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


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.


CONCLUSIONS
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.
de Alava
Enrique
E
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.
Ocaña
Alberto
A
Abad
Mar
M
Montero
Juan Carlos
JC
Esparís-Ogando
Azucena
A
Rodríguez
César A
CA
Otero
Ana P
AP
Hernández
Teresa
T
Cruz
Juan J
JJ
Pandiella
Atanasio
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020880:Neuregulins / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D000068878:Trastuzumab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab