Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials

Amphiregulin ( ) and epiregulin ( ) are ligands of . Predictive information for anti- treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. Ligand mRNA expression; mutations; and expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome. Of 688 patients with available material, high expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; = 0.001), and objective response rate (63.1% vs. 51.6%, = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: = 0.01, PFS: = 0.002). High mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: = 0.02, PFS: = 0.04) in WT mCRC. High mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti- treatment.