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  • Review Article
  • Published:

Treatment of HER2-positive breast cancer: current status and future perspectives

Abstract

The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research.

Key Points

  • HER2 gene amplification and/or overexpression occurs in about 20% of breast cancers and is associated with more-aggressive disease and, until the advent of HER2-targeted agents, a worse outcome

  • The monoclonal antibody, trastuzumab (which targets HER2), and the small-molecule tyrosine kinase inhibitor, lapatinib (which targets HER1 and HER2), have considerable efficacy in HER2-positive breast cancer

  • New agents in development include vaccines, modified antibodies and derivatives, tyrosine kinase inhibitors and other agents directed against HER2, other HER family members, and downstream and/or resistance pathways

  • Targets in downstream and/or resistance pathways of particular interest in HER2-positive breast cancer include mTOR, PI3K, IGF-1R, Akt, HSP90 and VEGF

  • In advanced-stage disease, randomized trials suggest that the antibody–drug conjugate, trastuzumab-DM1, and the dimerization inhibitor, pertuzumab, may have superior efficacy or add to the efficacy of trastuzumab-based therapy

  • Lapatinib, bevacizumab (which targets VEGF), neratinib (a dual HER1–HER2 inhibitor), and the peptide vaccines, GP2 and AE37, are all in adjuvant trials for HER2-positive early stage breast cancer

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Figure 1: Heterodimer formation of members of the HER family and downstream signaling.

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Acknowledgements

We would like to thank Claire Barton (consultant of Fondazione Michelangelo, the non-profit organization that organized the seminar on HER2) for assistance in preparing the manuscript.

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All authors contributed equally to all aspects of the article, including researching data, discussion of content, and writing, reviewing and editing the manuscript before submission.

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Correspondence to Luca Gianni.

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M. X. Sliwkowski declares that he owns shares and has a patent from Genentech. C. K. Osborne declares that he is a consultant for Genentech. He was previously a consultant for Astra Zeneca and Novartis and he also received a grant from GlaxoSmithKline. L. Gianni declares that he is a consultant for Astra Zeneca, Biogen Idec, Boehringer Ingelheim, Celgene, Eisai, Genentech, Genomic Health, GlaxoSmithKline, Millenium Takeda, Pfizer, Roche, and Sanofi Aventis. The other authors declare no competing interests.

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Novel strategies for the treatment of patients with HER2-positive breast cancer* (DOC 127 kb)

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Arteaga, C., Sliwkowski, M., Osborne, C. et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9, 16–32 (2012). https://doi.org/10.1038/nrclinonc.2011.177

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