Progress and challenges in the identification of biomarkers for EGFR and VEGFR targeting anticancer agents

Abstract

Molecularly targeted therapies aim to interfere with molecular mechanisms, selectively involved in carcinogenesis and tumor growth in order to optimize the efficacy and minimize the side effects of anticancer treatment. In the last decade, several receptor tyrosine kinase inhibitors (TKIs) have become approved for therapeutic use in hematological malignancies as well as solid tumors. However, a major challenge remains in the selection of patients most likely to respond to these agents. Successful examples of personalizing molecularly targeted therapies based on biomarkers include the use of trastuzumab in HER-2 overexpressing breast cancer and imatinib in c-KIT expressing gastrointestinal stromal tumor. In contrast, EGFR and anti-angiogenic TKIs have mostly been evaluated in unselected patient groups and so far no biomarkers that predict or reflect the efficacy of these TKIs have been validated in clinical practice. Nevertheless, potential biomarkers, including EGFR gene copy number and the absence of K-ras mutations for anti-EGFR agents, and functional imaging for anti-angiogenic agents, have been identified. These biomarkers await validation in randomized phase III trials to confirm their value in predicting drug efficacy. In order to maximize efficiency in the search for valid predictive biomarkers, there is an urgent need for the standardization of their assessment, as well as the techniques employed in their assays. This article will focus on studies that address biomarker discovery or validation for EGFR and anti-angiogenic TKIs, differentiating those markers that predict for drug efficacy (predictive markers) from those that reflect drug mechanisms of action or effects (pharmacodynamic markers).