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Phosphorylated HER2 predicts the benefit of trastuzumab and better survival after treatment

Introduction: Human epidermal growth factor receptor 2 (HER2) is present in normal breast epithelial cells, but its over-expression leads to deregulated signaling process and oncogenic transformation of the cells. HER2 is overexpressed in approximately 15-25% cases of invasive breast cancers (BC), resulting in a high risk of relapse and poor survival. Implementing anti-HER2 therapy, with trastuzumab, improved disease outcome, and survival of patients. Yet a significant number of patients do not respond to trastuzumab therapy. Phosphorylation of the tyrosine (Tyr-1248) on intracellular domain of the HER2 receptor represents the last step in process of its activation and results in downstream signaling. Therefore, phosphorylated HER2 (pHER2) is a true indicator of the receptor activity and function and the main prerequisite for achieving the pathological effect in cases of HER2 over- expression. Since over-expression of HER2 does not indicate receptor activity, we hypothesized that the difference in HER2 over-expression and activation may be the reason for trastuzumab resistance. Material and methods: This study was conducted on 124 tumor samples of patients with the HER2 positive ductal invasive BC. All patients have been treated with trastuzumab according to the standard protocols. Thirty-four patients (27.4%) had progression of the disease and considered to be resistant to trastuzumab therapy. Follow-up time was over 5 years. Evaluation of the HER2 phosphorylation was performed by immunohistochemical staining with a monoclonal antibody against the Tyr1248 phosphorylated site on the intracellular domain of the HER2 receptor (clone P2NA, Dako). Membrane/cytoplasmic staining of moderate (2+) and strong intensity (3+) in more than 10% of tumor cells is considered to be pHER2 positive. Results: Our results revealed that the HER2 receptor is predominantly phosphorylated (66.2% pHER2+) and positive pHER2 status is a marker of a good response to trastuzumab. Relapse of the disease was reported in 17.1% of patients with pHER2+ breast cancer comparing to 47.6% of pHER2‒ patients with recurrent disease (χ2=11.53 ; P <0.001). High incidence of disease recurrence was observed in patients with pHER2‒ who had positive lymph nodes at the time of surgery (66.7%) (χ2=30.97 ; P <0.001). Phosphorylation status is significant in the HER2 intrinsic group where disease recurrence occurred in 73.3% of pHER2‒ patients (χ2=21.58 ; P <0.001). Conclusion: The positive phosphorylation status of the HER2 determines patients who will benefit from trastuzumab therapy. Negative status of pHER2 refers to patients who should undergo dual therapy in first-line treatment, especially in cases with positive lymph nodes or the HER2 intrinsic breast cancer group.

breast cancer ; phosphorylated HER2 ; resistance ; trastuzumab

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