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

Abstract

Amphiregulin (<i>AREG</i>) and epiregulin (<i>EREG</i>) are ligands of <i>EGFR</i>. Predictive information for anti-<i>EGFR</i> treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. Ligand mRNA expression; <i>RAS, BRAF, PIK3CA</i> mutations; and <i>EGFR</i> 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 <i>AREG</i> expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High <i>AREG</i> expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; <i>P</i> = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; <i>P</i> = 0.001), and objective response rate (63.1% vs. 51.6%, <i>P</i> = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: <i>P</i> = 0.01, PFS: <i>P</i> = 0.002). High <i>AREG</i> mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: <i>P</i> = 0.02, PFS: <i>P</i> = 0.04) in <i>RAS</i> WT mCRC. High <i>AREG</i> mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-<i>EGFR</i> treatment.