Review
ERBB2 oncogene in human breast cancer and its clinical significance

https://doi.org/10.1016/S0959-8049(97)10157-5Get rights and content

Abstract

We reviewed the relationships between ERBB2 amplification and/or overexpression in human breast cancer and the clinicopathological parameters described in the literature (97 studies involving 22 616 patients) in order to draw conclusions regarding its clinical interest. The mean of ERBB2 positivity (26%, ranging from 5 to 55%) is not dependent on the method used to evaluate ERBB2 amplification or overexpression. Despite the discrepancies observed between the different studies, several associations between ERBB2 positivity and the classical clinicopathological parameters were noted. There are clear relationships between ERBB2 positivity and the lack of steroid receptors, the histological subtypes of mammary tumours (ductal invasive and in situ), worse histological and nuclear grades, aneuploidy and high rate of proliferation. In univariate analyses, ERBB2 is strongly associated with poor prognosis. All these data indicate that ERBB2 is a marker of aggressiveness of the tumour. However, ERBB2 does not retain a clinical prognostic significance in multivariate analyses, since it is associated with several strong prognostic parameters. When considering the prognostic value of ERBB2 in relation to treatment, a significantly worse survival of the treated patients is noted in ERBB2 positive patients. This suggest that ERBB2 could be a marker of reduced response to chemotherapy and hormonal treatment. With respect to the tumour response to treatment, the results, provided as yet by pilot studies, remain controversial and further investigations are necessary to evaluate the predictive value of ERBB2. Finally, new therapeutic approaches targeting the cells overexpressing ERBB2 have been developed.

Introduction

The ERBB2 oncogene1, 2, also called HER2/neu[3], is the human homologue of the neu oncogene identified in DNA from rat neuroglioblastomas induced by ethyl-nitroso-urea[4]. Located on chromosome 17q, the gene encodes a trans-membrane glycoprotein (p185) with tyrosine kinase activity, which is closely related to epidermal growth factor receptor (EGFR)[5]. These proteins, together with those encoded by ERBB3 (HER3)6, 7and ERBB4 (HER4)[8], constitute the type I growth factor receptor gene family9, 10.

All four members of the family are expressed in breast cancer cells in vitro. For primary breast cancer, since increased levels of EGFR[11]and ERBB2[12]were first reported, several thousand cases have been studied and the clinical significance of EGFR has been extensively examined[13]. Elevated expression of ERBB3 has been observed14, 15, 16, but until now this has been poorly documented. Although isolated from breast cancer cells, ERBB4 expression has not yet been assayed in breast cancers.

Despite the numerous studies, the prognostic significance and the value of ERBB2 in predicting the response to treatment remain somewhat unclear. Here we review the biological and clinical data on ERBB2 in breast cancer and discuss the clinical usefulness of this parameter.

Section snippets

Analytical review method

For this paper, the review of Klijn and associates[13]on EGFR in breast cancer, was used as a model. We selected the papers reporting relevant data on one or more of the clinical aspects of ERBB2 in breast cancer. The source of the articles was the Cancerlit database. When the same group published several papers with increasing numbers of patients, we used the most recent paper. We found 97 different studies involving 22 616 patients. The relationship between ERBB2 and prognosis was described in

ERBB2 activation in human breast cancer

In human breast cancer, activation of the ERBB2 proto-oncogene by translocation has not yet been described, and rearrangements of ERBB2 have rarely been observed[12]. Activating trans-membrane point mutations, observed in the rat homologue neu oncogene[17], have not been found in human breast cancer[18]. The main mechanism of ERBB2 activation involves amplification, which has always been associated with overexpression, as revealed by increased levels of p185 and its mRNA12, 19. However, it

ERBB2 positivity in human breast cancer

Amplification of the ERBB2 gene was evaluated in most of the studies by Southern blot (34 studies, Table 1) and in recent reports by the polymerase chain reaction (PCR) method (five studies; Table 1). Overexpression has been determined by various methods (Table 2), including Northern blot (six studies), fluorescent in situ hybridisation (one study), Western blot (six studies), flow cytometry (one study) and immunohistochemistry (57 studies). The immunohistochemical staining, using at least 17

