Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC)

Giuliani, Rosa;Durbecq, Virginie;Di Leo, Angelo;Paesmans, Marianne;Cardoso, Fatima;et.al.
(2007) European Journal of Cancer — Vol. 43, n° 4, p. 725-735 (2007)

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Authors
  • Giuliani, Rosa
    Author
  • Durbecq, Virginie
    Author
  • Di Leo, Angelo
    Author
  • Paesmans, Marianne
    Author
  • D'Hondt, VéroniqueUCLouvain
    Author
  • Cardoso, Fatima
    Author
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Abstract
Aim: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T. (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. Methods: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. Results: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2 -> p-MAPKs. Conclusions: p-HER-2 and the magnitude of HeT-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials. (c) 2006 Elsevier Ltd. All rights reserved.
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Giuliani, R., Durbecq, V., Di Leo, A., Paesmans, M., Larsimont, D., Leroy, J.-Y., Borms, M., Vindeuoghel, A., Jerusalem, G., D’Hondt, V., Dirix, L., Canon, J.-L., Richard, V., Cocquyt, V., Majois, F., Reginster, M., Demol, J., Kains, J.-P., Delree, P., et al. (2007). Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC). European Journal of Cancer, 43(4), 725-735. https://doi.org/10.1016/j.ejca.2006.11.019 (Original work published 2007)