title: Proteins Involved in HER2 Signalling Pathway, Their Relations and Influence on Metastasis-Free Survival in HER2-Positive Breast Cancer Patients Treated with Trastuzumab in Adjuvant Setting.
abstract: OBJECTIVE
  Resistance to trastuzumab (which is a standard therapy for breast cancer patients with HER2 overexpression) is associated with higher risk of progression or cancer death, and might be related to activation of signalling cascades (PI3K/AKT/mTOR, Ras/Raf/MAPK) and decreased level of their inhibitors.
  
  
  METHODS
  Formalin-fixed paraffin-embedded tumour specimens from 118 HER2-overexpressing breast cancer patients treated with radical local therapy and trastuzumab in adjuvant setting were used for the assessment of: (1) PIK3CA gene mutations (p.H1047R and p.E545K) by qPCR, and (2) expression of Ki-67, EGFR, MUC4, HER3 and PTEN by immunohistochemistry.
  
  
  RESULTS
  Lower Ki-67LI was observed in EGFR-immunonegative and in PTEN-immunopositive tumours. MUC4-immunonegative tumours more frequently were PTEN- and HER3-immunonegative. Favourable metastasis-free survival was observed in patients with tumours characterized by Ki-67LI≤50% (p=0.027), HER3 immunonegativity or PTEN immunopositivity (vs. tumours with HER3 expression and lack of PTEN expression, p=0.043), additionally, the trend was observed for patients with pN0+pN1 pathological tumour stage (vs. pN2+pN3) (p=0.086). Cox model revealed that independent negative prognostic factors were: (i) Ki-67LI>50% (p=0.014, RR=4.6, 95% CI 1.4-15.4), (ii) HER3 immunopositivity together with PTEN immunonegativity (p=0.034, RR=3.7, 95% CI 1.1-12.5).
  
  
  CONCLUSIONS
  The results of our study suggest that combined analysis of HER3 and PTEN expression might bring information on trastuzumab sensitivity in the group of HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting.
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Adamczyk
authors.affiliation: Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Grela-Wojewoda
authors.affiliation: Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Domagała-Haduch
authors.affiliation: Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ambicka
authors.affiliation: Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Harazin-Lechowska
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.affiliation: Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Ida
authors.initials: I
authors.lastname: Cedrych
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Kaja
authors.initials: K
authors.lastname: Majchrzyk
authors.affiliation: Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczak
authors.affiliation: Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Ryś
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Niemiec
keywords: HER2-overexpressing breast cancer; HER3; MUC4; PIK3CA mutations.; PTEN