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Relationship of Epidermal Growth Factor Receptor Expression to ErbB-2 Signaling Activity and Prognosis in Breast Cancer Patients

From the Department of Internal Medicine, Yale Cancer Center, and Department of Pathology, Yale University School of Medicine, New Haven, CT; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK; and Geraldine Brush Cancer Research Center, California Pacific Medical Center, San Francisco, CA

Address reprint requests to Ann D. Thor, MD, Department of Pathology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd, Rm 451 BMSB, Oklahoma City, OK 73104; e-mail: ann-thor{at}ouhsc.edu

PURPOSE: To examine the relationship of epidermal growth factor receptor (EGFR) expression to ErbB-2 signaling activity in breast cancer and the impact that this interaction has on the prognosis of patients with early-stage breast cancer.

PATIENTS AND METHODS: Paraffin tumor sections were collected retrospectively from 807 breast cancer patients diagnosed between 1976 and 1983. Immunohistochemical assays for ErbB-2, phosphorylated (activated) ErbB-2, and EGFR were performed, and the results were correlated with clinicopathologic variables and outcome.

RESULTS: EGFR expression was detectable in 15% of 807 invasive breast cancers, including 35% of the 306 ErbB-2–positive patients. Conversely, the majority (87%) of EGFR-positive tumors co-overexpressed ErbB-2. Ninety-seven percent of tumors with phosphorylated ErbB-2 co-overexpressed EGFR. Patients whose cancers demonstrated ErbB-2 phosphorylation or co-overexpression of ErbB-2 and EGFR had the shortest survival. In contrast, patients whose tumors were negative for all three markers and those tumors that expressed only EGFR or only nonphosphorylated ErbB-2 had a relatively favorable outcome.

CONCLUSION: These data provide the first clinical evidence that EGFR expression is linked to activation of ErbB-2 in human breast cancers. We have further shown that the adverse prognostic value of ErbB-2 overexpression is observed only when ErbB-2 is in the phosphorylated (activated) state or coexpressed with EGFR. These data suggest that ligand-dependent mechanisms of ErbB-2 activation are important in human breast cancer. These results also suggest that agents targeting EGFR may be useful in the treatment of tumors with activated ErbB-2.

Supported by grant No. RO1CA82848 (A.D.T. and D.F.S.) from the US Public Health Service/National Cancer Institute, and grant Nos. DAMD17-97-1-7065 and R01CA45708 (M.P.D.) from the US Army Medical Research and Materiel Command Congressionally Directed Medical Research Programs.

D.F.S. and M.P.D. have a financial interest in antibody PN2A, and D.F.S. holds intellectual property relevant to phosphor-specific antibodies.

M.P.D. and D.F.S. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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