J Cancer 2017; 8(1):131-139. doi:10.7150/jca.16239

Research Paper

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

Agnieszka Adamczyk1✉, Aleksandra Grela-Wojewoda2, Małgorzata Domagała-Haduch2, Aleksandra Ambicka3, Agnieszka Harazin-Lechowska3, Anna Janecka1, Ida Cedrych2, Kaja Majchrzyk1, Anna Kruczak3, Janusz Ryś3, Joanna Niemiec1

1. Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
2. Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
3. Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.

Abstract

Aim: 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.

Material and 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).

Conclusion: 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.

Keywords: HER2-overexpressing breast cancer, PTEN, HER3, MUC4, PIK3CA mutations.

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How to cite this article:
Adamczyk A, Grela-Wojewoda A, Domagała-Haduch M, Ambicka A, Harazin-Lechowska A, Janecka A, Cedrych I, Majchrzyk K, Kruczak A, Ryś J, Niemiec J. 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. J Cancer 2017; 8(1):131-139. doi:10.7150/jca.16239. Available from http://www.jcancer.org/v08p0131.htm