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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4423-4430 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.0973 Human Epidermal Growth Factor Receptor 2 Status Correlates With Lymph Node Involvement in Patients With Estrogen Receptor (ER) –Negative, but With Grade in Those With ER-Positive Early-Stage Breast Cancer Suitable for Cytotoxic Chemotherapy
From the Endocrine Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital; Department of Oncology, Western General Hospital, Lothian University Hospitals Trust, Edinburgh; Molecular Medical Sciences, Department of Histopathology, University of Nottingham, Nottingham City Hospital, Nottingham; Department of Pathology, Western Infirmary, Glasgow; Department of Medicine, Breast Unit, Royal Marsden Hospital, London; Section of Clinical Trials—The Institute of Cancer Research Section of Clinical Trials Clinical Trials & Statistics Unit, Sutton, Surrey; Velindre National Health Service Trust, Whitchurch, Cardiff; and the Guys & St Thomas Hospital NHS Trust, London, United Kingdom Address reprint requests to John Bartlett, PhD, Endocrine Cancer Research Group, Edinburgh University Cancer Research Centre, Western General Hospital, Crewe Rd South, Edinburgh, EH4 2XR United Kingdom; e-mail: John.Bartlett{at}ed.ac.uk
Purpose Human epidermal growth factor receptor 2 (HER-2) expression is associated with increased risk of high-grade disease, nodal metastasis, and absence of estrogen receptors (ERs) in early breast cancer. We tested interactions between ER and HER-2 to determine if they may modulate breast cancer nodal metastasis and proliferation. Patients and Methods Tumors from the Cancer Research UK Taxotere as Adjuvant Chemotherapy phase III trial were tested for HER-2 using current diagnostic procedures. ER status, progesterone status, clinicopathologic characteristics, and patient age were included in a logistic regression analysis to identify associations with HER-2 status (positive v negative). Results A total of 841 (23.6%) of 3,565 samples were HER-2 positive (3+ by immunohistochemistry or positive by fluorescent in situ hybridization). ER-negative tumors were more likely to be HER-2 positive than were ER-positive tumors (odds ratio [OR] = 1.87, ER negative v ER positive; P < .001). For ER-positive tumors, risk of HER-2 positivity increased by grade (OR = 7.6, grade 3 v grade 1; P < .001) but not nodal status (OR = 1.3, four or more positive nodes v node negative; P = .08). Conversely, ER negative node-positive tumors were markedly more frequently HER-2 positive than node-negative cases (OR = 3.05, four or more positive nodes v node negative; P < .001) but independent of grade (OR = 0.82, grade 3 v grade 1; P = .76). Conclusion In early breast cancer patients selected for cytotoxic chemotherapy, we identified significant interactions between HER-2 and ER expression that correlate with tumor pathology. In ER-positive breast cancers, HER-2 expression correlates with grade, not nodal metastasis. In ER-negative breast cancers, HER-2 expression correlates with increased nodal positivity, not grade. ER and HER-2 expression may modify tumor pathology via ER/HER-2–mediated cross talk.
Interaction between the cell surface receptor tyrosine kinase human epidermal growth factor receptor 2 (HER-2) and the nuclear estrogen receptor (ER) is a critical pathway in hormone receptor–positive breast cancer.1-5 Modulation of ER function by HER-2 is believed to be a central mechanism underlying endocrine or tamoxifen resistance in breast cancer, and a key cause of tamoxifen failure in ER-positive tumors.2,3 The HER-2 oncogene is also implicated in resistance to anthracycline, taxane, and other chemotherapeutic agents.6-8 Recent evidence suggests interaction between HER-2 and ER may underpin a significant proportion of the effects of HER-2 gene amplification on outcome in breast cancer.5,9 HER-2 activates intracellular signaling cascades,10,11 which directly or indirectly lead to post-translational modification of the ER and its coactivators and repressors.3,12-14 In normal breast epithelium these pathways probably potentiate estrogenic effects, promoting normal cellular development. In breast cancers, HER-2 activation leads to a chronic activation of ER in the presence of low estrogen concentrations, leading to proliferation and tumor growth.3,5,15 Other members of the HER family also promote tamoxifen resistance5,16 and modify ER function.3,17 ER does not act passively in this pathway: it both activates intracellular signaling potentiating HER-2 activity18-21 and downregulates HER-2 expression.22,23 In HER-2–amplified breast cancers, this negative feedback loop is probably overcome by marked overexpression of HER-2 protein. HER-2 gene amplification is associated with increased tumor proliferation,16,24,25 which may, in part, explain the relationship between HER-2 and tumor pathology. HER-2 amplification is linked to high-grade disease, nodal metastases, tumor size, and differing pathologic subtypes,26-28 and is inversely correlated with ER status.27,28 The impact of HER-2 on proliferation, mediated predominantly via the RAS/MAPK cascade, may explain, in part, the relationship between gene amplification, differentiation (reflected in tumor grade), and tumor size.2,28,29 The relationship between HER-2 status and nodal status has been linked to AKT/PI3Kinase pathway activation and increased cell migration.30-32 Thus, despite the pluripotent activities of HER-2, one could hypothesize that interactions between HER-2 and different signaling pathways may result in quite distinct clinicopathologic entities. Cellular migration is regulated in a fashion discrete from the action of HER-2 on proliferation, and it is possible that activation of these distinct pathways may not be synchronous. Evidence for this hypothesis can be sought from clinical material, seeking evidence of switching of HER-2 function between pathways regulating proliferation and migration. If confirmed, it would suggest that the function of the HER-2 oncogene may be altered by other intracellular pathways. This study sought and found such evidence in clinical breast cancers, and suggests that ER can act as the switch between these two key HER-2–mediated activities.
