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)

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.