| Popis |
Background: The overexpression of HER-2 (c-erbB2/Neu) in breast cancer is associated with poor prognosis, tumor recurrence and shortened survival. The administration of the trastuzumab significantly improves patients prognosis. However, in spite of these successful results, trastuzumab is effective only in 20-40% of cases. PI3K/Akt and Ras/MAPK signaling pathways are activated through HER-2 receptor and both play important role in tumor behavior. Methods: The study included 76 women with verified Her-2+ metastatic breast cancer (MBC) who were treated with trastuzumab based palliative chemotherapy. Immunohistochemistry was performed on formalin fixed, paraffin embedded tissue sections with antibodies against Akt-1, Akt-2, phospho(p)-Akt-Ser-473 and p-Akt-Thr-308, PTEN, S6K, p-S6K- Ser235/236, MAPK, p-MAPK-Thr202/Tyr204. Except PTEN, the cytoplasmatic and nuclear fractions were assessed separately. Results: Patients whose tumors showed high Akt-2 expression (> 80% positive cells) accompanied with nuclear and cytoplasmatic (n+c) positivity of a) p-Akt-473, b) p-Akt-308, c) or both p-Akts (p-Akt-473/308) exhibited improved TTP compared to those with any Akt-2 expression, but negative for nuclear staining of any p-Akt: a) TTP (13.1 vs 7.6 months; P<0.018, Hazard Ratio 2.09, CI95% 1.13- 3.5; b) TTP (17.1 vs 7.6 months; P<0.007, Hazard Ratio 2.41, CI95% 1.25-4.0; c) TTP (13.1 vs 7.6 months; P<0.028, Hazard Ratio 1.9, CI95% 1.12-3.49. Of the remaining results, only S6K kinase had significant impact on TTP. Activation of S6K was associated with shorter TTP. Median follow-up was 9.2 months. Conclusions: This study was the first to prove that prediction of the response to trastuzumab treatment depends on the Akt kinase iso-form, activity and compartmentalization. Patients, whose tumors had high level of Akt-2 and concurrent nuclear and cytoplasmatic presence of the activated forms of Akt kinase, had greater benefit from trastuzumab based therapy. In contrast, activation of S6K was associated with worse prognosis. Supported by the Internal Grant Agency of Ministry of Health, Czech Republic, No.NR/8335-3.
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