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The Oncologist, Vol. 8, No. 4, 307–325, August 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
Breast Cancer

The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy

Jeffrey S. Rossa,b, Jonathan A. Fletcherc, Gerald P. Linetteb,d, James Stecb, Edward Clarkb, Mark Ayersb, W. Fraser Symmanse, Lajos Pusztaie, Kenneth J. Bloomf

a Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA; b Division of Molecular Medicine, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; c Department of Pathology, Brigham Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; d Department of Medicine, Washington University, St. Louis, Missouri, USA; e Departments of Medicine and Pathology, M.D. Anderson Cancer Center, Houston, Texas, USA; f US Labs, Inc., Irvine, California, USA

Correspondence: Jeffrey S. Ross, M.D., Albany Medical College, Department of Pathology, Mail Code 81, 47 New Scotland Avenue, Albany, New York 12208, USA. Telephone: 518-262-5461; Fax: 518-262-8092; e-mail: rossj{at}mail.amc.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Define the historical background and biological basis of the discovery of the HER-2/neu gene and its first use as a prognostic factor in breast cancer.
  2. Recall the uses of HER-2/neu testing prior to the approval of trastuzumab including the impact on anthracycline adjuvant and first-line chemotherapy responses.
  3. Explain the basic principles of all the HER-2/neu tests in clinical practice: IHC, FISH, Southern blot, PCR, tissue ELISA, and serum ELISA.
  4. Contrast the pros and cons and uses and limitations of the IHC versus the FISH approach to HER-2/neu testing.
  5. Critique the most recent data comparing IHC with FISH for the prediction of response to single-agent trastuzumab and trastuzumab in combination with standard chemotherapy for advanced metastatic breast cancer.
  6. Describe the HER-2/neu expression patterns in all types of breast conditions, including in situ carcinoma, lobular versus ductal carcinoma, Paget’s disease, male breast cancer, breast sarcomas, and benign breast disorders.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. In this review, the association of HER-2/neu gene and protein abnormalities with prognosis and response to therapy with trastuzumab and to other therapies in breast cancer is presented. By considering a series of 80 published studies encompassing more than 25,000 patients, the relative advantages and disadvantages of Southern blotting, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is presented as well as its potential impact on responses to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review also evaluates the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.

Key Words. Trastuzumab • IHC • FISH • Prognosis • review


   HER-2/NEU GENE (C-ERB B-2)
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
The human epidermal growth factor receptor 2 (HER-2)/neu (c-erbB-2) gene is localized to chromosome 17q and encodes a transmembrane tyrosine kinase receptor protein that is a member of the epidermal growth factor receptor (EGFR) or HER family (Fig. 1Go) [1]. This family of receptors is involved in cell-to-cell and cell-to-stroma communication primarily through a process known as signal transduction, in which external growth factors, or ligands, affect the transcription of various genes by phosphorylating or dephosphorylating a series of transmembrane proteins and intracellular signaling intermediates, many of which possess enzymatic activity. Signal propagation occurs as the enzymatic activity of one protein turns on the enzymatic activity of the next protein in the pathway [2]. Major pathways involved in signal transduction, including the Ras/mitogen-activated protein kinase pathway, the PI3K/Akt pathway, the Janus kinase/signal transducer and activator of transcription pathway, and the PLC-{gamma} pathway, ultimately affect cell proliferation, survival, motility, and adhesion.



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  		Figure 1. The HER (erb) gene family. Note that HER-2/neu has no known ligands and that HER-3 has no intrinsic tyrosine kinase activity. Abbreviations: TGF-{alpha} = transforming growth factor alpha; AR = amphiregulin; EGF = epidermal growth factor; HB-EGF = heparin binding EGF; ß-CEL = beta cellulin; EPI = epinephrine; NRG1 = neuregulin 1; NRG2 = neuregulin 2.

 
Receptor activation requires three variables, a ligand, a receptor, and a dimerization partner [3]. After a ligand binds to a receptor, that receptor must interact with another receptor of identical or related structure in a process known as dimerization in order to trigger phosphorylation and activate signaling cascades. Therefore, after ligand binding to an EGFR family member, the receptor can dimerize with various members of the family (EGFR, HER-2, HER-3, or HER-4). It may dimerize with a like member of the family (homodimerization) or it may dimerize with a different member of the family (heterodimerization). The specific tyrosine residues on the intracellular portion of the HER-2/neu receptor that are phosphorylated, and hence the signaling pathways that are activated, depend on the ligand and dimerization partner. The wide variety of ligands and intracellular crosstalk with other pathways allows for substantial diversity in signaling. While no known ligand for the HER-2/neu receptor has been identified, it is the preferred dimerization partner of the other family members. HER-2/neu heterodimers are more stable [4] and their signaling is more potent [2] than receptor combinations without HER-2/neu. HER-2/neu gene amplification and/or protein overexpression has been identified in 10%–34% of invasive breast cancers [1].


