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Publication:

Her-2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab-based therapy in patients with metastatic breast cancer (2006)

Author(s): Hudelist G, Kostler WJ, Czerwenka K, Kubista E, Attems J, Muller R, Gschwantler-Kaulich D, Manavi M, Huber I, Hoschutzky H, Zielinski CC, Singer CF

    Abstract: Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin(R)) has become a valuable therapeutic option for patients with Her-2/neu-overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu-overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p = 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR = 8.0, p = 0.021 and OR = 8.0, p = 0.021) and clinical benefit (OR = 5.47, p = 0.041 and OR = 6.22, p = 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR = 0.21, p = 0.01 and RR = 0.45, p = 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR = 0.17, p = 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy.

    Notes: Hudelist, Gernot Kostler, Wolfgang J Czerwenka, Klaus Kubista, Ernst Attems, Johannes Muller, Ruth Gschwantler-Kaulich, Daphne Manavi, Mahmood Huber, Isabell Hoschutzky, Heinz Zielinski, Christoph C Singer, Christian F Clinical Trial United States International journal of cancer. Journal international du cancer Int J Cancer. 2006 Mar 1;118(5):1126-34.

      • Date: 01-03-2006
      • Journal: International Journal of Cancer
      • Volume: 118
      • Issue: 5
      • Pages: 1126-1134
      • Publisher: John Wiley & Sons, Inc.
      • Publication type: Article
      • Bibliographic status: Published

      Keywords: Adult Aged Aged, 80 and over Antibodies, Monoclonal/immunology/*therapeutic use Antibody Specificity Breast Neoplasms/*drug therapy/enzymology/immunology/*pathology Disease Progression Enzyme Activation/drug effects Gene Expression Regulation, Neoplastic Humans Immunotherapy Middle Aged Neoplasm Metastasis/drug therapy/*pathology Peptides/immunology/pharmacology Phosphotyrosine/metabolism Prognosis Receptor, Epidermal Growth Factor/*metabolism Receptor, erbB-2/*metabolism Survival Rate

      Staff

      Dr Johannes Attems
      Reader in Neurodegenerative Pathology