Can we predict the response to epidermal growth factor receptor targeted therapy?

Epidermal growth factor receptor (EGFR) targeted therapy interferes with a molecular pathway that significantly regulates tumor growth, progression, and survival. Several clinical trials on EGFR targeted therapy revealed objective responses, and also improved survival in patients with different solid tumors. However, considerable differences in therapeutic efficacy were recognized across patient populations that might rely on specific characteristics of the individual patient, the tumor dependence on the EGFR pathway or alternative signaling pathways. Therefore, molecular markers that predict responsiveness to the specific targeted therapy are essential. Predictive markers will help to identify which individual patients might benefit the most from targeted therapy, and thus will help to increase efficacy and decrease toxicities. The occurrence of an acne-like skin rash was the first clinical surrogate marker in EGFR targeted therapy significantly associated with response rate. In gastrointestinal cancer patients promising predictive molecular markers have now been identified within the EGFR signaling pathway. K-ras mutations are associated with resistance to EGFR monoclonal antibodies (mAbs) in metastatic colorectal cancer patients. Moreover, high gene expression levels of EGFR ligands amphiregulin and epiregulin are indicative for improved progression-free survival (PFS) in response to EGFR targeted therapy. Favorable response to EGFR targeted therapy has been correlated with low gene expression levels of vascular endothelial growth factor (VEGF). Furthermore, germline polymorphisms within the genes of epidermal growth factor (EGF) and EGFR, cyclooxygenase-2 (Cox-2), cyclin D1, and FCGR2A/3A are of predictive value. However, these first encouraging findings are limited mostly due to the small patient numbers evaluated in retrospective studies. Thus, large prospective clinical trials are needed to validate these data.