The Taxotere As Adjuvant Chemotherapy Trial The Taxotere As Adjuvant Chemotherapy Trial (TACT; ISRCTN 79718493)33 compares the sequence of four cycles of docetaxel after four cycles of standard fluorouracil, epirubicin, and cyclophosphamide versus eight cycles of anthracycline-based chemotherapy in women with early breast cancer. Two anthracycline-containing regimens were allowed: four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil,34 or eight cycles of fluorouracil, epirubicin, and cyclophosphamide. The trial protocol was assessed and accepted by the local ethics committee for each participating institution, and all patients provided written, signed, informed consent before random assignment. Between February 2001 and June 2003, 4,162 patients with histologically confirmed, completely resected, invasive breast cancer, including axially clearance, for whom adjuvant chemotherapy was indicated, were randomly assigned onto the study.33 Prospective written consent was obtained from 4,020 (97%) of 4,124 patients from the United Kingdom to collect tissue, and 3,565 samples were collected and tested for HER-2 status in Glasgow, Nottingham, or London.35,36 Data collected from referring pathology laboratories by the coordinating trials office were provided for this analysis without linking to individual outcome data. Given that HER-2 testing was rarely performed at diagnosis during the period of recruitment, few patients would have been selected for adjuvant therapy on this basis.
Tissue Collection
Analysis of HER-2 Status
Immunohistochemistry
FISH
Statistics
Patient and tumor characteristics are presented by HER-2 status. Logistic regression was used to identify associations with HER-2 status (positive v negative) and these characteristics. Associations are presented as odds ratios and 95% CIs. Stepwise multiple logistic regression analyses were carried out using a 5% significance level to determine independent factors for prediction of HER-2 status (positive v negative). All available data were considered in the logistic regression analyses, including age (< 40, 40 to 49, 50 to 59, and The large size of this study gave sufficient statistical power to detect small associations (eg, differences in rates of the order of 6% or more with 90% power when comparing two groups of size 1,300 each). Caution was used in the interpretation of statistically significant numerically small differences that may have limited clinical or biologic significance.
Tumor Pathology HER-2 status based on IHC and/or FISH results was available for 3,565 of 4,124 TACT Trial patients (Table 1). The main reasons for missing results were pathologist did not send block (n = 455) or patient refused consent (n = 104). Of 3,565 tumor samples analyzed, 2,999 (84.1%) were invasive ductal carcinomas, 348 (9.8%) were invasive lobular carcinomas, 111 (3.1%) were mixed invasive ductal/lobular carcinomas, and 107 (3.0%) were other types. Most patients with known HER-2 status were node positive; there were just more than 20% node-negative patients. Just more than half of all patients had grade 3 tumors (56.6%) but 194 (5.4%) grade 1 tumors were included. Median tumor size was 2.5 cm; less than 10% of tumors were more than 5 cm in diameter. Median patient age at diagnosis was 49 years, with 609 patients recruited younger than age 40 years.
The main clinical and pathologic features of the trial and study subsets were almost identical: respectively, 80% and 79% of patients were node positive; in both the trial and study subsets, 57% were grade 3, 69% were ER positive, median tumor size was 2.5 cm, and median age was 49 years.
