Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets—PART 1: Biologic … – Cancer Network

Colorectal cancer is a common malignancy and the second leading cause of cancer-related death in the United States.[1] Around one-fifth of patients have metastatic disease at the time of diagnosis, and their overall survival (OS) rate is only 13.5% at 5 years.[2] Nevertheless, the median OS of patients with metastatic colorectal cancer is currently 3 years, with results from large prospective clinical trials showing a continuing increase in survival rates.[3,4] Oncologists have an array of choices to consider in terms of possible combinations of cytotoxic and biologic drugs for patients with metastatic colorectal cancer.

For the purpose of this review, we define biologic therapies as pharmaceuticals that target specific carcinogenic pathways. Approved therapies include agents targeting the epidermal growth factor receptor (EGFR) and those targeting proteins essential to angiogenesis, including the vascular endothelial growth factor (VEGF) (Figure). Given the abundance of current therapeutic options for the treatment of colorectal cancer, there is often no single correct answer to the question of which therapies to select and how to sequence them. In this article, we will highlight the mechanisms of action of selected classes of biologic therapies, identify predictive biomarkers, and address how best to combine biologic agents with conventional cytotoxic chemotherapy.

The ErbB family of receptor tyrosine kinases consists of the EGFR transmembrane glycoproteins Erbb1 (human epidermal growth factor receptor 1 [HER1]), HER2/neu (Erbb2), HER3 (Erbb3), and HER4 (Erbb4). EGFR is expressed in normal epithelial tissues and in several types of human cancers. Binding of EGF or other growth ligands to EGFR activates multiple downstream signal transduction pathways that promote cellular proliferation, including the RAS/RAF/MAPK/PI3K/AKT/mTOR pathways.[5] The anti-EGFR monoclonal antibodies cetuximab and panitumumab are approved by the US Food and Drug Administration (FDA) for use in patients with metastatic colorectal cancer who have KRAS wild-type tumors.[6,7]

Initially, EGFR expression was

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