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Activation (Tyrosine Phosphorylation) of ErbB-2 (HER-2/neu): A Study of Incidence and Correlation With Outcome in Breast Cancer

From the Evanston Hospital/Northwestern University, Evanston, IL; California Pacific Medical Center, University of California at San Francisco, and University of California at San Francisco Medical Center, San Francisco, CA; and Yale University School of Medicine, New Haven, CT.

Address reprint requests to A.D. Thor, MD, Department of Pathology, Evanston Hospital, 2650 Ridge Ave, Evanston, IL 60201; email a-thor{at}nwu.edu

PURPOSE: We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples.

MATERIALS AND METHODS: Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables.

RESULTS: Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2–negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2–positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high ( 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2–positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup.

CONCLUSION: PN2A immunostaining identified a subset (approximately 12% of ErbB-2–positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression ( 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.

D.F.S. has negotiated with a diagnostic company regarding the licensing of the antibody PN2A.

The content of the information contained herein does not necessarily reflect the position or the policy of the United States Government, and no official endorsement should be inferred.

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

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