   EXPRESSION AND PROGNOSIS IN BREAST CANCER
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
Both morphology-based and molecular-based techniques have been used to measure HER-2/neu status in breast cancer clinical samples [5–85]. Of the 81 studies considering 27,161 patients listed in Table 1Go, 73 (90%) of the studies and 25,166 (92%) of the cases found that either HER-2/neu gene amplification or HER-2 (p185HER2) protein overexpression predicted breast cancer outcome on either univariate or multivariate analysis. In 52 (71%) of the 73 studies that featured multivariate analyses of outcome data, the adverse prognostic significance of the HER-2/neu gene, message, or protein overexpression was independent of all other prognostic variables. Thirteen (16%) of the studies reported prognostic significance on univariate analysis only (in eight studies, multivariate analysis was not performed). Only eight (10%) of the studies [2, 4, 12, 34–36, 40, 55, 60], encompassing 1,995 (8%) of the patients, showed no correlation between HER-2/neu status and outcome. Of those eight studies, five (63%) used immunohistochemistry (IHC) on paraffin-embedded tissues as the HER-2/neu protein detection technique, two (25%) used Southern blot analysis, and one (13%) used a reverse transcription-polymerase chain reaction (RT-PCR) technique. All eight studies [41, 46, 48, 52, 62, 74, 75] that used the fluorescence in situ hybridization (FISH) technique and the one study that used the chromogenic in situ hybridization (CISH) technique [85] showed univariate prognostic significance of gene amplification, and eight of those (89%) showed prognostic significance in multivariate analyses as well.


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  		Table 1. HER-2/neu status and prognosis in breast cancer
 

   HER-2/NEU TESTING TECHNIQUES
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
IHC staining (Fig. 2Go) was the predominant method utilized. Unlike most IHC assays, the assessment of HER-2/neu status is semiquantitative rather than qualitative since HER-2/neu is expressed in all breast epithelial cells. In order to provide a meaningful interpretation of a HER-2/neu immunostain, it was necessary to establish a relationship between the number of HER-2/neu receptors on the surface of a cell and the distribution and intensity of the immunostain. Using cell lines, it was possible to establish a standardized IHC procedure and scoring system in which cells containing fewer than 20,000 receptors would show no staining (0), cells containing approximately 100,000 receptors would show partial membrane staining with less than 10% of the cells showing complete membrane staining (1+), cells containing approximately 500,000 receptors would show light to moderate complete membrane staining in more than 10% of the cells (2+), and cells containing approximately 2,300,000 receptors would show strong, complete membrane staining in more than 10% of the cells (3+). Studies have shown that when a standardized IHC assay is performed on specimens that are carefully fixed, processed, and embedded, there is excellent correlation between gene copy status and protein expression levels [1, 86–88]. However, alterations can be substantially impacted by technical issues, especially in archival, fixed, paraffin-embedded tissues. Advantages of IHC testing include its wide availability, relatively low cost, easy preservation of stained slides, and use of a familiar routine microscope. Disadvantages of IHC include the impact of preanalytic issues including storage, duration and type of fixation, intensity of antigen retrieval, type of antibody (polyclonal versus monoclonal), nature of system control samples, and, most importantly, the difficulties in applying a subjective slide scoring system. In a study of a large panel of antibodies, Press et al. reported a significant variation in detection rates of HER-2/neu protein by IHC using a large tissue block containing multiple breast tumors [89]. Problems with standardization in slide scoring have been highlighted recently in reference to the best method for using HER-2/neu status to predict response to the anti-HER-2/neu antibody therapeutic, trastuzumab (Herceptin®; Genentech Corporation; South San Francisco, CA) [90]. In that study, the authors found that a significant number of community-hospital-based IHC results that were used to establish the eligibility of patients to participate in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 clinical trial, compared with those obtained at commercial laboratories, could not be confirmed when tested in the central pathology facility [90]. Slide scoring can be improved by avoiding specimen edges, retraction artifacts, under- or overfixation, cases with substantial staining of benign elements, and tumor cells lacking a complete membranous staining pattern (the so-called "chicken wire" appearance). Recent data presented by the NSABP have shown that certified laboratories, defined as those laboratories performing high volumes of HER-2/neu testing and demonstrating high concordance between IHC and FISH results, approached 98% in interlaboratory concordance when tumors assessed as 3+ were reanalyzed by both IHC and FISH testing at the NSABP laboratory [91]. As a result, the NSABP recently initiated a program to allow only certified laboratories to perform the HER-2/neu testing on patients entering their adjuvant therapy clinical trials. Similarly, in a report from the Breast Intergroup Trial N9831, the poor concordance (74%) between local and central testing for HER-2 status resulted in modifications to the eligibility criteria for N9831 [92]. Since most of the submitting laboratories were reference laboratories, which cannot control tissue fixation or storage, it was suggested that preanalytical issues may not be the major cause of interlaboratory variability. Results from the United Kingdom National External Quality Assessment Scheme for Immunohistochemistry (UK NEQAS-ICC) also suggested that the lack of reproducibility of HER-2/neu scoring among laboratories was not the result of tumor heterogeneity or differences in fixation or processing but rather the result of how the scoring system was applied [93]. The use of a quantitative image analysis system can reduce slide-scoring variability among pathologists, especially in 2+ cases [94]. When 130 HER-2/neu immunostained slides were reviewed by 10 pathologists and then were later reviewed with the aid of image analysis, the use of image analysis eliminated most of the interobserver variability that was significant by routine microscopy (Fig. 3Go) [95]. Two commercially available HER-2/neu IHC kits, the HercepTestTM (Dako Corporation; Glostrup, Denmark; http://www.dakocytomation.dk) and the Ventana PATHWAYTM (Ventana Medical Systems; Tucson, AZ; http://www.ventanamed.com), are approved for sale for determining the eligibility of patients to receive trastuzumab by the U.S. Food and Drug Administration (FDA).



