2007
The impact of signaling pathways stimulated by HER2 receptor on prediction of clinical outcome in metastatic breast cancer patients treated with trastuzumab.
GRELL, Peter, Marek SVOBODA, Pavel FABIAN, Lenka RADOVÁ, Marta DZIECHCIARKOVA et. al.Základní údaje
Originální název
The impact of signaling pathways stimulated by HER2 receptor on prediction of clinical outcome in metastatic breast cancer patients treated with trastuzumab.
Název česky
Význam signálních drah stimulovaných HER2 receptorem v predikci odpovědi na léčbu trastuzumabem u pacientek s metastatickým karcinomem prsu.
Autoři
GRELL, Peter (703 Slovensko), Marek SVOBODA (203 Česká republika, garant), Pavel FABIAN (203 Česká republika), Lenka RADOVÁ (203 Česká republika), Marta DZIECHCIARKOVA (203 Česká republika), Markéta PALÁCOVÁ (203 Česká republika), Rudolf NENUTIL (203 Česká republika) a Rostislav VYZULA (203 Česká republika)
Vydání
Journal of Clinical Oncology, 2007, 0732-183X
Další údaje
Jazyk
angličtina
Typ výsledku
Článek v odborném periodiku
Obor
30200 3.2 Clinical medicine
Stát vydavatele
Spojené státy
Utajení
není předmětem státního či obchodního tajemství
Impakt faktor
Impact factor: 15.484
Kód RIV
RIV/00216224:14110/07:00028234
Organizační jednotka
Lékařská fakulta
UT WoS
000208457400398
Klíčová slova anglicky
breast cancer;trastuzumab;prognosis;prediction;HER-2/neu gene
Štítky
Příznaky
Mezinárodní význam, Recenzováno
Změněno: 14. 9. 2008 20:53, prof. MUDr. Marek Svoboda, Ph.D.
V originále
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.
Česky
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.
Návaznosti
| NR8335, projekt VaV |
|