Abstract LB-181: The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab

Abstract

Abstract 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. Supported by the Internal Grant Agency of Ministry of Health, Czech Republic, No.NT/14599 and Biomedreg CZ.1.05/2.1.00/01.0030. Citation Format: Marek Svoboda, Marta Khoylou, Peter Grell, Jiri Navratil, Pavel Fabian, Jaroslav Juracek, Marketa Palacova, Rostislav Vyzula, Marian Hajduch. The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-181. doi:10.1158/1538-7445.AM2014-LB-181