Research Papers:

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

Renata Duchnowska _, Piotr J. Wysocki, Konstanty Korski, Bogumiła Czartoryska- Arłukowicz, Anna Niwińska, Marlena Orlikowska, Barbara Radecka, Maciej Studziński, Regina Demlova, Barbara Ziółkowska, Monika Merdalska, Łukasz Hajac, Paulina Myśliwiec, Dorota Zuziak, Sylwia Dębska-Szmich, Istvan Lang, Małgorzata Foszczyńska-Kłoda, Bożenna Karczmarek-Borowska, Anton Żawrocki, Anna Kowalczyk, Wojciech Biernat, Jacek Jassem and for the Central and East European Oncology Group (CEEOG)

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Oncotarget. 2016; 7:550-564. https://doi.org/10.18632/oncotarget.6375

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Renata Duchnowska1, Piotr J. Wysocki2, Konstanty Korski3, Bogumiła Czartoryska-Arłukowicz4, Anna Niwińska5, Marlena Orlikowska6, Barbara Radecka7, Maciej Studziński8, Regina Demlova9, Barbara Ziółkowska10, Monika Merdalska11, Łukasz Hajac12, Paulina Myśliwiec13, Dorota Zuziak14, Sylwia Dębska-Szmich15, Istvan Lang16, Małgorzata Foszczyńska-Kłoda2, Bożenna Karczmarek-Borowska17, Anton Żawrocki18, Anna Kowalczyk18, Wojciech Biernat18, Jacek Jassem18, for the Central and East European Oncology Group (CEEOG)

1Military Institute of Medicine, Oncology Department, Warsaw, Poland

2West Pomeranian Cancer Center, Szczecin, Poland

3Greater Poland Cancer Center, Poznań, Poland

4Białystok Oncology Center, Białystok, Poland

5The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

6Warmia and Masuria Oncology Center, Olsztyn, Poland

7Opole Oncology Center, Poland

8Oncology Center, Bydgoszcz, Poland

9Masaryk Memorial Cancer Institute, Brno, Czech Republic

10Chemotherapy Department, Regional Hospital, Wrocław, Poland

11Oncology Center, Kielce, Poland

12Oncology Center, Wrocław, Poland

13 Oncology Center, Zielona Góra, Poland

14Oncology Center, Bielsko-Biała, Poland

15Medical University of Łódź, Łódź, Poland

16Department of Medical Oncology, National Institute of Oncology, Budapest, Hungary

17Department of Chemotherapy, Subcarpathian Oncology Center, Rzeszów, Poland

18Medical University of Gdańsk, Gdańsk, Poland

Correspondence to:

Renata Duchnowska, e-mail: [email protected]

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


Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog 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 E with 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 lapatinib seems 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 lapatinib with MAPK pathway inhibitors.

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