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  		Figure 2. HER-2/neu testing in breast cancer. A) HER-2/neu gene amplification detected by FISH (Abbott-Vysis PathVysionTM System). B) HER-2/neu gene amplification detected by CISH (Zymed System). C) Immunohistochemistry using HercepTestTM system with continuous membranous 3+ immunostaining for HER-2/neu protein.

 


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  		Figure 3. Image analysis and HER-2/neu slide scoring. Shown is the interobserver variability among 10 pathologists reviewing the same 130 HER-2/neu immunostained slides. Concordance with gene amplification status, assessed by FISH, is plotted on the y axis. Slides assessed as 2+ or 3+ were called positive. Manual assessment showed significant interobserver variability, while assessment with the aid of image analysis showed little variability. Additionally, all pathologists improved their concordance with the aid of image analysis. ACIS = automated cellular imaging system; NS = nonsignificant.

 
Southern and slot blotting were the first gene-based HER-2/neu detection methods used in breast cancer specimens. These methods can be significantly hampered when tumor cell DNA extracted from the primary carcinoma sample is diluted by DNA from benign breast tissue and inflammatory cells. The FISH technique (Fig. 2Go), which is morphology driven and, like IHC, can be automated, has the advantages of a more objective scoring system and the presence of a built-in internal control consisting of the two HER-2/neu gene signals present in all non-neoplastic cells in the specimen. Disadvantages of FISH testing include the higher cost of each test, longer time required for slide scoring, requirement of a fluorescent microscope, inability to preserve the slides for storage and review, and, occasionally, difficulty in identifying the invasive tumor cells. Two versions of the FISH assay are FDA approved: the Ventana INFORMTM (Ventana Medical Systems) test that measures only HER-2/neu gene copies and the Abbott-Vysis PathVysionTM (Abbott Laboratories; Abbott Park, IL; http://www.abbottdiagnostics.com) test that includes a chromosome 17 probe in a dual color format. Published studies indicate that the two assays are highly correlative [96]. The CISH technique (Fig. 2Go) features the advantages of both IHC (routine microscope, lower cost, familiarity) and FISH (built-in internal control, subjective scoring, more robust DNA target) but is not, to date, FDA approved for selecting patient eligibility for trastuzumab treatment [97, 98]. The single CISH-based study cited in Table 1Go showed independent significance of gene amplification and adverse disease outcome [85]. Indeed, the CISH and IHC detection methods can be combined, so as to provide simultaneous evaluation of gene copy number and protein expression (Fig. 4Go), but such methods are experimental and have not yet been adopted in clinical practice. The RT-PCR technique [99, 100] has predominantly been used to detect HER-2/neu mRNA in peripheral blood and bone marrow samples, has correlated more with gene amplification status than IHC levels [101], and has failed to predict survival but did correlate with estrogen receptor/progesterone receptor (ER/PR) status and tumor grade status in one breast cancer outcome study of 365 patients [66]. With the advent of laser capture microscopy and the acceptance of RT-PCR as a routine and reproducible laboratory technique, the use of RT-PCR to assess HER-2/neu status may increase in the future.



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  		Figure 4. Simultaneous HER-2/neu gene amplification and protein overexpression determination. HER-2/neu combined gene and protein evaluation in pleural effusion by CISH (DAB = brown) and IHC (Vector-blue), respectively. A single breast carcinoma cell with HER-2/neu gene amplification and protein overexpression is seen among non-neoplastic cells. DAB = diaminobenzedine.