Hormonal receptor status

The mean ERBB2 positivity is 2.4 times higher in oestrogen receptor (ER) negative than in ER positive tumours (35.5% versus 13.3%), and it is twice as high in progesterone receptor (PR) negative than in PR positive tumours (32.2% versus 14.8%) (Table 4). Accordingly, Heintz and colleagues[40]reported that 79 and 61% of ERBB2 negative tumours were, respectively, ER and PR positive, whilst only 53 and 24% of ERBB2 positive tumours were ER and PR positive. Todd and associates[50]observed that ER

Prognostic value of ERBB2

The relationship between ERBB2 positivity and clinical outcome in primary breast cancer was examined, taking into consideration both the whole population of patients (lymph node-positive and negative patients, Table 7) and the two subpopulations of patients separately (lymph node positive patients, Table 8; lymph node negative patients, Table 9). In all the studies, the well accepted prognostic factors, such as the number of involved lymph nodes, the steroid receptors, histopathological grading

Hormonotherapy

When considering node-positive, steroid positive tumour patients, Borg and colleagues[58]noted a favourable effect of adjuvant tamoxifen on survival for patients with ERBB2 negative tumours, while patients with ERBB2 positive tumours did not benefit from tamoxifen administration. Giai and associates[72]observed that node positive breast cancer patients co-expressing ERBB2 and RAS had a worse outcome than patients not co-expressing these oncogenes, when treated with tamoxifen. Recently,

Hormonotherapy

Wright and colleagues[106]reported that among patients receiving endocrine therapy as first-line treatment for relapse, 7% of ERBB2 positive patients responded to tamoxifen treatment compared with 37% of ERBB2 negative patients (P<0.05). Moreover, ERBB2 and EGFR appeared to have an additive effect in reducing the likelihood of response, since 0 of 8 patients with EGFR and ERBB2 positive tumours benefitted from endocrine therapy[106]. Similarly, Nicholson and colleagues[110]observed ERBB2

Therapeutic perspectives

As several lines of evidence have suggested that breast cancer patients with ERBB2 overexpression exhibit a reduced response to conventional treatments, new therapeutic approaches, targeting the cells overexpressing ERBB2 and based on monoclonal antibodies (MAbs) or on antisense technology, have been developed.

In the first approach, murine MAbs directed against the extracellular domain of p185 have been shown to inhibit the growth, in cell lines and in xenograft models, of human breast cancer

Conclusion

The variations in ERBB2 positivity in human breast cancer were analysed taking into account the different methods used for evaluation. The range of ERBB2 positivity described in the different papers was very wide in every method. In immunohistochemical studies, a probable explanation for the variable overexpression rates reported in the literature was provided by Press and colleagues[187], who demonstrated the highly variable ability of the ERBB2 antibodies to detect overexpression in archival

Acknowledgements

Supported by grants from the Ligue Nationale Contre le Cancer (LNCC, Paris) and the Comité Départemental du Nord of the LNCC (Lille); by the Groupement Intérregional de Recherche en Cancérologie (ARERS funds, Reims) and by the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC Flandres-Artois). The authors are grateful to Susan Richardson for the English corrections.

References (187)

  • M.H Kraus et al.

    Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors

    Proc Natl Acad Sci

    (1989)
  • Plowman GD, Whitney GS, Neubauer MG, et al. Molecular cloning and expression of an additional epidermal growth factor...
  • Plowman GD, Culouscou JM, Whitney GS, et al. Ligand-specific activation of HER4/p180erB4, a fourth member of the...
  • T Rajkumar et al.

    The type I growth factor receptors in human breast cancer

    Br Cancer Res Treat

    (1994)
  • Sainsbury JRC, Farndon JR, Needham GK, Malcolm AJ, Harris AL. Epidermal growth factor receptor status as predictor of...
  • D.J Slamon et al.

    Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

    Science

    (1987)
  • J.G.M Klijn et al.

    The clinical significance of epidermal growth reactor receptor (EGF-R) in human breast cancer: a review on 5232 patients

    Endocrine Rev

    (1992)
  • Lemoine NR, Barnes DM, Hollywood DP, et al. Expression of the ERBB3 gene product in breast cancer. Br J Cancer 1992,...
  • Gasparini G, Gullick WJ, Maluta S, et al. C-erbB3 and c-erbB-2 protein expression in node-negative breast carcinoma—an...
  • Travis A, Pinder SE, Robertson JFR et al. C-erbB3 in human breast carcinoma: expression and relation to prognosis and...
  • N.R Lemoine et al.

    Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer

    Oncogene

    (1990)
  • G Pauletti et al.

    Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization

    Oncogene

    (1996)
  • M Guérin et al.

    Overexpression of either c-myc or c-erbB-2/neu proto-oncogenes in human breast carcinomas: correlation with poor prognosis

    Oncogene Res

    (1988)
  • Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer....
  • Dati C, Muraca R, Tazartes O, et al. C-erbB-2 and ras expression levels in breast cancer are correlated and show a...
  • Robertson KW, Reeves JR, Smith G, et al. Quantitative estimation of epidermal growth factor receptor and c-erbB-2 in...
  • M.J Cline et al.

    Proto-oncogene abnormalities in human breast cancer: correlations with anatomic features and clinical course of disease

    J Clin Oncol

    (1987)
  • J.M Varley et al.

    Alterations to either c-erbB-2 (neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis

    Oncogene

    (1987)
  • Venter DJ, Tuzi NL, Kumar S, Gullick WJ. Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas:...
  • D Zhou et al.

    Association of multiple copies of the c-erbB-2 oncogene with spread of breast cancer

    Cancer Res

    (1987)
  • Berger MS, Locher GW, Saurer S, et al. Correlation of c-erbB-2 gene amplification and protein expression in human...
  • J Fontaine et al.

    Gene amplification and expression of the neu (c-erbB-2) sequence in human mammary carcinoma

    Oncology

    (1988)
  • Adnane J, Gaudray P, Simon M, et al. Proto-oncogene amplification and human breast tumor phenotype. Oncogene 1989, 4,...
  • Guérin M, Gabillot M, Mathieu MC, et al. Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory...
  • M Gutman et al.

    Amplification of c-myc and c-erbB-2 proto-oncogenes in human solid tumors: frequency and clinical significance

    Int J Cancer

    (1989)
  • Ro J, El-Naggar A, Ro JY, et al. C-erbB-2 amplification in node-negative human breast cancer. Cancer Res 1989, 49,...
  • R Seshadri et al.

    The significance of oncogene amplification in primary breast cancer

    Int J Cancer

    (1989)
  • Zeillinger R, Kury F, Czerwenka K, et al. HER-2 amplification, steroid receptors and epidermal growth factor receptor...
  • D.J Zhou et al.

    Proto-oncogene abnormalities in human breast cancer: c-ERBB-2 amplification does not correlate with recurrence of disease

    Oncogene

    (1989)
  • Borg A, Tandon AK, Sigurdsson H, et al. Her-2/neu amplification predicts poor survival in node-positive breast cancer....
  • Brouillet JP, Theillet C, Maudelonde T, et al. Cathepsin D assay in primary breast cancer and lymph nodes: relationship...
  • N.H Heintz et al.

    Amplification of the c-erbB-2 oncogene and prognosis of breast adenocarcinoma

    Arch Pathol Lab Med

    (1990)
  • Kury F, Sliutz G, Schemper M, et al. HER-2 oncogene amplification and overall survival of breast carcinoma patients....
  • S.L Meyers et al.

    Analysis of the int-1, int-2, c-myc, and neu oncogenes in human breast carcinomas

    Cancer Res

    (1990)
  • A Borg et al.

    ERBB2 amplification in breast cancer with a high rate of proliferation

    Oncogene

    (1991)
  • G.M Clark et al.

    Follow-up study of HER-2/neu amplification in primary breast cancer

    Cancer Res

    (1991)
  • H Olsson et al.

    Her-2/neu and INT2 proto-oncogene amplification in malignant breast tumors in relation to reproductive factors and exposure to exogenous hormones

    J Natl Cancer Inst

    (1991)
  • Tommasi S, Paradiso A, Mangia A, et al. Biological correlation between HER-2/neu and proliferative activity in human...
  • Ciocca DR, Fujimura FK, Tandon AK, et al. Correlation of HER-2/neu amplification with expression and with other...
  • R.K Tiwari et al.

    HER-2/neu amplification and overexpression in primary human breast cancer is associated with early metastasis

    Anticancer Res

    (1992)
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