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

PURPOSE: Amphiregulin (AREG) and epiregulin (EREG) are ligands of EGFR. Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. EXPERIMENTAL DESIGN: Ligand mRNA expression; RAS, BRAF, PIK3CA mutations; and EGFR 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 AREG expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High AREG expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (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 objective response rate (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 with 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.

Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group.

Skin toxicity is a frequent adverse event of epidermal growth factor receptor (EGFR) targeting agents. Occurrence of cetuximab-induced skin toxicity (Cet-ST) correlates with better treatment response and longer survival times. Molecular markers predicting Cet-ST are still missing. This investigation analyzed the value of Cet-ST for treatment efficacy in a randomized trial comparing cetuximab plus capecitabine/irinotecan to cetuximab plus capecitabine/oxaliplatin as first-line treatment of metastatic colorectal cancer. Patient characteristics and molecular parameters (KRAS mutation, EGFR-FISH, EGFR-IHC and EGFR intron-1 polymorphism) of the tumour were correlated with response and Cet-ST. Cet-ST grade 0-1 was observed in 31%, grade 2-3 in 69% of patients. Outcome favoured patients with grade 2-3 Cet-ST with regard to overall response rate (62 vs. 41%), PFS (7.8 vs. 5.2 months) and overall survival (OS) (30.3 vs. 18.0 months). First-cycle rash was observed in 66% of patients and corresponded with longer survival (30.7 vs. 20.2 months, p = 0.007). Patients without Cet-ST had a poor outcome (PFS, 1.9 months; OS, 11 months). The correlation of Cet-ST with survival was specifically evident in patients with KRAS codon-12-mutated tumours assumed to be cetuximab resistant. In multivariate analysis of patient characteristics, male gender and younger age were significantly correlated with Cet-ST. Among molecular parameters, no significant correlation with Cet-ST was found. Cet-ST is an early predictor of treatment efficacy in cetuximab-treated patients. This effect of Cet-ST is independent of the KRAS mutation status, suggesting that Cet-ST rather relates to constitutional factors of the patient than alterations of the EGFR pathway in the tumour.