 
The enzyme-linked immunosorbent assay (ELISA) technique, when performed on tumor cytosols made from fresh tissue samples, avoids the potential antigen damage associated with fixation, embedding, and uncontrolled storage. In the six published studies listed in Table 1Go, ELISA-based measurements of HER-2/neu protein in tumor cytosols, mostly performed in Europe, have uniformly correlated with disease outcome [47, 49, 68, 70, 73, 84]. However, the small size of breast cancers associated with expanded screening programs in the U.S. generally precludes tumor tissue ELISA methods because insufficient tumor tissue is available to produce a cytosol.


   HER-2/NEU STATUS AND THE PREDICTION OF RESPONSE TO TRASTUZUMAB THERAPY
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
Using recombinant technologies, trastuzumab, a monoclonal IgG1 class humanized murine antibody, was developed by the Genentech Corporation to specifically bind the extracellular portion of HER-2/neu. This antibody therapy was initially targeted specifically for patients with advanced relapsed breast cancer that overexpressed the HER-2/neu protein [102]. Since its launch in 1998, trastuzumab has become an important therapeutic option for patients with HER-2/neu-overexpressing breast cancer. Trastuzumab is widely used for its approved indication as a treatment for advanced metastatic disease and is also being studied as an adjuvant treatment for earlier stage disease and in neoadjuvant treatment protocols [103–106]. Using an IHC assay to select patients for the phase III pivot trial, the addition of trastuzumab to chemotherapy (either anthracycline plus cyclophosphamide or taxane) was associated with a longer time to disease progression (median, 7.4 versus 4.6 months, p < 0.001), a higher rate of objective response (50% versus 32%, p < 0.001), a longer duration of response (median, 9.1 versus 6.1 months, p < 0.001), a lower rate of death at 1 year (22% versus 33%, p = 0.008), a longer survival (median survival, 25.1 versus 20.3 months, p = 0.01), and a 20% reduction in the risk of death [107]. Class III or IV cardiac dysfunction occurred in 27% of the anthracycline- and cyclophosphamide-plus-trastuzumab-treated group compared with 8% of the group given an anthracycline and cyclophosphamide alone [107]. Cardiac toxicity has remained a significant limiting factor for the use of trastuzumab since its FDA approval in late 1998 [108]. The best method to identify patients who may respond to trastuzumab therapy has been a source of controversy. The original IHC technique used in the trastuzumab pivot trial was the clinical trial assay (CTA), which consisted of two antibodies: A) 4D5, the monoclonal antibody that is the actual antigen-binding murine component of trastuzumab and is not commercially available, and B) CB-11, a monoclonal antibody directed toward the internal domain of the p185HER2 receptor, which is commercially available both as a research reagent and as an FDA-approved diagnostic (PATHWAYTM). The original CTA was succeeded by the FDA-approved polyclonal HercepTestTM. There is good concordance between the CTA and the HercepTestTM, although 58 of 274 tumors that scored as positive with the CTA were scored as negative with the HercepTestTM, and 59 of 274 tumors that scored as negative with the CTA were scored as positive with the HercepTestTM [109]. After its FDA approval and launch, the HercepTestTM assay was initially criticized for yielding false positive results [110], although better performance was ultimately achieved when the test was performed exactly according to the manufacturer’s instructions. Concern over IHC accuracy using standard formalin-fixed, paraffin-embedded tissue sections [90] has encouraged the use of the FISH assay for its ability to predict trastuzumab response rates. Retrospective studies, reporting that FISH could outperform IHC in predicting trastuzumab response (Fig. 5Go) [111], and well-documented lower response rates of 2+ IHC staining versus 3+ staining tumors [112] have resulted in an approach that either uses IHC as a primary screening tool, with FISH testing of all 2+ cases, or primary FISH-based testing. However, there are currently no published studies describing the response to trastuzumab in patients who were classified for HER-2/neu status by FISH testing alone. Moreover, the original comparison study of IHC and FISH [111] included both 2+ and 3+ cases in the IHC analyses and, when only 3+ IHC cases are evaluated, the response rates to trastuzumab therapy either as a single agent or in combination with cytotoxic drugs in the 3+ IHC group were virtually identical to those seen in the FISH-positive group. In a recently published study where trastuzumab was used as a single agent, the response rate in 111 assessable patients with 3+ IHC staining was 35% and the response rate for 2+ cases was 0%; the response rates in patients with and without HER-2/neu gene amplification detected by FISH were 34% and 7%, respectively [112]. In another study of breast cancer treated with trastuzumab plus paclitaxel, in patients with HER-2/neu-overexpressing tumors, overall response rates ranged from 67%–81% compared with 41%–46% in patients with normal expression of HER-2/neu [113]. The CB11 and TAB250 antibodies for IHC and FISH featured the strongest significance [113]. Interestingly, in a recently published review from New York and Italy, it was noted that, although FISH-based testing is more expensive and not as widely available as IHC, the data suggest that FISH was actually the most cost-effective option [114]. In summary, while the superiority of one method over the other remains controversial [86, 115–117], most laboratories are either screening all cases with IHC and triaging selected cases for FISH testing or using FISH as the only method for HER-2/neu testing. In a recently published consensus statement, the main conclusion was that whatever method was used to test for HER-2/neu status, that technology must be completely validated and backed by a regular internal and external quality control and quality-assurance program [118]. For the laboratories that use IHC as the primary screen, the decision as to when to triage to FISH testing is also controversial. Some laboratories refer only their 2+ IHC cases, some triage 1+ and 2+ cases, and others refer 1+, 2+, and any other cases where the HER-2/neu IHC results are not consistent with other disease parameters such as grade, stage, ploidy, S phase, and hormone-receptor status.



