Background: Previous data suggests the EGF ligands EREG/AREG may predict outcome of KRAS wt patients (pts) treated with cet in the chemo-refractory setting but this finding has not been previously reported from first line randomised trials. Methods: FFPE samples from primary tumours of pts in Arms A&B of the COIN trial of Ox fluoropyrimidine (Fp) +/- cet were analysed for EGFR IHC, KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. Ligand levels were assessed against baseline data, prognostic markers as uni/multivariate analyses and as predictive markers in wild type (wt) and mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG continuous, using Flexible Parametric survival analysis. Results: 952/1630 (57%) of pts were evaluable for all parameters. High EREG/AREG levels were associated with KRAS wt (p<0.005), BRAF wt, absence of MSI and with primary tumour in left colon/rectum, presence of liver metastases, post randomisation radical surgery, high CEA (p<0.05) and ALKP. In the control arm, high EREG/AREG conferred a better prognosis among KRAS wt pts in a multivariate analysis. High EREG predicted for OS benefit from cet. treatment in KRAS wt pts, (n=525, p=0.017) and, separately, in pts treated with FOLFOX (n=310, p=0.021), with greatest effect in the “combined” subgroup (KRAS wt + FOLFOX, n=176, p=0.0042). Conversely a trend towards disbenefit was observed in KRAS wt pts treated with XELOX (n=349, p=0.14). Conclusions: The data suggest a prognostic effect of EREG/AREG in aCRC. The original hypothesis, that KRAS wt patients with high EREG expression have improved outcome with cet, is limited to patients treated with FOLFOX in the first-line setting. This data further suggests that capecitabine in combination with oxaliplatin and cetuximab produces a sub-optimal outcome.