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Neuregulin Expression Modulates Clinical Response to Trastuzumab in Patients With Metastatic Breast Cancer

Enrique de Alava, Alberto Ocaña, Mar Abad, Juan Carlos Montero, Azucena Esparís-Ogando, César A. Rodríguez, Ana P. Otero, Teresa Hernández, Juan J. Cruz, Atanasio Pandiella

From the Centro de Investigación del Cáncer–Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas–Universidad de Salamanca, and Hospital Universitario de Salamanca, Salamanca, Spain

Address reprint requests to Atanasio Pandiella, MD, Centro de Investigación del Cáncer, Campus Miguel de Unamuno, 37007-Salamanca, Spain; e-mail: atanasio{at}usal.es

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-NRG2c) 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-NRG2c 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.

Supported by Grant No. BMC2003-01192 from the Ministry of Science and Technology of Spain and by grants from the Autonomous Government of Castilla y León SAN191/SA06/06 to our Center's Tumor Bank and to the Regional Tumor Bank Network of Castilla y León. Our Cancer Research Institute receives support from the European community through the Regional Development Funding Program and from Cancer Center Network Program of the Instituto de Salud Carlos III (ISCIII). J.C.M. and A.E.-O. were supported by Asociacion Española Contra el Cancer (AECC) and ISCIII contracts, respectively.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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