Amphiregulin expression is a predictive biomarker for EGFR inhibition in metastatic colorectal cancer: combined analysis of three randomized trials.

Background: Amphiregulin (AREG) and epiregulin (EREG) are ligands of the epidermal growth factor receptor (EGFR). Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. Methods: Ligand mRNA expression, RAS, BRAF,PIK3CA mutations and EGFR expression were assessed by RTqPCR, pyrosequencing and immunohistochemistry, 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 3rd quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalised spline regression analysis tested interaction of mRNA expression and outcome. Results: Of 688 patients with available material, high AREG expression was detected in 343 (> median) and 172 (> 3rd quartile) patients, respectively. High AREG expression was associated with significantly higher OS (26.2 vs. 21.5 months, HR 0.80 [95% CI 0.68 - 0.94], p = 0.007), PFS (10.0 vs. 8.1 months, HR 0.74 [95% CI 0.63 - 0.86], p = 0.001) and ORR (63.1 % vs. 51.6 %, p = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: p = 0.01, PFS: p = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared to bevacizumab (OS: p = 0.02, PFS: p = 0.04) in RAS WT mCRC. Conclusions: High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.