Predictive biomarkers of anti-EGFR monoclonal anti-body in colorectal cancer

The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, triggers a downstream signaling cascade through areas such as the RAS-RAF-MAPK and PI3K-AKT pathways, which are involved in cell proliferation, survival and motility. Inhibiting EGFR activation has demonstrated significant promise as a molecular targeting therapy for various solid tumors. Two monoclonal antibodies (mAbs) targeting EGFR, cetuximab and panitumumab, are established to be new treatment options for metastatic colorectal cancer (mCRC). Among activating mutations in downstream of EGFR, the KRAS mutation, which is present in 40% of mCRC patients, has shown to be a predictive biomarker for resistance to anti-EGFR antibody therapy based on Caucasian studies. However, only a small proportion of patients achieved an objective response and benefit from anti-EGFR antibody, even among those with wild-type KRAS tumors. Other downstream factors in EGFR signaling are now being explored, such as the BRAF, PIK3CA, PTEN genes. Cetuximab, a chimeric immunoglobulin 1 (IgG₁) monoclonal antibody, may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is influenced by FCγR II a-H131R and FCγRIIIa-VI58F polymorphisms. Additional analysis of BRAF, PIK3CA, PTEN ana FcγR genes in KRAS wild-type patients could narrow down the selection of patients who are most likely to benefit from anti-EGFR antibody therapy.