Neuregulin expression modulates clinical response to trastuzumab in patients with metastatic breast cancer

Purpose Human epidermal growth factor receptor 2 (HER-2) overexpression has been associated with the genesis and progression of a subset of breast cancers. The function of HER-2 may be upregulated by overexpression or by the availability of neuregulins (NRGs), a group of transmembrane growth factors. Transmembrane NRGs strongly activated HER-2 and cell proliferation in breast cancer cells that did not overexpress HER-2, and treatment with trastuzumab prevented the proliferative action of transmembrane NRG. This raised the relevant clinical question of whether patients considered as HER-2 negative, but expressing transmembrane NRG, may benefit from treatment with trastuzumab. Patients and Methods MCF7 cells expressing transmembrane NRG (MCF7-NRG alpha 2c) were injected into mice, and their sensitivity to trastuzumab was assessed. A retrospective study of 124 patients with early-stage or metastatic breast cancer was conducted. Expression of transmembrane NRG was evaluated by immunohistochemistry. In 11 patients, Western blot for NRGs was also carried out. Statistics were performed to analyze possible correlations between NRG expression and response to trastuzumab-based therapies, event-free survival, and overall survival (OS). Results Trastuzumab inhibited tumor growth in mice injected with MCF7-NRG alpha 2c cells. Transmembrane NRG was frequently expressed in breast cancer patients. Overexpression of transmembrane NRG significantly correlated with a longer event-free survival and OS in patients with low or normal HER-2 expression who were treated with trastuzumab-based therapies but not in patients with HER-2 overexpression. Conclusion We suggest that the spectrum of patients who may benefit from trastuzumab-based therapies may be widened to include patients with metastatic breast cancer without HER-2 amplification but who express transmembrane NRGs.