Anticancer Res. 2013 Jun;33(6):2509-15.

Correlation of Phosphorylated HER2 with Clinicopathological Characteristics and Efficacy of Trastuzumab Treatment for Breast Cancer

Running title: Phosphorylated HER2 and Trastuzumab Efficacy for Breast Cancer

SNJEŽANA RAMIĆ1, KSENIJA ASIĆ1, MELITA PERIĆ BALJA1, FRANE PAIĆ2, VESNA BENKOVIĆ3 and FABIJAN KNEŽEVIĆ1

1Department of Pathology, University Hospital for Tumors, Sestre Milosrdnice Clinical Hospital Centre, Zagreb, Croatia;

2Laboratory for Epigenetic and Molecular Medicine, Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia;

3Department of Animal Physiology, Division of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia

 

Correspondence to:

Snježana Ramić, molecular biologist, Department of Pathology, University Hospital for Tumors, Sestre Milosrdnice Clinical Hospital Centre, Ilica 197, 10000 Zagreb, Croatia.

Tel: +38513713611, e-mail: snjezana.ramic@zg.t-com.hr

 

Abstract.

Aim: To determine the correlation of phosphorylated human epidermal growth factor receptor 2 (pHER2) with clinicopathological characteristics of breast cancer (BC) and response to trastuzumab-based therapy. Patients and Methods: pHER2 was determined immunohistochemically in 88 cases of HER2-positive and 50 cases of HER2-negative BC. All patients with HER2-positive BC received trastuzumab-based therapy and 16 of them (18.2%) had disease progression during therapy treatment (I. e. trastuzumab-resistant).

The results: pHER2 was predominantly expressed in HER2-positive BC, with 55 cases (62.5%) of tumours expressing pHER2. Six cases of HER2-negative breast cancer (12.5%) displayed a positive expression of pHER2. Expression of pHER2 correlated with younger age of patients and negative oestrogen receptor status. Acquisition of resistance to trastuzumab correlated with negativity for pHER2 (p=0.028).

Conclusion:Positive expression of pHER2 may yield additional information about the poor prognosis of BC while pHER2 negativity in HER2-positive BC could be used for pre-selection of patients displaying resistance to trastuzumab treatment.

Key Words: Breast cancer, HER2, Phosphorylation, Trastuzumab therapy.

PMID: 23749902


SUPPLEMENT:

Human epidermal growth factor receptor 2 (HER2) is a transmembrane growth factor receptor that regulates cell growth and proliferation. Phosphorylation of the HER2 receptor (pHER2) is a precondition for downstream signalling and represents the functional and active form of HER2. The main site of its auto-phosphorylation is on tyrosine 1248 residue (Tyr1248). In pathological conditions, its ability to form dimers with all receptors from the EGFR family results in uncontrolled growth and migration of tumour and poor prognosis. Ligand-independent homodimerization is a preferred mechanism in HER2-overexpressing tumours and a reason for receptor deregulated phosphorylation/activation and oncogenic transformation of cells. HER2 is overexpressed in 20-25% of breast cancer (BC) cases. In patients with HER2 overexpressing BC, trastuzumab-based therapy is administered resulting in prolonged progression-free and overall survival. However, still more than 30% of patients with HER2 positive tumours do not respond to trastuzumab therapy, although trastuzumab therapy is effective. The aim of the study was to determine the correlation of phosphorylated HER2 with clinicopathological characteristics of BC and response to trastuzumab-based therapy.

Figure 1 shows pHER2 expression according to HER2 score. Using immunohistochemical staining, pHER2 was predominantly expressed in HER2-positive BC, with 55 cases (62.5%) of tumours expressing pHER2. Our work indicates that when HER2 is overexpressed, it is commonly activated. Six cases of HER2-negative cancer (12.5%) displayed a positive expression of pHER2. This weak pHER2 expression correlated with weak to moderate expression of HER2 on the cell membrane, which was negative, according to the Hercep test score. Results from other studies who had found pHER2-positive/fluorescence in situ hybridization-negative tumours using a quantitative protein microarray assay also confirmed our findings of HER2-negative cases expressing pHER2. These results support the hypothesis that even lower levels of HER2 may be sufficient to elicit a potent mitogenic effect. The finding of low HER2-expressing tumours with positive pHER2 could also indicate HER2 activation through heterodimerization with HER1 and HER3. Heterogeneity between pHER2 and HER2 expression presented in Figure 1 demonstrates that positive pHER2 expression cannot be used as a surrogate for HER2 positivity.

Acquisition of resistance to trastuzumab correlated with negativity for pHER2 ((χ2= 4.84, p=0.028). Trastuzumab resistant tumours expressed lower levels of pHER2 with only 37.5% (6/16) of cases having positive pHER2 compared to 68.1% (49/72) of pHER2-positive cases in trastuzumab-sensitive tumours (Figure 2). Only four trastuzumab-sensitive tumours (5.5%) had complete absence of pHER2 immunohistochemical staining.

Expression of pHER2 with HER2 expression could determine a more accurate prognosis. Patients with HER2-positive/pHER2-negative tumours could be categorized as poor candidates, who would not respond to trastuzumab therapy and perhaps who could benefit from double anti-tyrosine kinase therapy in the first-line treatment (lapatinib, pertuzumab). It still remains unknown, whether patients with lower HER2 expression, but pHER2-positive tumours, are candidates for any therapy with tyrosine kinase inhibitors.

SR-FIG1Figure 1. Distribution of pHER2 expression in relation to HER2 score according to Hercep Test and gene amplification status.

 

SR-FIG2Figure 2. Number of pHER2-positive tumours in relation to efficacy of trastuzumab-based therapy.

 

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