Serum HER-2/neu in the management of breast cancer patients

doi:10.1016/S0009-9120(03)00026-2

Clinical Biochemistry

Volume 36, Issue 4, June 2003, Pages 233-240

https://doi.org/10.1016/S0009-9120(03)00026-2 Get rights and content

Abstract

The clinical role of HER-2/neu, a 185 kD epithelial transmembranous protein, has evolved after the approval of the anti-HER-2/neu targeted monoclonal antibody trastuzumab (Herceptin) for the therapy of metastatic breast cancer. The extracellular domain of HER-2/neu undergoes proteolytic cleavage from the full-length protein by metalloproteases, and is shed into the blood as a circulating antigen. While HER-2/neu gene amplification and/or protein overexpression are detected in approximately 25% of primary breast cancers, serum HER-2/neu levels are elevated beyond the upper limit of normal in 50 to 60% of stage IV breast cancer patients. HER-2/neu in serum can be detected by enzyme immunoassays (manual and automated versions). It has been shown to have prognostic and predictive information in breast cancer patients. Monitoring for recurrence by serum HER-2/neu reaches a high sensitivity for HER-2/neu positive tumors. Longitudinal follow-up of patients during any kind of systemic therapy allows for monitoring of the therapeutic success. When utilized in these applications, serum HER-2/neu testing is complementary to HER-2/neu tissue results and to the determination of classical tumor markers such as CA 15–3, CA 27.29 and CEA, which are not targeted by specific forms of systemic therapy.

Introduction

The clinical role of HER-2/neu (c-erbB-2) has evolved in recent years, especially after the approval of the anti-HER-2/neu targeted monoclonal antibody trastuzumab (Herceptin^®, Genentech^® Inc., South San Francisco, CA) for the treatment of advanced breast cancer. Since the determination of the HER-2/neu status is the basis of patient selection for Herceptin therapy, its laboratory evaluation must be highly reliable, valid and reproducible. Serum HER-2/neu is a circulating oncoprotein, which is cleaved from the full-length, membrane-bound HER-2/neu protein. It can be detected in the serum of healthy individuals as well as in patients with various solid tumors. This review will summarize the role of HER-2/neu in the biology of breast cancer, the determination of the HER-2/neu status and the clinical value of testing for serum HER-2/neu. Furthermore, we suggest an algorithm for the use of serum HER-2/neu over the disease course of breast cancer from locally confined disease to metastatic spread, with patient stratification based on the HER-2/neu status of the primary tumor.

Section snippets

Structure and biology of HER-2/neu

HER-2/neu is a 185 kD glycoprotein normally expressed in the epithelia of numerous organs such as lungs, bladder, pancreas, breast, and prostate [1], [2], [3]. Overexpression and/or overamplification of HER-2/neu in epithelial tumors leads to a strong increase in the density of HER-2/neu in the cell membranes [4]. HER-2/neu is a member of the epidermal growth factor receptor (EGFR) family, which is comprised of 4 family members, designated HER-1 (synonym: EGFR) through HER-4. The HER-2/neu

Immunohistochemistry

In the Herceptin pivotal trials, immunohistochemical analysis of tumor material was used to assess the HER-2/neu status. Since then, immunohistochemistry (IHC) has been considered as the reference method, or gold standard, in HER-2/neu testing [14]. IHC detects the degree of HER-2/neu protein overexpression in paraffin-embedded tissue samples by using mono- or polyclonal antibodies, which bind to the HER-2/neu expressed on the cell membranes. The resultant antigen-antibody complexes are

Serum testing for HER-2/neu

Both HER-2/neu gene amplification and protein overexpression can be evaluated in tumor tissue. However, circulating levels of serum HER-2/neu can also be used to evaluate the HER-2/neu status (Figure 1). Since HER-2/neu bearing epithelial cells shed the extracellular domain (ECD) into the serum, serum HER-2/neu levels can be detected by enzyme-linked immunosorbent assays (ELISA). Currently, two FDA-approved ELISA assays are available that measure the concentration of circulating HER-2/neu: a

Clinical role of serum HER-2/neu testing

The specific clinical benefits of serum HER-2/neu testing are being clarified by numerous investigations ongoing worldwide. Several studies indicate a role for forecasting of disease-free and overall survival (i.e., prognostication). Other trials, specifically in metastatic breast cancer populations, compare patient subsets with elevated baseline serum HER-2/neu levels vs. the subgroup with a normal serum HER-2/neu baseline concentration for predicting response to treatment (i.e., a predictive

Algorithm for the use of serum HER-2/neu

The algorithm as shown in Figure 3 is a suggestion for the integration of serum HER-2/neu measurements into the clinical practice. It should not be interpreted being inconsistent with the recommendations for the use of tumor markers by leading oncological societies. Rather, it should be considered as a ‘work in progress’ in favor of individualized medicine (i.e., selecting optimal therapies based upon information as provided by diagnostic methods) [36].