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  		Figure 5. FISH versus IHC and survival in Herceptin® single-agent and combination chemotherapy for advanced metastatic breast cancer. Survival curves demonstrate a significantly (p < 0.05) greater median duration of survival for patients treated with either Herceptin® (H) alone or H plus chemotherapy (CT) in patients whose primary tumors were classified by FISH (PathVysionTM test) for HER-2/neu gene amplification status versus patients who were classified by IHC (Genentech CTA with antibodies 4D5 and CB-11). Data from Genentech Clinical Trial H-0648 cited by Mass R et al. [111].

 

   PREDICTION OF RESPONSE OF BREAST CANCER TO OTHER THERAPIES
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
The best established correlate between HER-2/neu status and nontrastuzumab therapy response is the reported resistance of HER-2/neu-positive patients to hormonal therapy alone [119–122]. Tumors that overexpress HER-2/neu are more likely to be ER– and PR– than tumors that do not show overexpression. In fact, when measured as continuous variables, the expression of HER-2/neu appears to be inversely related to the expression of ER and PR, even in hormone-receptor-positive tumors [123]. In some studies, HER-2/neu-positive tumors were specifically resistant to tamoxifen therapy [56, 68, 71, 75, 124, 125]. However, in other studies, HER-2/neu status failed to predict tamoxifen resistance in ER+ cases [126]. In another study, ER+ HER-2/neu-positive tumors were not only resistant to tamoxifen, but single-agent tamoxifen treatment actually had an adverse impact compared with untreated patients [127]. However, this finding has not, to date, been confirmed by large intergroup studies in the U.S. [128]. Most recently, data from a relatively small study of ER+ HER-2/neu-positive tumors suggested that there was a relatively better response to alternative hormonal therapies, such as an aromatase inhibitor, than to tamoxifen in a neoadjuvant setting [129]. Studies of the association of HER-2/neu protein overexpression with the response of tumors in patients treated with cytoxan, methotrexate, and 5-fluorouracil (CMF) adjuvant chemotherapy [35, 127] and with taxane-based regimens [130–132] have been controversial, with some reports claiming that HER-2/neu status impacted disease outcome while others found no significant differences [133, 134]. However, in another study, HER-2/neu-positive breast cancers were three times more sensitive to paclitaxel [135]. HER-2/neu overexpression has also been associated with enhanced response rates to anthracycline-containing chemotherapy regimens in some, but not all, studies [36, 106, 136–140]. Since anthracyclines are topoisomerase inhibitors and topoisomerase II{alpha} is frequently coamplified with HER-2/neu, it has been suggested that HER-2/neu may be serving as a surrogate marker. Cell lines transfected with HER-2/neu and then exposed to doxorubicin in vitro did not show enhanced sensitivity to the chemotherapy relative to the parent cell lines [141]. However, it was recently shown that HER-2/neu protein expression, but not topoisomerase II{alpha} expression, predicted the response of breast cancer to the antitopoisomerase anthracycline epirubicin [142]. Other studies have consistently linked coexpression and coamplification of the topoisomerase II{alpha} and HER-2/neu genes with adverse prognosis and sensitivity to anthracycline drugs [140, 143–147]. HER-2/neu immunostaining has successfully predicted local recurrence in patients receiving surgery and radiation [148, 149]. In summary, although strong trends have been presented in the published studies, including the resistance to tamoxifen and sensitivity to anthracycline-based regimens for HER-2/neu-positive tumors, more studies are needed using appropriate control arms to confirm these important associations. Should this be accomplished, it would seem likely that HER-2/neu testing, which achieved standard-of-care status in the American Society of Clinical Oncology breast cancer clinical practice guidelines in 2001, would be of even greater value in the management of breast cancer patients.


