UNLABELLED: 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.

Białystok Oncology Center Białystok Poland

Chemotherapy Department Regional Hospital Wrocław Poland

Department of Chemotherapy Subcarpathian Oncology Center Rzeszów Poland

Department of Medical Oncology National Institute of Oncology Budapest Hungary

Greater Poland Cancer Center Poznań Poland

Masaryk Memorial Cancer Institute Brno Czech Republic

Medical University of Gdańsk Gdańsk Poland

Medical University of Łódź Łódź Poland

Military Institute of Medicine Oncology Department Warsaw Poland

Oncology Center Bielsko Biała Poland

Oncology Center Bydgoszcz Poland

Oncology Center Kielce Poland

Oncology Center Wrocław Poland

Oncology Center Zielona Góra Poland

Opole Oncology Center Poland

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

Warmia and Masuria Oncology Center Olsztyn Poland

West Pomeranian Cancer Center Szczecin Poland

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Predictive value of quantitative HER2, HER3 and p95HER2 levels in HER2-positive advanced breast cancer patients treated with lapatinib following progression on trastuzumab