Association between EGFR gene copy number and KRAS status and impact on outcome prediction in colorectal cancer patients treated with cetuximab.

11093 Background: KRAS mutations (mut) occur in 40% of colorectal cancers (CRC) and together with increased EGFR gene copy number (GCN) are determinants of outcome in CRC patients (pts) treated with cetuximab. We aimed to assess whether these two markers are associated and their impact on patients' outcome.,87 pts with metastatic CRC treated with cetuximab alone or with irinotecan were concomitantly analyzed for EGFR GCN by fluorescent in situ hybridization (FISH), and for KRAS exon 2 mut status by Taqman. FISH was scored retaining the mean GCN in 100 tumor cells and a ROC curve analysis was fitted to outcome data to define a relevant cutoff for response prediction. A logistic regression model for objective response (OR) and a Cox regression model for progression-free survival (PFS) and overall survival (OS) were built. Kaplan-Meier plots were constructed for PFS and OS and compared with the Log rank test.,KRAS mut were identified in 33% of pts. Using 2.83 GCN as a cutoff for mean EGFR GCN yielded 74% specificity and 68% sensitivity for OR prediction. A lower mean EGFR GCN was detected in KRAS mut than in KRAS-wild type (WT) tumors (2.26 vs 2.77; Mann-Whitney U test, p=0.022). A logistic regression model with KRAS mut status, EGFR GCN and their interaction indicated that mean EGFR GCN contributes information for OR prediction (p=0.016). Similar findings were observed in a Cox regression model with respect to OS (p=0.005) but not to PFS (p=0.14). In KRAS WT pts, a FISH-positive status was related with longer median OS (13.3 vs 8.4 months, p=0.019) but not with PFS (6.9 vs 4.4 months, p=0.16). An EGFR GCN-KRAS mut interaction was observed for OS (p=0.002) and PFS (p=0.056) indicating that the relation between mean EGFR GCN and survival differs between WT and mut pts. For KRAS mut pts, a mean EGFR GCN ≥2.83 was related with shorter median PFS (2.8 vs 3.9 months, p=0.084) and OS (3.8 vs 7.5 months, p=0.006).,KRAS status and EGFR GCN both contain valuable information with respect to outcome prediction. Thus, analysis of EGFR GCN refines outcome prediction in pts with known KRAS status. Importantly, the negative impact of increased EGFR GCN on PFS and OS in KRAS mut pts treated with cetuximab is unexpected and deserves further investigations. [Table: see text].