title: Plasticity of Resistance and Sensitivity to Anti-Epidermal Growth Factor Receptor Inhibitors in Metastatic Colorectal Cancer.
abstract: Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer mortality worldwide. Survival in the metastatic setting has been gradually improved by the addition to cytotoxic chemotherapy of agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in differing pathways of carcinogenesis. The knowledge of molecular abnormalities underlying colorectal tumourigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced in recent years by comprehensive sequencing studies. From these genome-scale analyses, we know that a handful of genes are commonly affected by somatic mutations, whereas recurrent copy-number alterations and chromosomal translocations are rarer in this disease. Even though some of these molecular abnormalities make genes acting as drivers of cancer progression, translation of this recognition for therapeutic purposes is still limited, encompassing only as standard of care the exclusion of RAS-mutated cancers for better selecting patients to candidate to EGFR-targeted therapy with monoclonal antibodies. However, the effort of ameliorating molecular selection should not be considered exhausted by demonstration of RAS and BRAF-induced resistance, as the genomic landscape of response to EGFR blockade has been demonstrated to be wider and dynamically multifaceted. In this chapter we will review main molecular biomarkers of de novo (primary) and acquired (secondary) resistance to EGFR-targeted monoclonal antibodies in metastatic CRC and discuss therapeutic implications.
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy. andrea.sartorebianchi@ospedaleniguarda.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.|Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors
keywords: Cetuximab; Colorectal cancer; EGFR; Liquid biopsy; Panitumumab; RAS