Review
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2018; 10(7): 159-171
Published online Jul 15, 2018. doi: 10.4251/wjgo.v10.i7.159
HER2 inhibition in gastro-oesophageal cancer: A review drawing on lessons learned from breast cancer
Hazel Lote, Nicola Valeri, Ian Chau
Hazel Lote, Nicola Valeri, Centre for Molecular Pathology, Institute of Cancer Research, Sutton SM2 5NG, United Kingdom
Hazel Lote, Nicola Valeri, Ian Chau, Department of Medicine, Royal Marsden Hospital, Sutton SM2 5PT, United Kingdom
Author contributions: Lote H wrote the original manuscript and revised it following peer review comments; Valeri N reviewed the manuscript; Chau I reviewed and contributed to the content of the manuscript.
Supported by National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, No. A62, No. A100, No. A101 and No. A159; Cancer Research UK funding, No. CEA A18052.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ian Chau, FRCP (Hon), MD, MRCP, Doctor, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton SM2 5PT, United Kingdom. ian.chau@rmh.nhs.uk
Telephone: +44-208-6613582 Fax: +44-208-6613890
Received: January 25, 2018
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
Abstract

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.

Keywords: Human epidermal growth factor receptor 2, Gastro-oesophageal cancer, Trastuzumab, Resistance, Biomarkers, Breast cancer

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.