Assessment of HER2 status in breast cancer: why, when and how?

doi:10.1016/S0959-8049(99)00264-6

European Journal of Cancer

Volume 36, Issue 2, January 2000, Pages 170-176

https://doi.org/10.1016/S0959-8049(99)00264-6 Get rights and content

Abstract

Human epidermal growth factor receptor 2 (HER2) is overexpressed, usually as a result of HER2 proto-oncogene amplification, in 20–30% of breast cancers. A HER2-positive status is generally associated with more aggressive disease and a worse prognosis. Furthermore, a positive HER2 status may predict the likelihood of resistance to some conventional therapies, as well as probably being predictive of sensitivity to anthracycline dose intensification. In addition to this prognostic/predictive value, HER2 is a target for specific therapy, with anti-HER2 monoclonal antibody therapy available in the USA. This article reviews the different assays used to determine HER2 status, discussing their relative advantages/disadvantages and the need for their standardisation before integration alongside other pathological indices into the clinical management of breast cancer.

Introduction

The human epidermal growth factor receptor-2 (HER-2) proto-oncogene encodes a 185-kDa glycoprotein, often simply called the HER2 or c-erbB2 protein or receptor. HER2 plays a key role in one of the best studied growth factor receptor systems in breast cancer, the HER (or erbB, or Type 1) tyrosine kinase receptor family. This family comprises four homologous epidermal growth factor (EGF) receptors: HER1 (EGFR/ erbB1), HER2 (erbB2), HER3 (erbB3) and HER4 (erbB4) [1]. Each of these receptors comprises an extracellular ligand-binding domain, a transmembrane lipophilic segment and an intracellular protein kinase domain with a carboxyl terminal segment containing sites of phosphorylation or tyrosine residues [2].

The HER family plays an important role in regulating cell growth, survival and differentiation in a complex manner. Various ligands have been identified that activate individual HER receptors, although no ligand has been identified that binds directly to the HER2 receptor. However, cell surface HER receptor monomers form homodimers with the same receptor or heterodimers with other members of the HER family in response to ligand binding [3]. HER2 is the preferred heterodimerisation partner within the family [4] and can be stabilised and transactivated in heterodimers by ligands for the partner HER monomer, such as HER1 or HER3 [1]. This heterodimerisation between HER2 and the other receptors of the family allows the participation of HER2 in signal transduction, even in the absence of a cognate ligand. In fact, heterodimers containing HER2 appear to show particularly high signalling potency compared with other homodimer or heterodimer combinations [5], which may explain the particularly significant role of HER2 in the oncogenic phenotype [6].

In vitro and animal studies have indicated that HER2 gene amplification and protein overexpression play a pivotal role in oncogenic transformation, tumorigenesis and metastasis 7, 8, 9. HER2 gene amplification and/or HER2 protein overexpression can occur in a relatively high percentage of various tumour types [10], for example 20–30% of breast and ovarian carcinomas 11, 12. Furthermore, the growth of tumours and human breast cancer cell lines overexpressing the HER2 receptor is inhibited by anti-HER2 monoclonal antibodies (MAbs), opening a new avenue for targeted cancer therapy 13, 14.

The normal epithelial cell possesses two copies of the HER2 gene and expresses low levels of HER2 protein on the cell surface, equivalent to some tens of thousands of receptors per cell. With oncogenic transformation, HER2 gene amplification generating more than the normal two gene copies and/or increased mRNA transcription leads to 10- to 100-fold increases in HER2 receptor monomers on the cell surface, i.e. HER2 overexpression equivalent to millions of receptors. The extracellular domain of the HER2 receptor (ECD^HER2) may be shed from the cell surface and detected in the circulation in some cases [15].

Section snippets

Why measure HER2 status?

The pathologist plays a central role in the accurate diagnosis of breast cancer and in the subsequent assessment of prognostic and predictive factors that assist in treatment and management decisions. The primary prognostic factors in breast cancer remain those determined by clinical or standard pathological approaches: axillary lymph node status, tumour size, histological or nuclear grade, and histological subtype. Although predictive factors are more valuable clinically, the only clearly

When to measure HER2 status?