   SERUM HER-2/NEU ANTIGEN LEVEL AS A TUMOR MARKER
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
Circulating HER-2/neu receptor protein levels have successfully predicted the presence and progression of HER-2/neu-positive breast cancer. In 22 published studies on 4,088 patients, 16 (73%) studies involving 3,458 (85%) of the patients reported a significant correlation between serum HER-2/neu protein levels and either disease recurrence, metastasis, or shortened survival [125, 150–164]. Two studies involving 379 patients reported no significant association between serum level and prognosis [165, 166]. Of the 11 studies in which serum HER-2/neu protein levels were tested for their ability to predict response to therapy, eight (73%) found that elevated serum HER-2/neu protein levels predicted therapy resistance [152, 159–161, 164–166] whereas three other studies did not demonstrate this association [158, 166, 167]. Serum HER-2/neu levels have correlated with lower survival rates and an absence of clinical response to hormonal therapy in ER+ tumors in some studies [125, 164], but not in others [161]. Serum HER-2/neu protein measurements have successfully predicted resistance to high-dose chemotherapy and bone marrow transplantation [159, 160]. Elevated levels of serum extracellular domain have been associated with response to trastuzumab-based therapy [122, 168, 169].


   HER-2/NEU EXPRESSION AND BREAST PATHOLOGY
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
HER-2/neu overexpression has been consistently associated with higher grade and extensive forms of ductal carcinoma in situ [170–172]. HER-2/neu gene amplification occurs at a lower rate (<10%) and has been linked to an adverse outcome [80]. The frequency of HER-2 amplification appears to be strongly correlated with tumor grade and ductal versus lobular status. Only 1 of 73 grade I invasive ductal carcinomas and 1 of 67 classic lobular carcinomas showed amplification of the HER-2/neu gene. HER-2/neu overexpression has been a consistent feature of both mammary and extramammary Paget’s disease [173, 174]. The majority of studies that have compared HER-2/neu status in paired primary and metastatic tumor tissues have found an overwhelming consistency of the patient’s status regardless of the method of testing (IHC versus FISH) [175–180]. In one study of node-positive tumors that were defined as biclonal by DNA ploidy profile, HER-2/neu status was determined by IHC in 17 primary tumors and their 82 axillary lymph node metastases [180]. Despite this apparent heterogeneity of the predominant clone measured by ploidy status, in each metastatic site, the HER-2/neu status was consistent between primary tumors and their corresponding metastases [180]. HER-2/neu amplification and overexpression has been associated with adverse outcome in some studies of male breast carcinoma [181–184], but not in others [185–187]. Finally, low level HER-2/neu overexpression has been identified in benign breast disease biopsies and associated with a greater risk of subsequent invasive breast cancer [188].


   INTERACTION OF HER-2/NEU EXPRESSION WITH OTHER PROGNOSTIC VARIABLES
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
Phosphorylated HER-2/neu...
 Summary
 References
 
HER-2/neu gene amplification and protein overexpression have been associated consistently with high tumor grade, DNA aneuploidy, high cell proliferation rate, negative assays for nuclear protein receptors for estrogen and progesterone, p53 mutation, topoisomerase II{alpha} amplification, and alterations in a variety of other molecular biomarkers of breast cancer invasiveness and metastasis [1,87–88, 189–191].


   PHOSPHORYLATED HER-2/NEU OCPROTEIN AS A POTENTIAL PROGNOSTIC AND PREDICTIVE MARKER
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
Summary
 References
 
It has been argued that one potential confounding aspect of the existing HER-2 tests is that they only detect gene amplification or protein overexpression that does not necessarily reflect the functional activity of the receptor. If HER-2 is truly important in the pathobiology of breast cancer, the receptor must be activated to exert its effects. A common feature of signal transduction through membrane-bound receptor tyrosine kinases is autophosphorylation of the receptor. Autophosphorylation of HER-2, therefore, may be used as a surrogate for active signaling. Monoclonal antibodies have been developed to detect autophosphorylated HER-2 by IHC [192]. In invasive breast cancer with HER-2 overexpression, the receptor appears to be activated only in a small subset (12%) of patients [192, 193]. Interestingly, the proportion of cases with phosphorylated HER-2 appears to be greater (58%) in ductal carcinoma in situ [194]. In one large study of 800 cases of invasive breast cancer with HER-2 overexpression, only cases with phosphorylated HER-2 displayed adverse prognoses [193]. Cases with overexpressed but unphosphorylated receptors had prognoses as favorable as non-HER-2-overexpressing cases, which supports the concept that phosphorylated HER-2 may be a more powerful prognostic marker than overall HER-2 protein overexpression. The role of phosphorylated HER-2 as a predictor of response to trastuzumab therapy is currently unknown. Tissue specimens from the pivotal Herceptin® studies are being reanalyzed to answer this very important question.