ER and PgR Expression
HER-2 Expression
Relationship Between HER-2 Status and Clinical and Pathologic Variables
Patients with four or more positive nodes were at significantly greater risk of being HER-2 positive (odds ratio, 1.43; 95% CI, 1.15 to 1.78; P < .001), although those with one to three positive nodes did not appear to have a markedly increased chance of being HER-2 positive. Grade 3 tumors were approximately twice as likely to be HER-2 positive when compared with grade 2 tumors, and almost five-fold more likely to be HER-2 positive than grade 1 tumors (P < .0001 for both comparisons). Increasing tumor size (assessed as a categoric variable) was statistically significantly associated with increased frequency of HER-2 positivity for tumors between 2 and 5 cm (odds ratio, 1.33; 95% CI, 1.12 to 1.58; Fig 1A), and for tumors more than 5 cm in diameter (odds ratio, 1.60; 95% CI, 1.21 to 2.12; P = .001 for both comparisons). Tumors of ductal histologic type were more frequently HER-2 positive than those of other pathologic types, including mixed ductal/lobular or lobular type (Fig 1B). There was no evidence that age as a continuous variable was associated with the risk of tumor HER-2 positivity, but when dichotomized at a cut point of 40 years, younger women had a higher rate of HER-2 positivity.
Multivariate Logistic Regression Analysis ER status seemed to be related to age and risk of HER-2 positivity (Fig 1C). For ER-negative tumors, there was no significant change in HER-2 positivity with age; for ER positive tumors, patients older than age 40 years were 0.57 times (95% CI, 0.45 to 0.73 times) less likely to be HER-2 positive than patients younger than age 40 years. Therefore the trend (Table 1) is due to the association in the ER-positive cases.
Interacting Factors Relative to ER Status
For ER-positive tumors, the relative risk of HER-2 positivity seems to increase by grade independent of nodal status (Fig 2A), with no significant increase in frequency of HER-2 positivity between node-negative and node-positive patients, even for those with more than four positive nodes. The predicted frequency of HER-2 positivity in grade 3 ER-positive tumors (25.1% to 30.7%) was almost double that of grade 2 tumors (12.2% to 16.3%) and almost six-fold higher than that predicted in the small number of ER-positive G1 tumors (4.1% to 5.4%). For ER-negative tumors, these relationships appeared to be reversed (Fig 2B). ER-negative node-positive tumors were markedly more frequently HER-2 positive than tumors in node-negative patients independent of tumor grade. ER-negative tumors presenting with more than four positive nodes were predicted to be more likely to be HER-2 positive (44.5% to 49.6%) than those presenting with one to three positive nodes (31.1% to 35.5%) or no positive nodes (20.8% to 24.4%; Table 3).
This study suggests, for the first time to our knowledge, that the impact of overexpression of the HER-2 oncogene on classical pathologic features may be influenced by tumor ER expression. In ER-positive breast cancers, HER-2 overexpression is associated significantly with increased histologic tumor grade, but not the extent of ipsilateral axillary lymph node involvement. In contrast, in ER-negative breast cancer, HER-2 overexpression is associated with increased lymph node involvement but does not seem to influence primary tumor grade (Fig 2A; Table 3). This study was undertaken in early breast cancers selected for cytotoxic chemotherapy, and it would be interesting to investigate this relationship more widely in other patient groups. As reported previously,28 univariate analysis reveals a correlation between increasing tumor grade, increasing size, increasing nodal status, tumor type, patient age, and increased risk of HER-2 positivity (Fig 1). In multivariate analysis there is also evidence suggesting an interaction between ER and HER-2, and histopathologic features. Multivariate analysis provided a powerful tool for the investigation of observed interactions between ER status, HER-2 status and nodal status, grade, and patient age. However, it should be remembered that this study had high power to detect small statistically significant differences. These data suggest that the risk of nodal metastases among HER-2–positive breast cancers is associated with ER status, and may indicate different biologic roles for HER-2 in ER-positive and ER-negative cancers. One caveat worth noting is that this study is based on analysis of locally determined ER/PgR status. Although the quality of local ER testing has been open to question,41 recent data42,43 suggest a high degree of concordance between local and central ER testing. Although it is important that this study be repeated using centrally evaluated hormone receptors, the current observations are based on the most optimal data available to us. The strong association between ER and PgR status, in patients for whom both variables were reported, makes it difficult to distinguish between them as predictors of HER-2 status. These data suggest an additional level of complexity underlying our previously reported analysis in this patient group,28 and may indicate that the relationship between HER-2 and ER expression has functional consequences for clinical tumor biology. This study suggests the hypothesis that the inter-relationship between HER-2 