Significance of Akt activation and compartmentalization for prediction of outcome in Her-2 positive breast cancer patients treated with trastuzumab.

SVOBODA, Marek, Peter GRELL, Pavel FABIAN, Lenka RADOVÁ, Markéta PALÁCOVÁ, Rudolf NENUTIL a Rostislav VYZULA. Significance of Akt activation and compartmentalization for prediction of outcome in Her-2 positive breast cancer patients treated with trastuzumab. Breast Cancer Research and Treatment. Nizozemí: Springer, 2007, roč. 106, Supp 1, s. S173, 1 s. ISSN 0167-6806.

Základní údaje

• Originální název: Significance of Akt activation and compartmentalization for prediction of outcome in Her-2 positive breast cancer patients treated with trastuzumab.
• Název česky: Význam aktivace a kompartmentalizace Akt kinasy pro predikci vývoje onemocnění u pacientek s Her-2 pozitivním karcinomem prsu.
• Autoři: SVOBODA, Marek, Peter GRELL, Pavel FABIAN, Lenka RADOVÁ, Markéta PALÁCOVÁ, Rudolf NENUTIL a Rostislav VYZULA.
• Vydání: Breast Cancer Research and Treatment, Nizozemí, Springer, 2007, 0167-6806.

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Článek v odborném periodiku
• Obor: 30200 3.2 Clinical medicine
• Stát vydavatele: Nizozemské království
• Utajení: není předmětem státního či obchodního tajemství
• Impakt faktor: Impact factor: 4.453
• Organizační jednotka: Lékařská fakulta
• UT WoS: 000251398500480
• Klíčová slova anglicky: Akt;trastuzumab;prediction;breast cancer
• Štítky: Akt, breast cancer, Prediction, trastuzumab
• Příznaky: Mezinárodní význam, Recenzováno

Anotace

Introduction: Breast carcinomas with overexpression of Her-2 receptor (Her-2+) have an unfavourable prognosis, but the application of the trastuzumab increases the patients survival in both palliative and adjuvant treatments. However, in spite of these successful results, trastuzumab is only effective in 2040% of cases. Akt, a serine/threonine kinase, is the key molecule of the phosphatidylinositol 3-kinase signaling pathway. Akt gets activated at the Thr-308 and Ser-473 residues in response to the growth factor and cytokine receptors stimulation and Her-2 receptor activation. Depending on the Akt isoforms and subcellular localization, the activated Akt accounts for variety of cellular reactions. The aim of our study was to verify the hypothesis whether the expression and activation of the selected isoforms of Akt kinase accounts for the trastuzumab treatment response prediction in patients with Her-2+ metastatic breast cancer (MBC). Methods: 76 women with verified Her-2+ MBC were treated with trastuzumab. Immunohistochemistry was performed with mAb against Akt-1, Akt-2, p-Akt-S473 and p-Akt-T308. The expression was considered positive (or highly positive) if 5% (or 80%) or more tumor cells were stained with the Ab. In the cases of p-Akt-S473 and p-Akt-T308, the cytoplasmatic and nuclear fractions were assessed separately. Results: In 96% patients, the treatment with trastuzumab was combined with cytostatics (89% taxane). The majority of patients (59%) started the immunotherapy within the 1st-line cancer treatment. Patients whose tumours showed high Akt-2 expression accompanied with strong nuclear and various cytoplasmatic (n+c) positivity of p-Akt-S473 and/or p-Akt-T308 exhibited improved OS (overall survival) and TTP (time to progression) compared to those with low or negative Akt-2 expression or who were Akt-2 positive, but negative for nuclear staining of p-Akt-S473 and/or p-Akt-T308. Thus, patients with high expression of Akt-2 and p-Akt-S473(n+c) had superior medians of TTP (13,1 vs 7,6 months; p<0.018) and OS (102.2 vs 58.4 months; p<0.042) when compared with those as defined above. Similar results were found in the case of high Akt-2 and p-Akt-T308(n+c) expression. On the other hand, the proof of high Akt-2 kinase expression accompanied with the positivity of p-Akt-S473 and/or p-Akt-T308 found only in cytoplasm predicted unfavourable results. Conclusion: This study was the first to prove that the significance of Akt kinase for the prediction of the response to the treatment with trastuzumab depends on the Akt kinase isoform, activity and compartmentalization. Supported by IGA MH, CZ. No.:NR/8335-3.

Anotace česky

Introduction: Breast carcinomas with overexpression of Her-2 receptor (Her-2+) have an unfavourable prognosis, but the application of the trastuzumab increases the patients survival in both palliative and adjuvant treatments. However, in spite of these successful results, trastuzumab is only effective in 2040% of cases. Akt, a serine/threonine kinase, is the key molecule of the phosphatidylinositol 3-kinase signaling pathway. Akt gets activated at the Thr-308 and Ser-473 residues in response to the growth factor and cytokine receptors stimulation and Her-2 receptor activation. Depending on the Akt isoforms and subcellular localization, the activated Akt accounts for variety of cellular reactions. The aim of our study was to verify the hypothesis whether the expression and activation of the selected isoforms of Akt kinase accounts for the trastuzumab treatment response prediction in patients with Her-2+ metastatic breast cancer (MBC). Methods: 76 women with verified Her-2+ MBC were treated with trastuzumab. Immunohistochemistry was performed with mAb against Akt-1, Akt-2, p-Akt-S473 and p-Akt-T308. The expression was considered positive (or highly positive) if 5% (or 80%) or more tumor cells were stained with the Ab. In the cases of p-Akt-S473 and p-Akt-T308, the cytoplasmatic and nuclear fractions were assessed separately. Results: In 96% patients, the treatment with trastuzumab was combined with cytostatics (89% taxane). The majority of patients (59%) started the immunotherapy within the 1st-line cancer treatment. Patients whose tumours showed high Akt-2 expression accompanied with strong nuclear and various cytoplasmatic (n+c) positivity of p-Akt-S473 and/or p-Akt-T308 exhibited improved OS (overall survival) and TTP (time to progression) compared to those with low or negative Akt-2 expression or who were Akt-2 positive, but negative for nuclear staining of p-Akt-S473 and/or p-Akt-T308. Thus, patients with high expression of Akt-2 and p-Akt-S473(n+c) had superior medians of TTP (13,1 vs 7,6 months; p<0.018) and OS (102.2 vs 58.4 months; p<0.042) when compared with those as defined above. Similar results were found in the case of high Akt-2 and p-Akt-T308(n+c) expression. On the other hand, the proof of high Akt-2 kinase expression accompanied with the positivity of p-Akt-S473 and/or p-Akt-T308 found only in cytoplasm predicted unfavourable results.Conclusion: This study was the first to prove that the significance of Akt kinase for the prediction of the response to the treatment with trastuzumab depends on the Akt kinase isoform, activity and compartmentalization. Supported by IGA MH, CZ. No.:NR/8335-3.

Návaznosti

• NR8335, projekt VaV: Název: Predikce chemosenzitivity / chemorezistence na cílenou protinádorovou terapii u pacientek s karcinomem prsu s prokázanou HER-2 pozitivitou, na podkladě analýzy Akt signální dráhy a sérové hladiny HER-2 receptoru