Prospective pharmacogenetic analysis in advanced colorectal cancer (CRC) patients receiving first-line cetuximab-UFT-irinotecan therapy: Importance of gene polymorphisms related to antibody-dependent cellular cytotoxicity (ADCC)

Abstract

4069 Background: Our purpose was to test the predictive value of germinal gene polymorphisms potentially linked to cetuximab, fluoropyrimidine and irinotecan pharmacodynamics on toxicity, clinical response, time to progression (TTP) and overall survival (OS). Methods: 52 patients with advanced CRC were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial (33 men, 19 women, mean age 63, range 36–84, PS 0–1). Treatment consisted in cetuximab (day 1-day 8-day 15, 250 mg/m2/week following a 400 mg/m2 loading dose) associated with irinotecan (day 1, 250 mg/m2) and UFT-folinic acid (day 1 to day 14, 250 mg/m2/day UFT, 90 mg/day folinic acid). Median number of administered cycles was 7 (range 1–8). The following gene polymorphisms were analyzed on blood genomic DNA: EGFR (CA repeats in intron 1, - 216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UGT1A1 (TA repeats), TYMS (28 bp repeats including the G>C mutation on the 3R allele, 6 bp deletion in 3’ UTR), MTHFR (677C>T, 1298A>C). Results: Grade 3–4 toxicity was recorded in 59.6 % of patients. The toxicity score (sum of maximum grade for each toxicity pattern) was significantly linked to the FCGR2A genotype (median score 9, 9.5 and 13 in Arg/Arg, Arg/His and His/His patients, respectively, p = 0.035) and to the EGFR -191 genotype (median score 11 in CC patients versus 8.5 in CA patients, p = 0.040). Response rate was 49% (3 CR and 21 PR over 49 assessable patients) and was significantly higher in patients bearing the FCGR3A Val allele (62.1 % in Val/Val or Val/Phe versus 26.3 % in Phe/Phe, p = 0.020) or the TYMS 3RG allele (65.0 % versus 28.6 % in patients with no 3RG allele, p = 0.029). Gene polymorphisms did not influence TTP. A multivariate Cox analysis including gene polymorphisms and PS showed that overall survival was improved in patients bearing the FCGR3A Val allele (relative risk of death was 2.25 in Phe/Phe patients relative to Val-containing genotypes, 95% CI 1.03–4.91, p = 0.041). Conclusions: Present data suggest the importance of ADCC in cetuximab pharmacodynamics, as outlined by the role of FCGR gene polymorphisms on toxicity, responsiveness and survival. No significant financial relationships to disclose.