Prognostic value of amphiregulin and epiregulin mRNA expression in metastatic colorectal cancer patients

Abstract

Epidermal growth factor receptor (EGFR) and its ligands amphiregulin (AREG) and epiregulin (EREG) play a central role in the development of colorectal cancer, but the prognostic values of AREG and EREG are controversial. We conducted a meta-analysis of studies that investigated AREG and/or EREG mRNA levels in primary tumors to determine their prognostic value in metastatic colorectal cancer (mCRC). In addition, RAS status was assessed. Relevant articles were identified by searching the EMBASE, PubMed, and Cochrane Library databases. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Nine studies involving 2167 patients were included in this meta-analysis. High AREG expression was associated with longer overall survival (OS) and progression-free survival (PFS). High EREG expression was also associated with prolonged OS and PFS. In RAS wild-type (WT) patients who received anti-EGFR therapy, high AREG and EREG expression was associated with longer OS. Our results indicate that high AREG and EREG mRNA expression are independent favorable prognostic biomarkers in mCRC. The expression of these ligands should be considered when evaluating prognoses in RAS-WT patients receiving anti-EGFR therapy.

AREG mediates the epithelial‑mesenchymal transition in pancreatic cancer cells via the EGFR/ERK/NF‑κB signalling pathway

“…Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family and is expressed in a plethora of neoplasms, including ovarian, breast, bladder, colon, lung, major salivary glands and pancreatic cancers (10)(11)(12)(13)(14)(15)(16). AREG interacts with epidermal growth factor receptor (EGFR) to trigger numerous signalling cascades that mediate cell survival, proliferation, and motility.…”

“…AREG was linked to a reduced life span in bladder cancer (12) and lung cancer patients (13). However, AREG overexpression was associated with a longer disease-free survival in colorectal cancer (14) and mucoepidermoid carcinoma patients (15). In our previous study, it was revealed that AREG expression was correlated with a poor prognosis in pancreatic cancer patients (16).…”

Molecular biomarkers in current management of metastatic colorectal cancer

“…Most studies demonstrated association between high AREG and EREG mRNA expression and better survival in patients with CRC receiving anti-EGFR. In a metanalysis, these associations were still statistically significant only in patients with wild-type KRAS mCRC [38] . In a tumor analysis of CO.17 trial, the benefit of cetuximab was found only in high expression but not low expression of EREG mRNA in patients with wild-type KRAS mCRC [39] .This predictive effect was not shown in patients with mutant KRAS mCRC.…”

Predictive Biomarkers for Monoclonal Antibody Therapies Targeting EGFR (Cetuximab, Panitumumab) in the Treatment of Metastatic Colorectal Cancer

“…A meta-analysis including eight studies that used anti-EGFR therapy alone or in combination with chemotherapy reported that AREG/EREG mRNA overexpression was associated with longer overall survival in patients with wild-type RAS tumors who received cetuximab or panitumumab treatment; AREG overexpression was further associated with longer PFS. In contrast, AREG and EREG was found not to have predictive value in patients with mutant KRAS tumors [82]. Given these encouraging data, further examination of these ligands in prospective controlled trials appears warranted.…”