In most studies to date, HER2 status has been determined retrospectively using fresh frozen or paraffin-embedded tissue employing immunohistochemical (IHC) assays, which detect HER2 protein overexpression. However, it is becoming more important that HER2 status is determined prospectively so that it can be used as a prognostic/predictive factor and to guide therapeutic possibilities. If the determination of HER2 status is to guide the application of adjuvant therapy, the analysis will clearly

How to measure HER2 status?

Numerous techniques have been used and are being developed to determine HER2 status, although some of them are only suitable for research purposes rather than routine screening of patients. Various target molecules related to HER2 amplification/overexpression, i.e. DNA, mRNA and receptor protein, can be used in different assays. Each technique has advantages and disadvantages which need to be weighed against each other in any assessment of the most appropriate technique for routine laboratory

Conclusions

HER2 is a proto-oncogene that encodes a human epidermal cell growth factor receptor-like protein. Overexpression of HER2 protein, which is usually the consequence of HER2 gene amplification, results in oncogenic transformation. HER2 gene amplification occurs with a frequency of up to 20–30% in breast cancer. Clear HER2 protein overexpression is generally only detected in tumours that show HER2 gene amplification. A HER2-positive status generally appears to be a good indicator of poor prognosis,

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Patients with HER2+ breast cancer do not belong to the target population but some of them may have been included in the patient population. As patients with HER2+ tumours have a poor prognosis [40] without treatment, their inclusion in our study is in favour of an indication for chemotherapy. Second, uPA/PAI-1 testing was not compared to multigene tests because no study compared directly the effectiveness of these decision-making tools.
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ReviewAssessment of HER2 status in breast cancer: why, when and how?

Abstract

Introduction

Section snippets

Why measure HER2 status?

When to measure HER2 status?

How to measure HER2 status?

Conclusions

FEBS Lett.

Biochim. Biophys. Acta. Rev. Cancer

J. Immunol. Methods

Eur. J. Cancer

Gene

Eur. J. Cancer

Eur. J. Cancer

Pathology

Specificity within the EGF family/erbB receptor family signalling network

Bioessays

Receptor protein-tyrosine kinases and their signal transduction pathways

Ann. Rev. Cell. Biol.

ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling

EMBO J.

ErbB-2 is a common auxiliary subunit of NDF and EGF receptorsimplications for breast cancer

EMBO J.

A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor

Mol. Cell. Biol.

Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu

Breast Cancer Res. Treat.

Transformation mediated by the human HER-2 gene independent of epidermal growth factor receptor

Oncogene

Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells

Proc. Natl. Acad. Sci. USA

Studies of the HER-2/neu protooncogene in human breast and ovarian cancer

Science

Human breast cancercorrelation of relapse and survival with amplification of the HER-2/neu oncogene

Science

Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer

J. Clin. Oncol.

Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth

Br. J. Cancer

The HER-2/neu oncogene in breast cancerprognostic factor, predictive factor, and target for therapy

Stem Cells

Low concentrations of c-erbB-2 mRNA (real time RT-PCR) are associated with a poor prognosis in 404 unselected primary human breast cancers

Proc. Am. Assoc. Cancer Res.

Quantitative radioimmunohistochemical measurements of p185 (erbB-2) in frozen tissue sections

J. Histochem. Cytochem.

Quantitative estimation of epidermal growth factor receptor and c-erbB-2 in human breast cancer

Cancer Res.

Quantitation of c-erbB-2 in primary breast cancergene amplification is not the whole picture

Br. J. Cancer

Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma and limited prognostic value in Stage II breast cancer

N. Engl. J. Med.

Integration of new therapies into management of metastatic breast cancer: a focus on chemotherapy, treatment selection through use of molecular markers, and newly developed biologic therapies in late clinical development

HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells

Oncogene

20 year update of the Naples GUN trial of adjuvant breast cancer therapy: evidence of interaction between c-erb-B2 expression and tamoxifen efficacy

Proc. Am. Soc. Clin. Oncol.

Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer

J. Clin. Oncol.

Expression of epidermal growth factor receptor and c-erb B2 during the development of tamoxifen resistance in human breast cancer

Clin. Cancer Res.

Review
Assessment of HER2 status in breast cancer: why, when and how?

Increased expression of the putative growth factor receptor p185^HER2 causes transformation and tumorigenesis of NIH 3T3 cells

Phase II study of weekly intravenous recombinant humanized anti-p185^HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer