The impact of Ras/MAPK/S6K signaling pathway on prediction of
clinical outcome in metastatic Her-2 positive breast cancer
patients treated with trastuzumab

a 2014

The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab

SVOBODA, Marek; Marta KHOYLOU; Petr GRELL; Jiří NAVRÁTIL; Pavel FABIAN et al.

Základní údaje

Originální název

The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab

Název česky

Vliv Ras/MAPK/S6K signální dráhy na predikci léčebné odpovědi u metastatických Her-2 positivních pacientek s nádory prsu léčených trastuzumabem

Autoři

SVOBODA, Marek; Marta KHOYLOU; Petr GRELL; Jiří NAVRÁTIL; Pavel FABIAN; Jaroslav JURÁČEK; Markéta PALÁCOVÁ; Rostislav VYZULA a Marian HAJDÚCH

Vydání

AACR Annual Meeting 2014 April 5-9, 2014 San Diego Convention Center San Diego, California, 2014

Další údaje

Jazyk

čeština

Typ výsledku

Konferenční abstrakt

Obor

30200 3.2 Clinical medicine

Stát vydavatele

Česká republika

Utajení

není předmětem státního či obchodního tajemství

Označené pro přenos do RIV

Organizační jednotka

Lékařská fakulta

Klíčová slova česky

trastuzumab; nádory prsu; prognóza; Her-2 mutace

Klíčová slova anglicky

trastuzumab; breast cancer; prognosis; Her-2 mutation

Změněno: 30. 4. 2014 16:32, Mgr. Petra Vychytilová, Ph.D.

Anotace

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 30-50% of cases. PI3K/Akt and Ras/MAPK signaling pathways are activated through Her-2 receptor and other growth factors’ receptors 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 S6K, p-S6K-Ser235/236, MAPK, p-MAPK-Thr202/Tyr204, GSK3β, p-GSK3β-Ser9, mTOR, p-mTOR-Ser2448. The cytoplasmatic and nuclear fractions of the staining were assessed separately. Results: Patients whose tumors showed cytoplasmic (c) and nuclear (n) expression of p- GSK3β-Ser9 exhibited worse PFS compared to tumors with negative p-GSK3β-Ser9 (PFS 5,1 vs 9,1 months; P=0,006). Similar results were also found in p-S6K kinase activity, with the difference that it was possible to observe the dependence on the p-S6K kinase compartmentalization. Patients whose tumors showed p-S6K-Ser235/236 expression accompanied with only cytoplasmatic (c) or nuclear and cytoplasmatic (n+c) staining exhibited worse PFS compared to tumors with negative p-S6K-Ser235/236 expression (negat) (c vs negat: 6,3 vs 16,1 months, P=0,006; n+c vs negat: 7,8 vs 16,1 months, P=0,025). Of the remaining kinases, we showed no effect of their expression on treatment outcome. Conclusions: This study confirms that prediction of the response or resistance to trastuzumab treatment depends on the S6K and GSK3β kinase activity. Patients, whose tumors had high level of p-S6K or p-GSK3β, had poorer benefit from trastuzumab based therapy. These patients are candidates for targeted blockade of PI3K/Akt and/or RAS/MAPK signaling pathways.

Citovat

SVOBODA, Marek; Marta KHOYLOU; Petr GRELL; Jiří NAVRÁTIL; Pavel FABIAN; Jaroslav JURÁČEK; Markéta PALÁCOVÁ; Rostislav VYZULA a Marian HAJDÚCH. The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab. In AACR Annual Meeting 2014 April 5-9, 2014 San Diego Convention Center San Diego, California. 2014.

@proceedings{1181686,
   author = {Svoboda, Marek and Khoylou, Marta and Grell, Petr and Navrátil, Jiří and Fabian, Pavel and Juráček, Jaroslav and Palácová, Markéta and Vyzula, Rostislav and Hajdúch, Marian},
   booktitle = {AACR Annual Meeting 2014 April 5-9, 2014 San Diego Convention Center San Diego, California},
   keywords = {trastuzumab; breast cancer; prognosis; Her-2 mutation},
   language = {cze},
   title = {The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab},
   year = {2014}
}

TY  - CONF
ID  - 1181686
AU  - Svoboda, Marek - Khoylou, Marta - Grell, Petr - Navrátil, Jiří - Fabian, Pavel - Juráček, Jaroslav - Palácová, Markéta - Vyzula, Rostislav - Hajdúch, Marian
PY  - 2014
TI  - The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab
KW  - trastuzumab
KW  - breast cancer
KW  - prognosis
KW  - Her-2 mutation
N2  - 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 30-50% of cases. PI3K/Akt and Ras/MAPK signaling pathways are activated through Her-2 receptor and other growth factors’ receptors 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 S6K, p-S6K-Ser235/236, MAPK, p-MAPK-Thr202/Tyr204, GSK3β, p-GSK3β-Ser9, mTOR, p-mTOR-Ser2448. The cytoplasmatic and nuclear fractions of the staining were assessed separately. Results: Patients whose tumors showed cytoplasmic (c) and nuclear (n) expression of p- GSK3β-Ser9 exhibited worse PFS compared to tumors with negative p-GSK3β-Ser9 (PFS 5,1 vs 9,1 months; P=0,006). Similar results were also found in p-S6K kinase activity, with the difference that it was possible to observe the dependence on the p-S6K kinase compartmentalization. Patients whose tumors showed p-S6K-Ser235/236 expression accompanied with only cytoplasmatic (c) or nuclear and cytoplasmatic (n+c) staining exhibited worse PFS compared to tumors with negative p-S6K-Ser235/236 expression (negat) (c vs negat: 6,3 vs 16,1 months, P=0,006; n+c vs negat: 7,8 vs 16,1 months, P=0,025). Of the remaining kinases, we showed no effect of their expression on treatment outcome. Conclusions: This study confirms that prediction of the response or resistance to trastuzumab treatment depends on the S6K and GSK3β kinase activity. Patients, whose tumors had high level of p-S6K or p-GSK3β, had poorer benefit from trastuzumab based therapy. These patients are candidates for targeted blockade of PI3K/Akt and/or RAS/MAPK signaling pathways.
ER  -

SVOBODA, Marek; Marta KHOYLOU; Petr GRELL; Jiří NAVRÁTIL; Pavel FABIAN; Jaroslav JURÁČEK; Markéta PALÁCOVÁ; Rostislav VYZULA a Marian HAJDÚCH. The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab. In \textit{AACR Annual Meeting 2014 April 5-9, 2014 San Diego Convention Center San Diego, California}. 2014.

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