Anti-Tumour TreatmentEvolution of anti-HER2 therapies for cancer treatment
Introduction
The ErbB family of receptors [1] comprises of four homologous proteins that reside on the cell surface: epidermal growth factor receptor (EGFR; also known as ERBB1; HER1); ERBB2 (also known as HER2; Neu); ERBB3 (or HER3); and ERBB4 (or HER4) (see Fig. 1). This review will focus on HER2 as a target in cancer, with overexpression and amplification identified in a variety of cancer types (Table 1). HER2 over-expression and amplification has been shown to be associated with poor outcomes in breast and gastric/gastroesophageal junction (GEJ) cancers [2], [3], [4], [5], [6], [7], [8]; however its effect on other tumour types is not well defined [9], [10], [11], [12], [13]. The response to targeting HER2 in patients with HER2 overexpression/amplification is influenced by several clinicopathological features including tumour histology [7], [14], degree of anaplasia [15], stage of disease [11], [12] and presence of underlying risk factors [3], [4]. Amplification or overexpression of HER2 also serves as a predictive biomarker for anti-HER2 treatment in a variety of tumour types including breast, gastric and gynaecological cancers [6], [7], [8], [9], [12], [14], [16], [17], [18]. We summarise key results from clinical trials involving approved therapies targeting HER2 and provide an overview of emerging preclinical and clinical data relevant to improving the use of HER2-directed therapies in a variety of tumour types. We analyse the role of molecular imaging for determining HER2 expression heterogeneity and the optimisation of patient selection for particular drug combinations. The limitations of current HER2 therapies and opportunities for future HER2 research are discussed.
Section snippets
HER2 function
The extracellular domain of HER2 is unable to bind any known natural ligand [19]. HER2 naturally adopts the conformation that favours oligomerisation and activation of the HER2 kinase (which for other ErbB family members requires ligand activation, Fig. 1) [20]. The structure of HER2 [21] makes the dimerization arm permanently available for homo- or heterodimerization with other ERRB-family receptors (Fig. 1). Activation of these receptors by soluble growth factors results in homodimeric or
Mechanism of action of anti-HER2 directed therapies
Given the compelling nature of HER2 as a target for cancer therapy, a number of different approaches to its inhibition have been tested. This review will focus on HER2 targeting therapies which have successfully entered clinical practise (Fig. 3).
Novel HER2 targeting agents in development
Whilst the success of current anti-HER2 treatments has been significant, a large number of patients with loco-regional disease relapse following neo/adjuvant treatment and HER2-positive metastatic disease remains a significant cause of morbidity and mortality. The challenge now faced involves improving patient outcomes further by developing therapies that circumvent current resistance mechanisms. A number of novel anti-HER2 treatments are being developed based on the insights gained from
HER2 molecular imaging as potential biomarkers and research tools
Given the predictive and prognostic value of HER2, in particular in breast and gastric/GEJ cancers, accurate determination of HER2 status and identifying patients that will benefit from anti-HER2 therapy is critical. One of the challenges faced is identifying the degree of HER2 amplification/overexpression required to derive benefit from trastuzumab therapy. In contrast to most trials, two trials evaluating adjuvant trastuzumab found no significant association between HER2 gene copy number and
Conclusions
The success of trastuzumab in improving patient survival and QoL has revolutionised the care of patients with breast cancer. Trastuzumab remains a mainstay of treatment for HER2 positive breast cancer. However, the field of HER2-therapeutics continues to grow as multiple challenges remain both in breast cancer and in other cancers. In breast cancer, the problems of resistance and of better patient selection are now the focus of much research. Newer agents have attempted to overcome resistance
Declaration of interest
H.K. Gan has research funding from AbbVie Pharmaceuticals, is on an Advisory board for AbbVie and Merck Serono, and has received travel support/honoraria/speaker bureau for Merck Serono, AbbVie, Pfizer, Bayer, Novartis and Merck. A.M. Scott has research funding support from AbbVie Pharmaceutics and Daiichi-Sankyo Co, is an inventor of mAb806, and has a consultancy and stock ownership of Life Science Pharmaceuticals. A. Burgess is an inventor of mAb806. The authors have funding support from
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