Predicting response to EGFR inhibitors in metastatic colorectal cancer: current practice and future directions

Abstract

The identification of KRAS mutational status as a predictive marker of response to antibodies against the epidermal growth factor receptor (EGFR) has been one of the most significant and practice-changing recent advances in colorectal cancer research. Recently, data suggesting a potential role for other markers (including BRAF mutations, loss of phosphatase and tension homologue deleted on chromosome ten expression, and phosphatidylinositol-3-kinase-AKT pathway mutations) in predicting response to anti-EGFR therapy have emerged. Ongoing clinical trials and correlative analyses are essential to definitively identify predictive markers and develop therapeutic strategies for patients who may not derive benefit from anti-EGFR therapy. This article reviews recent clinical trials supporting the predictive role of KRAS, recent changes to clinical guidelines and pharmaceutical labeling, investigational predictive molecular markers, and newer clinical trials targeting patients with mutated KRAS.

Figure 1.

EGFR signaling pathway. Ligands bind to EGFR and stimulate dimerization of the receptor. RAS is, in turn, activated, stimulating both the PI3K–AKT and RAF–MEK–MAPK pathways, resulting in cell proliferation, survival, and invasion. Abbreviations: EGFR, epidermal growth factor receptor; GRB2, growth factor receptor-bound protein 2; HB-EGF, heparin-binding EGF-like growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal–related kinase kinase; PI3K, phosphatidylinositol-3-kinase; SOS, son of sevenless; TGF-α, transforming growth factor α. Reprinted from Raponi M, Winkler H, Dracopoli NC. KRAS mutations predict response to EGFR inhibitors. Curr Opin Pharmacol 2008;8:413–418, copyright 2008, with permission from Elsevier.