Predictors of sensitivity and resistance to epidermal growth factor receptor inhibitors

Lung cancer is one of the leading types of cancer with an associated high mortality. Currently, treatment with conventional cytotoxic agents remains suboptimal. Inhibition of the epidermal growth factor receptor (EGFR) with monoclonal antibodies or small-molecule inhibitors of the tyrosine kinase (TK) domain of the receptor have demonstrated modest, albeit significant, antitumor activities in patients with non-small-cell lung cancer (NSCLC). The goal of any targeted therapy is to direct treatment to those patients who are more likely to derive benefit from such a treatment. Two interventions may improve the predicted sensitivity to these agents: (1) the use of a real predictor before treatment, represented by pharmacodiagnostic tests, and (2) studying the relationship between an early event after treatment and outcome, represented by pharmacodynamic tests. Pharmacodiagnostic factors that have been studied include the clinical features and histologic subtype of the tumor, the presence of somatic mutations in the TK domain of the EGFR, the expression of the receptor itself, and the activation of the receptor signaling pathway. Pharmacodynamic events associated with improved outcome include drug-induced rash and regulation of the receptor expression. Currently, the best established determinant of response to small-molecule inhibitors of the EGFR is the presence of activating mutations in the receptor TK domain. However, it is not known whether these functional mutations are involved in the response of NSCLC to monoclonal antibodies. Further investigation is needed to better predict patients who are more likely to benefit from these drugs.