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Overcoming Treatment Resistance in HER2-Positive Breast Cancer

Potential Strategies

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Abstract

Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been developed, resulting in dramatic improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being investigated. Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alteration in binding of trastuzumab to HER2; and loss of HER2 expression. Proposed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT or estrogen receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.

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Acknowledgements

The authors thank Dr Roberta Sottile for her assistance in preparing the manuscript.

Dr Fabio Puglisi has received consulting fees or honorarium from Roche and GlaxoSmithKline. Dr Grazia Arpino has received consulting fees or honorarium from Roche and GlaxoSmithKline. All other authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Department of Oncology, University Hospital of Udine, Piazzale SM Misericordia 15, I-33100, Udine, Italy

    Fabio Puglisi MD, PhD & Alessandro Marco Minisini

  2. Department of Medical and Biological Sciences, University of Udine, Udine, Italy

    Fabio Puglisi MD, PhD

  3. Department of Clinical and Molecular Oncology and Endocrinology, University of Naples, Federico II, Naples, Italy

    Carmine De Angelis & Grazia Arpino

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  1. Fabio Puglisi MD, PhD
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  2. Alessandro Marco Minisini
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  3. Carmine De Angelis
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  4. Grazia Arpino
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Correspondence to Fabio Puglisi MD, PhD.

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Puglisi, F., Minisini, A.M., De Angelis, C. et al. Overcoming Treatment Resistance in HER2-Positive Breast Cancer. Drugs 72, 1175–1193 (2012). https://doi.org/10.2165/11634000-000000000-00000

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