and ER acts as a functional switch to promote either tumor proliferation or cellular migration/metastasis, resulting in the differences observed in the presenting pathology of these molecular subtypes of breast cancer. Gene amplification of the HER-2 oncogene is an early event in breast cancers and is linked to increased proliferation and cell migration.16,24,25,44-48 HER-2 amplification alone seems insufficient to promote invasion, given that studies of ductal carcinoma in situ show no link between HER-2 expression and invasion.46 Once the breast duct basement membrane is breached, however, the resultant invasive tumor is highly proliferative and susceptible to rapid spread, as shown by the association among HER-2 overexpression and high tumor grade, proliferative index, and increased frequency of node positivity.16,26-28 Recent data suggest that tumor proliferation and migration depend on distinct intracellular signaling pathways.2,28-32 Our data confirm previous reports that HER-2 overexpression in breast cancer is associated with ER-negative and PgR-negative disease.28,49-51 We also confirm that invasive lobular cancers infrequently overexpress HER-2.52 However, the frequency of HER-2 positivity in this group was not sufficiently low to exclude them from HER-2 screening, as previously suggested.53 Tumors of low grade, low stage, and small size, as well of those from elderly patients, are at reduced risk of HER-2 expression if they are ER positive.28 Nonetheless, combining pathologic characteristics, even with ER status, did not provide a sufficiently powerful tool for the prediction of HER-2 overexpression. Receiver operating characteristic analysis of factors within this population could not provide a strong predictor of HER-2 positivity. In no pathologically identifiable tumor group was the frequency of HER-2 expression sufficiently low as to preclude assessment of these patients for potential treatment with adjuvant trastuzumab, nor has it been possible to link these factors to potential trastuzumab response. Despite the size of this study, with centralized testing of all patients, we are unable to recommend the exclusion of any patients from testing for HER-2 on the basis of clinicopathologic correlates. Our data are consistent with previous reports that HER-2 status is related to tumor size, nodal status, grade, pathologic type, patient age, and hormone receptor status.28 However, we also identified a significant interaction between HER-2 and ER expression with respect to nodal status. In ER-positive breast cancers, HER-2 expression is associated with increased tumor grade but not nodal metastasis. Conversely, in ER-negative breast cancers, HER-2 expression is associated with increased nodal status but not increased grade. ER could therefore modify the effect of HER-2 expression on breast tumor pathology presumably via ER/HER-2–mediated cross talk. A number of potential pathways that mediate this effect are known and additional research may provide insight into the potential for this interaction to function as a therapeutic target. Confirmation of this hypothesis would provide additional evidence to support the segregation of breast cancers into multiple subgroups, based on both HER-2 and ER expression, and suggest potential targets for future interventions in these different subgroups.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: John M.S. Bartlett, Dako, Denmark, Abbott Vysis, Roche, Pfizer; Ian Ellis, Dako; Mitch Dowsett, Pfizer, Roche; David Cameron, Aventis, Pfizer, Roche; Paul Ellis, Sanofi Aventis, Pfizer Stock: N/A Honoraria: John M.S. Bartlett, Pfizer, Roche, Dako; David A. Cameron, Aventis, Pfizer, Roche; Judith M. Bliss, Pfizer; Peter Barrett-Lee, Aventis, Pfizer, Roche; Paul Ellis, Sanofi Aventis Research Funds: John M.S. Bartlett, Roche; Ian Ellis, Roche; Mitch Dowsett, Roche; Clare Peckitt, Pfizer, Roche, Aventis; Judith M. Bliss, Pfizer, Roche, Aventis Testimony: N/A Other: Judith M. Bliss, Pfizer
Conception and design: John M.S. Bartlett, Ian O. Ellis, Mitch Dowsett, David A. Cameron, Emma Hall, Judith M. Bliss, Paul Ellis Administrative support: John M.S. Bartlett, Lindsay Johnson Provision of study materials or patients: Ian O. Ellis, David A. Cameron, Stephen Johnston, Peter Barrett-Lee, Paul Ellis Collection and assembly of data: John M.S. Bartlett, Ian O. Ellis, Mitch Dowsett, Elizabeth A. Mallon, Lindsay Johnson, Paul Ellis Data analysis and interpretation: John M.S. Bartlett, Roger A'Hern, Clare Peckitt, Judith M. Bliss Manuscript writing: John M.S. Bartlett, Ian O. Ellis, David A. Cameron, Clare Peckitt, Judith M. Bliss, Lindsay Johnson Final approval of manuscript: John M.S. Bartlett, Ian O. Ellis, Mitch Dowsett, Elizabeth A. Mallon, David A. Cameron, Stephen Johnston, Emma Hall, Roger A'Hern, Clare Peckitt, Judith M. Bliss, Lindsay Johnson, Peter Barrett-Lee, Paul Ellis Other: Emma Hall [Oversight of data cleaning and statistical analysis]
We thank the TACT Trial Management Group, supporting oncologists, pathologists, and patients who kindly agreed to enter the TACT trial.
Supported by Cancer Research UK and educational grants from Aventis, Roche, and Pharmacia Upjohn. Storage, construction of microarrays, and tissue HER-2 testing was funded by an educational grant from Roche. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2.0).
