HER2: An emerging target in colorectal cancer

Despite advances in the treatment of metastatic colorectal cancer (CRC) the 5-year survival of patients with this disease remains low. A small proportion of CRCs overexpress the HER2 oncogene and the effective targeting of this pathway in other malignancies such as breast and gastric cancer has led to efforts to determine if it can also be exploited as a target in CRC. Activation of the HER2 pathway as a bypass signalling pathway has been identified as a mechanism of resistance for antiepidermal growth factor receptor antibody therapy in both the first line and salvage settings. It has also been shown that RAS and BRAF wild type metastatic CRC enriches for the presence of HER2 amplification. This knowledge, in addition to preclinical data providing a rationale for dual anti-HER2 targeted therapy has led to several clinical trials. To date, recently published and presented early phase data provide promising evidence suggesting anti-HER2 therapy may have a potentially beneficial role in the treatment of HER2-positive metastatic CRC. Namely, the HERACLES-A and MyPathway studies have shown benefit in a small number of patients with the use of combination trastuzumab-lapatinib and trastuzumab-pertuzumab, respectively. However, data from larger clinical trials are required before HER2-directed therapy is incorporated into standard treatment paradigms for CRC. This review presents an overview of epidermal growth factor receptor and HER2 pathways in CRC and discusses preclinical and clinical studies carried out in this field to date. There is potential that with continued evolution of data in this area, HER2 may become a validated therapeutic target and thus, anti-HER2 therapy may become an additional treatment option for a small population of patients with metastatic CRC. (C) 2018 Elsevier Inc. All rights reserved.