Potential biomarkers for anti-EGFR therapy in metastatic colorectal cancer

Anti-epidermal growth factor receptor (EGFR) therapy has established efficacy in metastatic colorectal cancer, but a significant number of patients do not respond to such treatment. Recently, various biomarkers were reported to be useful in predicting resistance to anti-EGFR. All the potential biomarkers predicting resistance to anti-EGFR are reviewed herein from five aspects. First, upstream molecules, including epiregulin (EREG) and amphiregulin (AREG), might play different roles according to their abnormal levels in tumor tissue and serum. Second, the EGFR amplification and distinct polymorphisms may have roles in identifying patients for initial anti-EGFR mAbs therapy, while rare EGFR mutations have limited predictive values. Third, among the downstream molecularly related factors, rat sarcoma viral oncogene (Ras) has been identified as a successful predictor, while B-Raf proto-oncogene (BRAF) is considered as a prognostic factor rather than a predictor. Fourth, among the molecular bypass pathway components, phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) may be potential biomarkers in the future, while activation of hepatocyte growth factor (HGF)/c-Met signaling confers resistance to anti-EGFR therapy. Fifth, many microRNAs and additional molecular biomarkers are promising in predicting the efficacy of anti-EGFR therapy. Applications of multiple biomarkers are more effective than the use of a single biomarker in selecting patients who might benefit from cetuximab- or panitumumab-based treatments. Comprehensive molecular analyses of the EGFR signaling pathways should be considered in the future. Subsequent prospective trials will be required to further confirm the clinical utility of these biomarkers.