Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients

// Renata Duchnowska 1 , Piotr J. Wysocki 2 , Konstanty Korski 3 , Bogumila Czartoryska-Arlukowicz 4 , Anna Niwinska 5 , Marlena Orlikowska 6 , Barbara Radecka 7 , Maciej Studzinski 8 , Regina Demlova 9 , Barbara Ziolkowska 10 , Monika Merdalska 11 , Łukasz Hajac 12 , Paulina Myśliwiec 13 , Dorota Zuziak 14 , Sylwia Debska-Szmich 15 , Istvan Lang 16 , Malgorzata Foszczynska-Kloda 2 , Bozenna Karczmarek-Borowska 17 , Anton Żawrocki 18 , Anna Kowalczyk 18 , Wojciech Biernat 18 , Jacek Jassem 18 , for the Central and East European OncologyGroup (CEEOG) 1 Military Institute of Medicine, OncologyDepartment, Warsaw, Poland 2 West PomeranianCancer Center, Szczecin, Poland 3 Greater Poland Cancer Center, Poznan, Poland 4 Bialystok OncologyCenter, Bialystok, Poland 5 The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 6 Warmia and Masuria OncologyCenter, Olsztyn, Poland 7 Opole OncologyCenter, Poland 8 OncologyCenter, Bydgoszcz, Poland 9 Masaryk Memorial Cancer Institute, Brno, Czech Republic 10 Chemotherapy Department, Regional Hospital, Wroclaw, Poland 11 OncologyCenter, Kielce, Poland 12 OncologyCenter, Wroclaw, Poland 13 OncologyCenter, Zielona Gora, Poland 14 OncologyCenter, Bielsko-Biala, Poland 15 Medical University of Łodź, Łodź, Poland 16 Department of Medical Oncology, National Institute of Oncology, Budapest, Hungary 17 Department of Chemotherapy, Subcarpathian OncologyCenter, Rzeszow, Poland 18 Medical University of Gdansk, Gdansk, Poland Correspondence to: Renata Duchnowska, e-mail: rdtt@wp.pl Keywords: breast cancer, epidermal growth factor receptor type 2, lapatinib, mTOR, p-MAPK Received: May 19, 2015 Accepted: November 13, 2015 Published: November 24, 2015 ABSTRACT Molecular mechanisms of lapatinibresistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbBfamily signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatiniband capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensinhomolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin Ewith shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E(HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinibseems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinibwith MAPK pathway inhibitors.