Serum HER-2/neu testing is a

Conclusions

Measurements of levels of serum HER-2/neu provide prognostic and predictive information to the clinician and can be used for monitoring of metastatic breast cancer patients. HER-2/neu serum testing provides complementary information to the tissue determination as the HER-2/neu status might change over time which would lead to compromised selection of patients for specifically targeted therapies. Testing for serum HER-2/neu using manual or automated ELISA assays is technically robust, does not

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A novel binary luminophore based high-efficient electrochemiluminescence biosensor for ultrasensitive detection of human epidermal growth factor receptor-2
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The heterogeneity of BC resulted in a molecular classification into four subtypes: luminal A, luminal B, human epidermal growth factor receptor-2 (HER-2) positive, and basal-like [3]. Among them, HER-2 (also known as ErbB-2 or HER-2/nue) is a 185 kDa transmembrane glycoprotein complex that is over-expressed in approximately 25–30% of primary invasive BC, which is characterized by uncontrolled growing and spreading of the tumors [4,5]. Studies have shown that the blood HER-2 concentration in normal people is 2–15 ng mL−1, while that in BC patients is elevated to 15–75 ng mL−1 [6].
For the first time, a high-efficient and low-cost electrochemiluminescence (ECL) biosensor was constructed for ultrasensitive detection of breast cancer related human epidermal growth factor receptor-2 (HER-2) using a novel binary luminophore and low concentration of coreactant. Firstly, Au nanoparticles decorated graphite-like carbon nitride (g-C₃N₄@Au) was designed as sensing platform, which can generate ECL signal in the potential range from −1.2 V to 0 V when peroxydisulfate (S₂O₈²⁻) was used as the coreactant. Secondly, amino-modified capture probes (CP) were immobilized on the surface of g-C₃N₄@Au via Au-N bonds. In addition, Zr-based metal organic framework (Zr-MOF) modified bulk boron carbon oxynitride (BCNO), named ZMB, exhibited remarkable ECL intensity at the potential window of −2.0 V to 0 V with 0.8 mM S₂O₈²⁻. ZMB possessed a large specific surface area and abundant amino groups to anchor Au@Pt nanoparticles (Au@PtNPs). Therefore, HER-2 binding aptamers (HBA) could be anchored on Au@PtNPs to form the tracer label. Under optimal conditions, the proposed ECL biosensor displayed a wide linear range from 10 fg mL⁻¹ to 100 ng mL⁻¹ with a limit of detection (LOD) as low as 0.2 fg mL⁻¹. Importantly, this work utilized ZMB/S₂O₈²⁻ as new ECL system with satisfactory detection performances, which provided a potential approach to improve the sensitivity in clinical diagnosis.
Current immunoassay methods and their applications to clinically used biomarkers of breast cancer
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Breast cancer is the leading cause of cancer-related mortality worldwide, with a higher incidence in developed countries. The biomarkers for breast cancer such as estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, CA (cancer antigen) 15-3, CA 27.29, and carcinoembryonic antigen have been recommended for use in the laboratory based on the guidelines of American and European societies. Immunoassays have been frequently and consistently used to detect these clinically established biomarkers of breast cancer. Despite the higher accessibility of serum biomarkers, including CA 15-3, CA 27.29, and CEA, compared to tissue markers, variations in immunoassays affect their standardization and clinical utility. When reviewing the immunoassays used to detect these serum markers, we found that the most frequently used immunoassay was enzyme-linked immunosorbent assay, followed by electrochemiluminescent immunoassay, and then chemiluminescence immunoassay for CA 15-3 and CEA. Meanwhile, the chemiluminescence immunoassay was the most common technique for CA27.29. The electrochemiluminescent immunoassay and monoclonal fluorometric assay have become the preferred methods in 2010–2019 compared to 2000–2009. Analytical and clinical performance factors such as sensitivity, specificity, detection limit, hazard risk to laboratory personnel, speed, and economic feasibility influenced these changes in user preference. When using the immunoassays, there should be a comprehensive understanding of the principles, advantages, vulnerability, and precautions for interpretation. In the future, a combination of immunological biomarkers and genetic platforms will benefit patients with breast cancer by facilitating prognosis prediction and guiding therapeutic intervention.
Comparison of prophylactic and therapeutic immunisation with an ErbB-2 (HER2) fusion protein and immunoglobulin V-gene repertoire analysis in a transgenic mouse model of spontaneous breast cancer
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ErbB-2 ectodomain is cleaved by metalloproteases leaving the constitutively active, truncated, intracellular tyrosine kinase receptor in the tumour tissue [8]. This circulating serum ErbB-2, a 97–115 kDa oncoprotein, is detectable in patients as a prognostic disease marker [9]. In ErbB-2 associated breast cancer patients, a spontaneous anti-ErbB-2 immune response against this autologous, native ErbB-2 ectodomain has been documented in both early and late stage metastatic diseases [10–12].
ErbB-2 is associated with several solid tumours of which breast cancer is the commonest cancer in women worldwide. Though anti-ErbB-2 antibody appears to play a significant role in prevention and therapy, naturally occurring anti-ErbB-2 antibody associated with the cleaved ectodomain of overexpressed ErbB-2 self antigen is detectable in patients. It is therefore essential to understand the course of antibody mediated protection during disease progression. 100% of FVB/N^neu mice expressing mutated, constitutively active ErbB-2 develop mammary carcinoma. It has been shown that vaccination with ErbB-2 associated with a T helper cell epitope P30 can offer protection against transplantable tumour but it is unclear whether the same vaccine protects against naturally developing tumour. We have analysed the course of the disease following prophylactic, and therapeutic vaccination in this spontaneous, eutopic mammary carcinoma model that more closely resembles the human disease. 100% protection against tumour development was observed subsequent to prophylactic immunisation but disease progression was unaffected by therapeutic vaccination. The antibody response exhibited restricted expansion of the Immunoglobulin (Ig) variable (V)-gene repertoire by ErbB-2 specific B cells compared with the non-antigen specific B cell pool and control mice. The serum antibody profile was similar in therapeutically injected mice without any effect on tumour burden.
