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

For the Central and East European Oncology Group (CEEOG)

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)550-564
Number of pages15
JournalOncotarget
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

Fingerprint

AMP-Activated Protein Kinases
Cyclin E
Breast Neoplasms
70-kDa Ribosomal Protein S6 Kinases
Mitogen-Activated Protein Kinases
Disease-Free Survival
Biomarkers
Adenosine Monophosphate
Phosphoric Monoester Hydrolases
Estrogen Receptors
Proteins
Multivariate Analysis
lapatinib
Survival
Research
Therapeutics

Keywords

  • Breast cancer
  • Epidermal growth factor receptor type 2
  • Lapatinib
  • MTOR
  • P-MAPK

ASJC Scopus subject areas

  • Oncology

Cite this

Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients. / For the Central and East European Oncology Group (CEEOG).

In: Oncotarget, Vol. 7, No. 1, 01.01.2016, p. 550-564.

Research output: Contribution to journalArticle

For the Central and East European Oncology Group (CEEOG). / Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients. In: Oncotarget. 2016 ; Vol. 7, No. 1. pp. 550-564.
@article{89b7d020431f4fe49ea05ce1f70f4f52,
title = "Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients",
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",
author = "{For the Central and East European Oncology Group (CEEOG)} and Renata Duchnowska and Wysocki, {Piotr J.} and Konstanty Korski and Bogumiła Czartoryska-Arłukowicz and Anna Niwińska and Marlena Orlikowska and Barbara Radecka and Maciej Studziński and Regina Demlova and Barbara Zi{\'o}łkowska and Monika Merdalska and Łukasz Hajac and Paulina Mysliwiec and Dorota Zuziak and Sylwia Debska-Szmich and I. L{\'a}ng and Małgorzata Foszczyńska-Kłoda and Bozenna Karczmarek-Borowska and Anton Zawrocki and Anna Kowalczyk and Wojciech Biernat and Jacek Jassem and Wojciech Olszewski and Anna Surus-Hyla and Jolanta Zok and Wojciech Rogowski and Ewa Chmielowska and Rostislav Vyzula and Renata Horova and Jolanta Smok-Kalwat and Tomasz Jankowski and Agata Sałek and Alexander Eniu and Bolba, {Gabriela Morar} and Dorota P{\'o}łchłopek and Elzbieta Nowara and Dorota Bogus and Andrzej Kałmuk and Eduardes Aleknavicius and Iwona Rynkiewicz-Zander and Piotr Wiosek and Łukasz Głogowski and Ida Cedrych and Aleksandra Grela-Wojewoda and Monika Kulma-Kreft and Piotr Sawrycki and Zsuzsanna Kahan and Małgorzata Ploch-Glapińska",
year = "2016",
month = "1",
day = "1",
doi = "10.18632/ONCOTARGET.6375",
language = "English",
volume = "7",
pages = "550--564",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "1",

}

TY - JOUR

T1 - Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients

AU - For the Central and East European Oncology Group (CEEOG)

AU - Duchnowska, Renata

AU - Wysocki, Piotr J.

AU - Korski, Konstanty

AU - Czartoryska-Arłukowicz, Bogumiła

AU - Niwińska, Anna

AU - Orlikowska, Marlena

AU - Radecka, Barbara

AU - Studziński, Maciej

AU - Demlova, Regina

AU - Ziółkowska, Barbara

AU - Merdalska, Monika

AU - Hajac, Łukasz

AU - Mysliwiec, Paulina

AU - Zuziak, Dorota

AU - Debska-Szmich, Sylwia

AU - Láng, I.

AU - Foszczyńska-Kłoda, Małgorzata

AU - Karczmarek-Borowska, Bozenna

AU - Zawrocki, Anton

AU - Kowalczyk, Anna

AU - Biernat, Wojciech

AU - Jassem, Jacek

AU - Olszewski, Wojciech

AU - Surus-Hyla, Anna

AU - Zok, Jolanta

AU - Rogowski, Wojciech

AU - Chmielowska, Ewa

AU - Vyzula, Rostislav

AU - Horova, Renata

AU - Smok-Kalwat, Jolanta

AU - Jankowski, Tomasz

AU - Sałek, Agata

AU - Eniu, Alexander

AU - Bolba, Gabriela Morar

AU - Półchłopek, Dorota

AU - Nowara, Elzbieta

AU - Bogus, Dorota

AU - Kałmuk, Andrzej

AU - Aleknavicius, Eduardes

AU - Rynkiewicz-Zander, Iwona

AU - Wiosek, Piotr

AU - Głogowski, Łukasz

AU - Cedrych, Ida

AU - Grela-Wojewoda, Aleksandra

AU - Kulma-Kreft, Monika

AU - Sawrycki, Piotr

AU - Kahan, Zsuzsanna

AU - Ploch-Glapińska, Małgorzata

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Epidermal growth factor receptor type 2

KW - Lapatinib

KW - MTOR

KW - P-MAPK

UR - http://www.scopus.com/inward/record.url?scp=85017070299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017070299&partnerID=8YFLogxK

U2 - 10.18632/ONCOTARGET.6375

DO - 10.18632/ONCOTARGET.6375

M3 - Article

C2 - 26623720

AN - SCOPUS:85017070299

VL - 7

SP - 550

EP - 564

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 1

ER -