There has been enthusiasm that the addition of the targeted agents cetuximab, panitumuman and bevacizumab to chemotherapy can improve overall survival (OS) of patients with colorectal cancer (CRC).
However, latest clinical and genomics data limit now the expectations. Studies showed an improvement in progression-free survival (PFS) only in KRAS wild-type metastatic CRC. But the absence of OS benefit and in fact retrospective analysis of specimens from randomized trials on KRAS status, suggest caution on true therapeutic effects of these agents.
This perspective provides a comprehensive analysis of the results from clinical trials evaluating the efficacy and adverse effects of these targeted drugs in the systemic treatment of mCRC. It is also discussed the molecular mechanisms underlying CRC induction and metastasis that explain the resistance to these drugs. Moreover, considering the complexity and heterogeneity of the disease revealed by studies using next-generation DNA sequencing technology, it is described how efforts to complete the CRC somatic mutations catalogue, to provide insights how Wnt signaling pathway, beyond EGFR and VEGF pathways, has crucial role in CRC and to understand complex gene-gene, intratumoral cell-cell interactions and signaling pathways networks through molecular networks can create a future new generation of networks-based development of biologically targeted agents.
(Citation: Gastric & Breast Cancer 2010; 9(3): 88-94)