   SUMMARY
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
References
 
The testing of newly diagnosed breast cancer specimens for HER-2/neu status has now achieved "standard of practice" status for the management of breast cancer in the U.S. The discussion as to the best method to determine HER-2/neu status in these samples continues, with the FISH method gaining popularity due to the recent evidence that it, in comparison with IHC, may more accurately predict clinical responses to trastuzumab-based therapies. With trastuzumab achieving excellent results in the treatment of HER-2/neu-positive advanced disease and being under extensive evaluation in major clinical trials for its potential efficacy when used earlier, with the potential role for HER-2/neu testing as a predictor of response to other therapies being resolved by large prospective clinical outcome studies, and with the more convenient gene-based CISH technique waiting in the wings, the story of HER-2/neu testing in breast cancer will continue to unfold over the next several years.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 
The authors acknowledge the support of Millennium Pharmaceuticals, Ventana Medical Systems, Tripath Oncology, US Labs, Genentech, and Chromavision.


   REFERENCES
Top
 Learning Objectives
 Abstract
 HER-2/neu Gene (c-erb B-2)
 Expression and Prognosis in...
 HER-2/neu Testing Techniques
 HER-2/neu Status and the...
 Prediction of Response of...
 Serum HER-2/neu Antigen Level...
 HER-2/neu Expression and Breast...
 Interaction of HER-2/neu...
 Phosphorylated HER-2/neu...
 Summary
 References
 