Clinical usefulness of circulating ECD/HER-2 measurement for breast cancer patients' management
2011, Presse Medicale
Environ 15 à 20 % des cancers du sein surexpriment le récepteur human epidermal growth factor receptor-2 (HER-2). Cette surexpression est associée à un pronostic plus péjoratif et à la possibilité d’utilisation de thérapeutiques ciblées (trastuzumab ou lapatinib). Le clivage protéolytique de la partie extracellulaire de ce récepteur aboutit à la formation d’une forme soluble, appelée ECD/HER-2 qui peut être détectée dans les fluides biologiques en utilisant des méthodes de dosage de type immunochimique.
Le but de notre revue a été de déterminer l’utilité du dosage de l’ECD/HER-2 dans la prise en charge des cancers invasifs du sein.
Les articles publiés en langue anglaise et française jusqu’au 31 mars 2010 indexés dans la banque de données PubMed ont été revus (69 articles originaux et huit revues).
La détermination de la concentration d’ECD/HER-2 ne dispense pas de l’obtention de l’expression de HER-2 par l’analyse histologique de la tumeur, certaines tumeurs HER-2 négatives s’accompagnant d’une valeur circulante élevée d’ECD/HER-2 et à l’inverse, certaines tumeurs positives étant associées à des valeurs basses. Les concentrations d’ECD/HER-2 sont corrélées à l’extension tumorale, les formes précoces s’accompagnant dans environ 10 % des cas d’une élévation de l’ECD/HER-2 alors que celle-ci s’observe dans plus du tiers des formes métastatiques. L’élévation des valeurs d’ECD/HER-2 précède de plusieurs mois l’apparition des métastases symptomatiques. L’intérêt du suivi de l’ECD/HER-2 sous chimiothérapie, hormonothérapie ou trastuzumab reste contradictoire. De même, il ne paraît pas consensuel qu’une valeur élevée d’ECD/HER-2 avant tout traitement en situation adjuvante, représente un facteur pronostique indépendant.
Différents éléments, à la fois anatomopathologiques, biochimiques, cliniques et méthodologiques peuvent, en partie du moins, expliquer ces discordances.
De nouvelles études prospectives, utilisant des méthodes de dosage de type immunochimique, avec un seuil défini, comportant une analyse histologique exhaustive et un recueil complet des données cliniques sont nécessaires afin d’établir l’intérêt du dosage de l’ECD/HER-2 circulant en cancérologie mammaire.
About 15 to 20 % of breast cancer cases overexpress human epidermal growth factor receptor-2 (HER-2). This overexpression is associated with poor clinical prognosis but therapeutic success of trastuzumab or lapatinib. HER-2 extracellular domain (ECD) undergoes a proteolytic cleavage and is shed into biologic fluid as a circulating antigen called ECD/HER-2, which can be detected by immunochemical assays.
The aim of our review was to determine the clinical usefulness of ECD/HER-2 measurement in the management of breast cancer patients.
A Pubmed search for publications in English or French was carried out until March 31, 2010 (69 original articles and 8 reviews).
The measurement of ECD/HER-2 concentration does not exempt from the pathological determination of HER-2 expression in tumors; some HER-2 negative tumors are associated with high levels of ECD/HER-2, on the other hand, some HER-2 positive tumors present low levels of ECD/HER-2. The concentration of ECD/HER-2 is correlated to disease progression, since 10 % of loco-regional breast cancers and more than a third of metastatic breast cancers have high levels of ECD/HER-2. The elevation of ECD/HER-2 levels generally occurs several months before the diagnosis of symptomatic metastases. The relevance of ECD/HER-2 measurements during chemotherapy, hormone therapy and trastuzumab treatment remains uncertain. Similarly, it is not commonly agreed that high levels of ECD/HER-2 before any treatment in the case of an early breast cancer, is an independent prognostic factor.
A close analysis of a variety of pathological, biochemical, clinical and methodological data may explain these discrepancies.
New prospective studies using immunochemical measurements of ECD/HER-2 (with a consensual threshold) and based on both detailed pathological analyses and a comprehensive collection of clinical data are still required to establish the clinical usefulness of circulating ECD/HER-2 measurement for breast cancer patients’ management.
Evaluation of HER2/neu oncoprotein in serum and tissue samples of women with breast cancer: Correlation with clinicopathological parameters
2010, Breast
Citation Excerpt :
HER2 is a 185 kD integral membrane protein. Extracellular domain of HER2 is broken by metalloproteases and detached from other parts of HER2 and enters the blood circulation.8 Real-time PCR and ELISA are true quantitative methods, whereas IHC and FISH are morphologic in situ and semi-quantitative tests.
HER2/neu (HER2) is a proto-oncogen of the EGF Receptor family. The assessment of serum HER2 level is useful for predicting the patients’ response to chemotherapy or hormonal therapy and selection of proper patients for treatment with Herceptin.
We aimed to compare serum HER2 levels with immunohistochemistry in tumoral tissues and investigate correlation between these levels and various prognostic factors.
This cross-sectional study was conducted on 75 patients with breast carcinoma referred to surgical ward of Mashhad Imam Reza’s hospital from November 2008 to February 2009. Pre-operative serum samples were collected and stored in −20 °C.
Surgical samples were investigated for the type of carcinoma, tumor size, lymph node metastasis, stage as well as grade of the tumor. Tissue HER2 over-expression was evaluated by immunohistochemistry (IHC) staining and HER2 levels were studied by ELISA method. Statistical analysis was performed by SPSS software.
Serum HER2 cut-off level was 18.4 ng/ml; 46.7% of patients were serum HER2-positive and 43% were IHC positive. There was a high statistical correlation between these two parameters (P = 0.018).
Statistically, there was no significant correlation between serum HER2 and age, tumor size, stage, grade and metastatic lymph nodes (P > 0.05).
Serum HER2 level assay can be considered as a complementary method besides tissue methods.

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ReviewSerum HER-2/neu in the management of breast cancer patients

Abstract

Introduction

Section snippets

Structure and biology of HER-2/neu

Immunohistochemistry

Serum testing for HER-2/neu

Clinical role of serum HER-2/neu testing

Algorithm for the use of serum HER-2/neu

Conclusions

Cell

The neu oncogene encodes an epidermal growth factor receptor-related protein

Nature

Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene

Science

The c-erbB-2 protein in oncogenesismolecular structure to molecular epidemiology

Crit Rev Oncog

Conformation of the transmembrane domain of the epidermal growth factor receptor

J Protein Chem

Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein

EMBO J

Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancerprognostic significance

Int J Cancer

Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells

Cancer Res

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

Science

Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment

J Clin Oncol

Trastuzumab (herceptin), a humanized anti-her2 receptor monoclonal antibody, inhibits basal and activated her2 ectodomain cleavage in breast cancer cells

Cancer Res

HER2 overexpression and paclitaxel sensitivity in breast cancertherapeutic implications

Oncology (Huntingt)

Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts

Cancer Res

Her-2/neu analysis in archival tissue samples of human breast cancercomparison of immunohistochemistry and fluorescence in situ hybridization

J Clin Oncol

Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancera direct comparison of fluorescence in situ hybridization and immunohistochemistry

J Clin Oncol

Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, p185

Oncogene

Clinical utility of serum HER-2/neu testing on the Bayer Immuno 1 automated system in breast cancer

Anticancer Res

Automated assay for HER-2/neu in serum

Clin Chem

Hormonal treatment with sex steroids in women is associated with lower p105 serum concentrations

Anticancer Res

Review
Serum HER-2/neu in the management of breast cancer patients