4120 Background: Our group has recently shown that single-agent cetuximab in first-line treatment of elderly MCRC pts has a favorable safety profile and similar activity to that observed in pretreated pts: 15% RR and 54% disease control (DC) (ESMO 2006: A324O). In this study, we aimed to identify predictive factors of clinical benefit from cetuximab without chemotherapy. Methods: This was a optional prospective ancillary study conducted in 36 of 41 pts included in the TTD 04–01 trial to explore potential predictive factors of response or resistance to single-agent cetuximab (400 mg/m2 as initial dose and 250 mg/m2 weekly thereafter). To this end we conducted a comprehensive analysis of potential predictive assays including polymorphisms of intron 1 of the EGFR gene, EGFR gene copy number by FISH (Varella-García Diagn Pathol 2006), IHC expression of signaling pathway proteins (EGFR, MAPK, AKT, PTEN), K-RAS, B-RAF, PI3KCA and PTEN mutations, as well as basal serum levels and dynamic changes of circulating EGFR after 4 weeks of treatment. Results: 9 of 41 pts (22%; 95%CI: 11–38) achieved DC at 12 weeks (2 CR, 4 PR, and 3 SD) with a median time to progression (TTP) of 8,3 months (range 4–11.3), similar to that observed with FOLFOX or FOLFIRI in first line treatment. Increased EGFR copy number (FISH+: scores 5–6) was observed in a total of 11 pts (11/36: 30,5%). Five of these 11 FISH+ pts had DC at 12w (45%) vs. 3 of 25 FISH- pts (12%) (p=0.04). No correlation was found between DC at 12w and polymorphisms of intron 1 of the EGFR gene, basal serum levels and dynamic changes of EGFR, IHC expression of pEGFR and pMAPK, or PI3KCA mutations. Analyses of PTEN and AKT by IHC, as well as K-RAS and PTEN mutations are ongoing. Conclusions: Although cetuximab provides higher efficacy in combination with chemotherapy, 22% of MCRC pts treated with monotherapy in first-line treatment present a remarkable median TTP of 8,3 months. This subgroup of pts can be selected in advance based on FISH+ combined or not with other possible predictive factors still under analysis. The full detailed analysis of data will be presented at the meeting. [Table: see text]