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

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: High mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti- treatment.