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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Military Institute of Medicine, Oncology Department, Warsaw, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Duchnowska
authors.affiliation: West Pomeranian Cancer Center, Szczecin, Poland.
authors.forename: Piotr J
authors.initials: PJ
authors.lastname: Wysocki
authors.affiliation: Greater Poland Cancer Center, Poznań, Poland.
authors.forename: Konstanty
authors.initials: K
authors.lastname: Korski
authors.affiliation: Białystok Oncology Center, Białystok, Poland.
authors.forename: Bogumiła
authors.initials: B
authors.lastname: Czartoryska-Arłukowicz
authors.affiliation: The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Niwińska
authors.affiliation: Warmia and Masuria Oncology Center, Olsztyn, Poland.
authors.forename: Marlena
authors.initials: M
authors.lastname: Orlikowska
authors.affiliation: Opole Oncology Center, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Radecka
authors.affiliation: Oncology Center, Bydgoszcz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Studziński
authors.affiliation: Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Regina
authors.initials: R
authors.lastname: Demlova
authors.affiliation: Chemotherapy Department, Regional Hospital, Wrocław, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ziółkowska
authors.affiliation: Oncology Center, Kielce, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Merdalska
authors.affiliation: Oncology Center, Wrocław, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Hajac
authors.affiliation: Oncology Center, Zielona Góra, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Myśliwiec
authors.affiliation: Oncology Center, Bielsko-Biała, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Zuziak
authors.affiliation: Medical University of Łódź, Łódź, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Dębska-Szmich
authors.affiliation: Department of Medical Oncology, National Institute of Oncology, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Lang
authors.affiliation: West Pomeranian Cancer Center, Szczecin, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Foszczyńska-Kłoda
authors.affiliation: Department of Chemotherapy, Subcarpathian Oncology Center, Rzeszów, Poland.
authors.forename: Bożenna
authors.initials: B
authors.lastname: Karczmarek-Borowska
authors.affiliation: Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Anton
authors.initials: A
authors.lastname: Żawrocki
authors.affiliation: Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.affiliation: Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019927:Cyclin E / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D010766:Phosphorylation / Q000187:drug effects; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D055815:Young Adult
chemical_list: D019927:Cyclin E; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: breast cancer; epidermal growth factor receptor type 2; lapatinib; mTOR; p-MAPK