–14, 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). 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 of FCGR3A 158Phe>Val and TYMS 5′ UTR polymorphisms in responsiveness and survival of patients receiving cetuximab–fluoropyrimidine-based therapy.