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Oncotarget. 2016 Jan 5;7(1):550-64. doi: 10.18632/oncotarget.6375.

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

Author information

1
Military Institute of Medicine, Oncology Department, Warsaw, Poland.
2
West Pomeranian Cancer Center, Szczecin, Poland.
3
Greater Poland Cancer Center, Poznań, Poland.
4
Białystok Oncology Center, Białystok, Poland.
5
The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
6
Warmia and Masuria Oncology Center, Olsztyn, Poland.
7
Opole Oncology Center, Poland.
8
Oncology Center, Bydgoszcz, Poland.
9
Masaryk Memorial Cancer Institute, Brno, Czech Republic.
10
Chemotherapy Department, Regional Hospital, Wrocław, Poland.
11
Oncology Center, Kielce, Poland.
12
Oncology Center, Wrocław, Poland.
13
Oncology Center, Zielona Góra, Poland.
14
Oncology Center, Bielsko-Biała, Poland.
15
Medical University of Łódź, Łódź, Poland.
16
Department of Medical Oncology, National Institute of Oncology, Budapest, Hungary.
17
Department of Chemotherapy, Subcarpathian Oncology Center, Rzeszów, Poland.
18
Medical University of Gdańsk, Gdańsk, Poland.

Abstract

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.

KEYWORDS:

breast cancer; epidermal growth factor receptor type 2; lapatinib; mTOR; p-MAPK

PMID:
26623720
PMCID:
PMC4808017
DOI:
10.18632/oncotarget.6375
[Indexed for MEDLINE]
Free PMC Article

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