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Prognostic and Predictive Significance of ErbB-2 Breast Tumor Levels Measured by Enzyme Immunoassay

From the Stiftung Tumorbank Basel, Departments of Research, Gynecology, and Surgery, University Clinics, Kantonsspital, Basel; Department of Gynecology and Institute for Clinical Pathology, University Hospital, Zurich; Pathology Institute Triemli, Zurich, and Kantonsspital, Baden, Switzerland; Department of Medicine, University of California at San Francisco, San Francisco, CA; and Breast Cancer Center, Rheinfelden, Germany.

Address reprint requests to Urs Eppenberger, PhD, MD, Stiftung Tumorbank Basel, University Women’s Clinic, Kantonsspital Basel, Schanzenstrasse 46, CH-4031 Basel, Switzerland; email: urs-sere.eppenberger{at}unibas.ch

PURPOSE: A retrospective analysis to assess the prognostic and predictive clinical value of breast tumor ErbB-2 receptor expression quantified by enzyme immunoassay (EIA), to compare levels measured by EIA with ErbB-2 status determined by immunohistochemistry (IHC), and to correlate receptor content with levels of phosphorylated (Y1248-P) ErbB-2, a measure of functional tyrosine kinase activity.

MATERIALS AND METHODS: EIA quantification of ErbB-2 was performed on membrane extracts from 3,208 well-characterized primary breast cancers. Overall, relapse-free, distant disease-free, and local/regional-free patient survival data were available on 1,123 of these tumors. IHC scoring for ErbB-2 status (HercepTest; DAKO, Glostrup, Denmark) was performed on adjacent sections of 151 cases, and receptor functionality was measured in 230 tumors by an antibody specific for phosphorylated (Y1248-P) ErbB-2.

RESULTS: Unlike nonmalignant breast tissues, breast tumors showed increased ErbB-2 levels in a bimodal distribution, with 12% constituting a distinct set of ErbB-2–overexpressing tumors. The intermodal threshold value for ErbB-2 overexpression distinguished tumors with reduced estrogen and progesterone receptor content, high IHC score for ErbB-2, and significantly increased levels of phosphorylated (Y1248-P) ErbB-2 receptor. By multivariate analysis, EIA-determined ErbB-2 overexpression predicted significantly reduced patient survival that was unaffected by tamoxifen or cyclophosphamide, methotrexate, and fluorouracil adjuvant therapy.

CONCLUSION: Determination of ErbB-2 receptor expression by EIA offers a clinically valuable alternative to semiquantitative IHC assessment of breast tumor ErbB-2 overexpression and affords the opportunity to evaluate ErbB-2 phosphorylation, which may represent an important predictive parameter of receptor functionality.

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