Published online Jul 15, 2018. doi: 10.4251/wjgo.v10.i7.159
Peer-review started: January 26, 2018
First decision: March 7, 2018
Revised: May 25, 2018
Accepted: May 30, 2018
Article in press: May 30, 2018
Published online: July 15, 2018
Processing time: 170 Days and 23.3 Hours
Human epidermal growth factor receptor 2 (HER2)-inhibition is an important therapeutic strategy in HER2-amplified gastro-oesophageal cancer (GOC). A significant proportion of GOC patients display HER2 amplification, yet HER2 inhibition in these patients has not displayed the success seen in HER2 amplified breast cancer. Much of the current evidence surrounding HER2 has been obtained from studies in breast cancer, and we are only recently beginning to improve our understanding of HER2-amplified GOC. Whilst there are numerous licensed HER2 inhibitors in breast cancer, trastuzumab remains the only licensed HER2 inhibitor for HER2-amplified GOC. Clinical trials investigating lapatinib, trastuzumab emtansine, pertuzumab and MM-111 in GOC have demonstrated disappointing results and have not yet changed the treatment paradigm. Trastuzumab deruxtecan may hold promise and is currently being investigated in phase II trials. HER2 amplified GOC differs from breast cancer due to inherent differences in the HER2 amino-truncation and mutation rate, loss of HER2 expression, alterations in HER2 signalling pathways and differences in insulin-like growth factor-1 receptor and MET expression. Epigenetic alterations involving different microRNA profiles in GOC as compared to breast cancer and intrinsic differences in the immune environment are likely to play a role. The key to effective treatment of HER2 amplified GOC lies in understanding these mechanisms and tailoring HER2 inhibition for GOC patients in order to improve clinical outcomes.
Core tip: Human epidermal growth factor receptor 2 (HER2)-inhibition is an important therapeutic strategy in HER2-amplified gastro-oesophageal cancer (GOC). A significant proportion of GOC patients display HER2 amplification, yet HER2 inhibition in these patients has not displayed the success seen in HER2 amplified breast cancer. We evaluate current clinical and laboratory evidence surrounding HER2 inhibition in GOC. Inherent differences in the HER2 receptor, signalling pathways, associated microRNA signature and immune environment may partly explain the disappointing clinical trial outcomes seen in GOC. Only with improved understanding of HER2 inhibition can effective treatment be provided in order to improve clinical outcomes for patients.