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Future directions of bone-targeted therapy for metastatic breast cancer

Abstract

Bone is the most common metastatic site for breast cancer, and bone metastases can cause pain as well as risk of pathological fractures. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to bone metastasis. The interaction between tumor cells and the bone microenvironment results in a 'vicious cycle' that increases both bone destruction and tumor burden. The tumor secretes factors, such as parathyroid hormone-related peptide, that stimulate osteoclastogenesis. Similarly, the bone stroma produces growth factors, such as transforming growth factor β, that promote tumor growth in bone. Therapeutic targeting of these microenvironmental factors is under intensive investigation. Other attractive therapeutic targets include signaling molecules, such as receptor activator of nuclear factor κB ligand, Src kinase, and cathepsin K, all of which regulate osteoclast function, and chemokine receptor 4, which is involved in the homing of tumor cells to bone. In this Review, we describe the progress and future directions of novel bone-targeted therapies that may reduce or prevent destructive bone metastasis from breast cancer. Novel modalities for predicting and monitoring treatment response will also be described.

Key Points

  • A more thorough understanding of the interaction between tumor cells and the bone microenvironment will direct the development of novel bone-targeted treatments

  • Adjuvant bisphosphonate treatments, especially zoledronic acid, may have antitumor effects that both prevent and treat bone metastasis, as well as improving survival

  • Denosumab is a promising agent that might be more effective than bisphosphonates in preventing skeletal-related events in metastatic breast cancer; whether denosumab has antitumor effects is not yet clear

  • In addition to denosumab, Src kinase inhibitors are promising agents under development for the treatment of bone metastases from breast cancer

  • Systemic radionuclide therapy may have antitumor effects that lead to improved survival

  • Imaging modalities, gene-expression signatures, bone markers, disseminated tumor cells, and circulating tumor cells are under investigation as means of directing personalized treatment

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Figure 1: The interaction between tumor cells and the bone microenvironment.

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Acknowledgements

This work was supported in part by the NIH Cancer Center Support Grant CA016672, and by the Nellie B. Connally Breast Cancer Research Fund. We thank Sunita Patterson (Department of Scientific Publications at The University of Texas MD Anderson Cancer Center) for editorial assistance. C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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T. Onishi and N. T. Ueno contributed to discussion of content for the article, researched data to include in the manuscript, wrote the content, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer reviewers' comments. N. Hayashi researched data to include in the manuscript and contributed to the writing. R. L. Theriault and G. N. Hortobagyi reviewed and edited the manuscript before submission.

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Correspondence to Naoto T. Ueno.

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Competing interests

G. N. Hortobagyi has worked as a consultant for Merck and Sanofi-Aventis, and has received a grant/research support from and worked as a consultant for Novartis. N. T. Ueno has received a grant/research support from EUSA Pharma. T. Onishi, N. Hayashi, and R. L. Theriault declare no competing interests.

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Onishi, T., Hayashi, N., Theriault, R. et al. Future directions of bone-targeted therapy for metastatic breast cancer. Nat Rev Clin Oncol 7, 641–651 (2010). https://doi.org/10.1038/nrclinonc.2010.134

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