4063 Background: IGF-IR is supposed to have anti-apoptotic and mitogenic properties in colorectal cancer and by transactivation can promote EGFR phosphorylation. MMP-7 is produced by colorectal cancer cells and by degrading IGFBP-3 can activate IGF-IR. Methods: We retrospectively investigated the role of pIGF-IR immunoreactivity (IHC) (Rubini) and MMP-7 IHC in primary CRC or metastases, to predict response rate (RR), progression free survival (PFS) and overall survival (OS) in ACRC patients (pts) treated with either cetuximab or panitumumab as second or third line therapy. RAS mutational status of codons 12/13 was determined using quantitative PCR-based assay. CT scans were done every 1.5–2 months (m) until progressive disease. Results: A total of 99 pts with available tissue from 168 pts with ACRC treated with anti-EGFR therapy in 4 Spanish Institutions, were analysed for RAS mutational status, pIGF-1R and MMP-7. There were no major differences in RR (18.8 vs 16%), PFS [3.3 vs. 3.1 months (m)] and OS (7.7 vs. 7m) between the whole and selected cohort. Fifty-seven (57.6%) pts were male, the median age was 62 (range 34–79) years, the median number of previous chemotherapy lines was 2 (range 1–3) and PS was distributed as follow: PS0, 17 (17.2 %) pts; PS1, 66 (66.7%) pts and PS2, 16 (16.2%) pts. Expression of MMP-7 and pIGF-1R were observed in 48 (48.5%) and 52 (52.5%) pts respectively. Co-expression of MMP-7 and pIGF-1R [Double Positive (DP)] was observed in 26 (26.3 %) pts and in 16 (24%) out of 66 RAS wild-type (WTRAS) pts. There was no association between RAS mutational status and DP (p=0.52). DP progressed more than non-DP pts both in the overall sample (73 vs. 43%, p=0.028) and in WTRAS pts (75 vs. 32%, p=0.011). In the subset of WTRAS pts, DP pts also have a poorer OS: 6.4 (95% CI 5.8–7.1) m vs. 8.6 (95%CI 6.0–11.3) m (p=0.005), and a trend for worse PFS 2.7 vs 4.0 m (p=0.11). Conclusions: Co-expression of pIGF-1R and MMP7 is associated with resistance to anti- EGFR therapy in WTRAS pts. Our study suggests that pts with WTRAS and DP could be a target population to assay new anti-IGF-1R compounds. No significant financial relationships to disclose.