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

Neuregulin expression modulates clinical response to trastuzumab in patients with metastatic breast cancer De Alava E, Ocana A, Abad M et al. Clinical Oncology, 2007, 25, 2656-2663

This study could be highly significant and have implications for the management of breast cancer. Current treatment with the monoclonal antibody trastuzumab (Herceptin) is confined to patients possessing tumours which overexpress the human epidermal growth receptor (HER) 2 as measured by immunohistochemistry (IHC) or by fluorescence in situ hybridization (FISH). It is conventionally accepted that only patients with tumours demonstrating 3+ staining with IHC or with amplified HER2 gene by FISH, respond to trastuzumab therapy, and this is supported by results from clinical studies. However, occasionally patients without HER2 overexpressing tumours have been reported to have responded to this therapy, and this study provides some thought-provoking evidence of why this might happen. HER2 is part of a super-family of tyrosine kinase receptors which includes HER1, HER3 and HER4. Neuregulin (NRG) is known to bind HER3 and may activate HER2 by crosstalk in the absence of HER2 overexpression, and this provides a possible basis by which breast cancers expressing NRG may activate HER2 and respond to trastuzumab therapy in the presence of normal levels of HER2. The unexpected finding of this retrospective study was a group of tumours from 12 patients who had received trastuzumab therapy for supposed HER2-positive breast cancer, but who on retesting at a later date with the Hercep Test and FISH were re-designated as having HER2-negative tumours.

In 10 of these 12 patients treated with trastuzumab and a taxane, there was an improvement in overall survival (0S) in those with high levels of NRG. By contrast, a separate group of patients with high NRG levels but also HER2 overexpression did not show an improvement in OS compared to patients with HER2 overexpression but low levels of NRG. The results suggest that expression of transmembrane NRG can predict response to anti-HER2 therapy in breast cancers designated as HER2 negative. However, this is a very small retrospective study and clearly merits repetition in a large prospective series before these interesting results can be confirmed.