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Standardizing Slide-Based Assays in Breast Cancer: Hormone Receptors, HER2, and Sentinel Lymph Nodes
Clin. Cancer Res., May 15, 2007; 13(10): 2831 - 2835.
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A Di Leo
The state of HER-2 status
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A Goldhirsch, A. Coates, R. Gelber, J. Glick, B Thurlimann, H-J Senn, and On behalf of the St Gallen Expert Panel Members
First--select the target: better choice of adjuvant treatments for breast cancer patients
Ann. Onc., December 1, 2006; 17(12): 1772 - 1776.
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A. Vocaturo, F. Novelli, M. Benevolo, G. Piperno, F. Marandino, A. M. Cianciulli, R. Merola, R. P. Donnorso, I. Sperduti, S. Buglioni, et al.
Chromogenic In Situ Hybridization to Detect HER-2/neu Gene Amplification in Histological and ThinPrep(R)-Processed Breast Cancer Fine-Needle Aspirates: A Sensitive and Practical Method in the Trastuzumab Era
Oncologist, September 1, 2006; 11(8): 878 - 886.
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N. Yaal-Hahoshen, S. Shina, L. Leider-Trejo, I. Barnea, E. L. Shabtai, E. Azenshtein, I. Greenberg, I. Keydar, and A. Ben-Baruch
The Chemokine CCL5 as a Potential Prognostic Factor Predicting Disease Progression in Stage II Breast Cancer Patients
Clin. Cancer Res., August 1, 2006; 12(15): 4474 - 4480.
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M. Tanner, J. Isola, T. Wiklund, B. Erikstein, P. Kellokumpu-Lehtinen, P. Malmstrom, N. Wilking, J. Nilsson, and J. Bergh
Topoisomerase II{alpha} Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline-Based Adjuvant Chemotherapy in HER-2/neu-Amplified Breast Cancer: Scandinavian Breast Group Trial 9401
J. Clin. Oncol., June 1, 2006; 24(16): 2428 - 2436.
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C. Morrison, V. Zanagnolo, N. Ramirez, D. E. Cohn, N. Kelbick, L. Copeland, L. G. Maxwell, and J. M. Fowler
HER-2 Is an Independent Prognostic Factor in Endometrial Cancer: Association With Outcome in a Large Cohort of Surgically Staged Patients
J. Clin. Oncol., May 20, 2006; 24(15): 2376 - 2385.
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W. B. Ershler
Capecitabine monotherapy: safe and effective treatment for metastatic breast cancer.
Oncologist, April 1, 2006; 11(4): 325 - 335.
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G. A. Lazar, W. Dang, S. Karki, O. Vafa, J. S. Peng, L. Hyun, C. Chan, H. S. Chung, A. Eivazi, S. C. Yoder, et al.
Engineered antibody Fc variants with enhanced effector function.
PNAS, March 14, 2006; 103(11): 4005 - 4010.
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P Kauraniemi and A Kallioniemi
Activation of multiple cancer-associated genes at the ERBB2 amplicon in breast cancer.
Endocr. Relat. Cancer, March 1, 2006; 13(1): 39 - 49.
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M. R Kell and C. P Power
Adjuvant trastuzumab for breast cancer: Assessing HER2/neu status incurs more costs for treatment
BMJ, November 19, 2005; 331(7526): 1202 - 1202.
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E. Espinosa, J.A. F. Vara, A. Redondo, J.J. Sanchez, D. Hardisson, P. Zamora, F. G. Pastrana, P. Cejas, B. Martinez, A. Suarez, et al.
Breast Cancer Prognosis Determined by Gene Expression Profiling: A Quantitative Reverse Transcriptase Polymerase Chain Reaction Study
J. Clin. Oncol., October 10, 2005; 23(29): 7278 - 7285.
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A. Goldhirsch, J. H. Glick, R. D. Gelber, A. S. Coates, B. Thurlimann, H.-J. Senn, and and Panel Members
Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005
Ann. Onc., October 1, 2005; 16(10): 1569 - 1583.
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R. J. Gilbertson
ERBB2 in Pediatric Cancer: Innocent Until Proven Guilty
Oncologist, August 1, 2005; 10(7): 508 - 517.
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C. Tse, D. Brault, J. Gligorov, M. Antoine, R. Neumann, J.-P. Lotz, and J. Capeau
Evaluation of the Quantitative Analytical Methods Real-Time PCR for HER-2 Gene Quantification and ELISA of Serum HER-2 Protein and Comparison with Fluorescence in Situ Hybridization and Immunohistochemistry for Determining HER-2 Status in Breast Cancer Patients
Clin. Chem., July 1, 2005; 51(7): 1093 - 1101.
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Y. Ma, L. Lespagnard, V. Durbecq, M. Paesmans, C. Desmedt, M. Gomez-Galdon, I. Veys, F. Cardoso, C. Sotiriou, A. Di Leo, et al.
Polysomy 17 in HER-2/neu Status Elaboration in Breast Cancer: Effect on Daily Practice
Clin. Cancer Res., June 15, 2005; 11(12): 4393 - 4399.
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Z-H Xian, S-H Zhang, W-M Cong, W-Q Wu, and M-C Wu
Overexpression/amplification of HER-2/neu is uncommon in hepatocellular carcinoma
J. Clin. Pathol., May 1, 2005; 58(5): 500 - 503.
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 Cancer Res.Home page
J. M. Lafky, A. T. Baron, E. M. Cora, D. W. Hillman, V. J. Suman, E. A. Perez, J. N. Ingle, and N. J. Maihle
Serum Soluble Epidermal Growth Factor Receptor Concentrations Decrease in Postmenopausal Metastatic Breast Cancer Patients Treated with Letrozole
Cancer Res., April 15, 2005; 65(8): 3059 - 3062.
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P. Carter, L. Smith, and M. Ryan
Identification and validation of cell surface antigens for antibody targeting in oncology
Endocr. Relat. Cancer, December 1, 2004; 11(4): 659 - 687.
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S. Croci, G. Nicoletti, L. Landuzzi, C. De Giovanni, A. Astolfi, C. Marini, E. Di Carlo, P. Musiani, G. Forni, P. Nanni, et al.
Immunological Prevention of a Multigene Cancer Syndrome
Cancer Res., November 15, 2004; 64(22): 8428 - 8434.
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 Clin. Cancer Res.Home page
M. Milella, D. Trisciuoglio, T. Bruno, L. Ciuffreda, M. Mottolese, A. Cianciulli, F. Cognetti, U. Zangemeister-Wittke, D. Del Bufalo, and G. Zupi
Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in HER-2Gene-Amplified Breast Cancer Cells
Clin. Cancer Res., November 15, 2004; 10(22): 7747 - 7756.
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F. F. Solca, A. Baum, E. Langkopf, G. Dahmann, K.-H. Heider, F. Himmelsbach, and J. C. A. van Meel
Inhibition of Epidermal Growth Factor Receptor Activity by Two Pyrimidopyrimidine Derivatives
J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 502 - 509.
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 The OncologistHome page
C. Osborne, P. Wilson, and D. Tripathy
Oncogenes and Tumor Suppressor Genes in Breast Cancer: Potential Diagnostic and Therapeutic Applications
Oncologist, July 1, 2004; 9(4): 361 - 377.
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 JAMAHome page
E. L. Wiley and L. K. Diaz
High-Quality HER-2 Testing: Setting a Standard for Oncologic Biomarker Assessment
JAMA, April 28, 2004; 291(16): 2019 - 2020.
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 Mol. Cell. ProteomicsHome page
J. E. Celis, P. Gromov, T. Cabezon, J. M. A. Moreira, N. Ambartsumian, K. Sandelin, F. Rank, and I. Gromova
Proteomic Characterization of the Interstitial Fluid Perfusing the Breast Tumor Microenvironment: A Novel Resource for Biomarker and Therapeutic Target Discovery
Mol. Cell. Proteomics, April 1, 2004; 3(4): 327 - 344.
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D. Tripathy, D. J. Slamon, M. Cobleigh, A. Arnold, M. Saleh, J. E. Mortimer, M. Murphy, and S. J. Stewart
Safety of Treatment of Metastatic Breast Cancer With Trastuzumab Beyond Disease Progression
J. Clin. Oncol., March 15, 2004; 22(6): 1063 - 1070.
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 Clin. Cancer Res.Home page
D. G. Kirsch and F. H. Hochberg
Targeting HER2 in Brain Metastases from Breast Cancer
Clin. Cancer Res., November 15, 2003; 9(15): 5435 - 5436.
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