Pharmacogenetic analysis of toxicity after 5-fluorouracil (5FU) or 5FU/oxaliplatin therapy for metastatic colorectal cancer: Preliminary results in FFCD 2000–05 trial

2508 Background: The FFCD 2000–05 randomized trial compared simplified LV5FU2 followed by FOLFOX6 (arm 1) to FOLFOX6 followed by FOLFIRI (arm 2) in the treatment of metastatic colorectal cancer. The aim was predicting the toxicity profile of oxaliplatin after the first line treatment using pharmacogenetic data. Methods: Patients (pts) with available blood samples were compared to the other pts for clinical prognostic factors (chi2 test). A logistic model was computed to test the association between polymorphisms and toxicity in each arm. An interaction test was used to assess a differential effect according to treatment (predictive effect), in order to identify a predictive effect of oxaliplatin. Grade 3–4 hematological and non-hematological toxicities (H-tox and NH-tox) at 4 months and grade 2–4 neurological at 6 months were the endpoints of the study. Thirteen genetic variants in 10 candidate genes were selected for pharmacogenetic analysis: ERCC1_04 (rs3212961), ERCC1_05 (rs11615), ERCC1_06 (rs3212948), ERCC1_24 (rs3212955), ERCC2_02 (rs1799793), ERCC2_03 (rs13181), ERCC2_06 ( rs238406 ), ERCC2_09 (rs1799787), GSTM1 (null/present), GSTT1 (null/present), TS (TSER, Ins/del6bp) and UGT1A1 (rs8175347). Genotyping was performed using Taqman probes, QMPSF and fragment analysis. Results: 327 pts (156/171) out of 410 were included (61 had no blood samples, 16 had less than 2 cycles, 3 had incomplete data on toxicity, 3 had insufficient DNA). No difference was found between included and excluded pts in the analysis for gender, age, OMS, number of metastatic organs and adjuvant chemotherapy. Pts received similar 5FU doses in both arms. Number of patients with at least one toxicity in arms 1/2 were as followed: 5/54 grade 3–4 H-tox, 28/47 grade 3–4 NH-tox, and 0/103 grade 2–4 neurological. The genotype CC of ERCC2_02 correlated with higher NH-tox at 4 months in arm 2 (p=0.0008, OR=0.31, 95%CI=[0.15–0.62] versus p=0.87, OR=0.93, CI=[0.39–2.21] in arm 1) compared to genotypes CT and TT, with borderline interaction (p=0.05). Conclusions: These preliminary results on early toxicity in first-line are in favour of an effect of ERCC2_02 on NH-tox of FOLFOX6 and a predictive effect on NH-tox of oxaliplatin. [Table: see text]