Originally published as JCO Early Release 10.1200/JCO.2007.13.6580 on April 7 2008

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Influence of Activation State of ErbB-2 (HER-2) on Response to Adjuvant Cyclophosphamide, Doxorubicin, and Fluorouracil for Stage II, Node-Positive Breast Cancer: Study 8541 From the Cancer and Leukemia Group B

Michael P. DiGiovanna, David F. Stern, Susan Edgerton, Gloria Broadwater, Lynn G. Dressler, Daniel R. Budman, I. Craig Henderson, Larry Norton, Edison T. Liu, Hyman B. Muss, Donald A. Berry, Daniel F. Hayes, Ann D. Thor

From the Yale University School of Medicine and Yale Comprehensive Cancer Center, New Haven, CT; University of Colorado Health Sciences Center, Denver, CO; Duke University Medical Center, Durham; University of North Carolina, Chapel Hill, NC; Monter Cancer Center of North Shore University Hospital, Lake Success; Memorial Sloan-Kettering Cancer Center, New York, NY; University of California San Francisco, CA; University of Vermont, Burlington, VT; University of Texas M.D. Anderson Cancer Center, Houston TX; University of Michigan Medical Center, Ann Arbor MI; and the Genome Institute of Singapore, Singapore

Corresponding author: Michael P. DiGiovanna, MD, PhD, Yale University School of Medicine, Section of Medical Oncology, 333 Cedar St, Room WWW 217, New Haven, CT 06510; e-mail: michael.digiovanna{at}yale.edu

Purpose: ErbB-2 (human epidermal growth factor receptor 2) overexpression may be predictive of relative resistance and/or sensitivity to specific chemotherapeutic agents. Results from a previous study from the Cancer and Leukemia Group B (CALGB 8541) demonstrated an interaction between ErbB-2 and increasing dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Other studies have suggested that evaluation of the phosphorylated/activated form of ErbB-2 might be more precise in defining the impact of ErbB-2 in breast cancer. We have evaluated tumor tissue sections from CALGB 8541 patients to determine whether the interaction of ErbB-2 with CAF dose is dependent on ErbB-2 activation state, and whether phosphorylated ErbB-2 is an adverse prognostic factor in patients treated with CAF.

Patients and Methods: Patients were randomly assigned to one of three dosing regimens of CAF. Paraffin samples from 992 of 1,572 patients who participated in CALGB 8541 were available. Of the 570 tumors with any staining for ErbB-2, 488 had tissue available for assay for phosphorylated ErbB-2, which was performed by immunohistochemistry.

Results: Of 910 total assessable cases, 112 of 488 ErbB-2-positive cases (23%) stained positively for phosphorylated ErbB-2. The previously described interaction of dosing regimen of CAF with ErbB-2 was not dependent on phosphorylation status of ErbB-2.

Conclusion: Monitoring phosphorylation of ErbB-2 with an antiphospho-ErbB-2 antibody did not add further precision to identifying those patients most likely to benefit from increased dose of anthracycline-based adjuvant chemotherapy. Favorable outcomes are observed in ErbB-2-overexpressing patients treated with high-dose CAF regardless of ErbB-2 phosphorylation state.

published online ahead of print at www.jco.org on April 7, 2008

Cancer and Leukemia Group B (CALGB) 8541 was supported, in part, by grants from the National Cancer Institute (CA31946) to the CALGB (Richard L. Schilsky) the CALGB Statistical Center (Stephen George, CA33601), CA77651 (G.B.), CA47559 (L.G.D.), CA35279 (D.R.B.), CA60138 (L.C.H.), CA77651 (L.N.), and CA77406 (H.B.M.); by UO1CA64507 (D.F.H.) and UO1CA64061 (E.T.L., L.G.D.); RO1CA45708 (D.F.S.); DAMD17-97-1-7065 from the Department of Defense (M.P.D.); and the Fashion Footwear Association of New York/QVC Presents Shoes on Sale (D.F.H.). A complete list of participating institutions appears in the online-only Appendix.

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

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

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