[Molecular predictive markers of EGFR-targeted therapy in metastatic colorectal cancer]

Abstract

The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor are effective in approximately 10% and 20% of EGFR expressing, chemotherapy resistant metastatic colorectal cancer patients in monotherapy and in combination with chemotherapy, respectively. The evidence that EGFR expression by immunohistochemistry does not predict clinical outcome in EGFR targeted treatment has led to an intensive search for additional predicitive biomarkers. Oncogenic activation of signalling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor supressor gene is central to the progression of colorectal cancer. Tumor KRAS mutation, which may be present in 35%-45% of patients with colorectal cancer, is now recognized as an important predictive marker of resistance to cetuximab or panitumumab treatment and is also widely used in clinical practice. Among tumors carrying wild-type KRAS, mutations of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to the anti-EGFR monoclonal antibody treatment. On the other hand, EGFR ligands overexpression detected in tumor tissue is a promising positive predictive marker. There are also some initial observations that gene expression profiling could also contribute to clinical decision-making about the cetuximab and panitumumab treatments. These observations require further validation in prospective clinical trials before incorporation into clinical practice.