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Strategies for the discovery and development of therapies for metastatic breast cancer

Nature Reviews Drug Discovery volume 11, pages 479–497 (2012)Cite this article

Subjects

Key Points

  • Metastasis is the major cause of morbidity for patients with breast cancer, as few curative therapies are available.

  • To develop more effective treatments, a better understanding of metastasis and the genes that regulate the process is necessary.

  • Owing to early tumour cell dissemination before primary tumour diagnosis, target genes need to be identified that have a functional role in metastatic progression after tumour cell entry into the circulation.

  • Current therapies that target the primary tumour may not necessarily target disseminated tumour cells or subsequent metastases. The use of circulating tumour cells to predict and monitor patient response to therapies may be important for improving individualized therapeutics.

  • There are two general ways of identifying metastasis-associated genes as potential therapeutic targets. Human gene expression profiling or tissue arrays of primary tumours, disseminated tumour cells and metastases can be used to find genes whose expression correlates with clinical parameters such as disease-free survival. Assessment of a functional role in the process can be achieved using appropriate animal models of metastatic disease. Alternatively, metastasis-regulating genes can be identified using mouse models and subsequently verified as being relevant in human breast cancer by analysing transcript or protein levels in tissue samples.

  • Approximately 20% of the patients who are diagnosed with breast cancer will subsequently develop metastatic disease. Challenges exist in identifying the patients for whom adjuvant chemotherapy is required. Testing the efficacy of current and emerging therapeutics against disseminated tumour cells in the adjuvant setting is of crucial importance for the future.

Abstract

Nearly all deaths caused by solid cancers occur as a result of metastasis — the formation of secondary tumours in distant organs such as the lungs, liver, brain and bone. A major obstruction to the development of drugs with anti-metastatic efficacy is our fragmented understanding of how tumours 'evolve' and metastasize, at both the biological and genetic levels. Furthermore, although there is significant overlap in the metastatic process among different types of cancer, there are also marked differences in the propensity to metastasize, the extent of metastasis, the sites to which the tumour metastasizes, the kinetics of the process and the mechanisms involved. Here, we consider the case of breast cancer, which has some marked distinguishing features compared with other types of cancer. Considerable progress has been made in the development of preclinical models and in the identification of relevant signalling pathways and genetic regulators of metastatic breast cancer, and we discuss how these might facilitate the development of novel targeted anti-metastatic drugs.

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Figure 1: The process of metastasis, depicting current and potential stages of therapeutic intervention.
Figure 2: The contribution of host cells to metastatic progression.
Figure 3: Preclinical models of metastasis used to identify metastasis-regulating genes and to test new therapies.
Figure 4: The process of filtering potential metastasis-regulating genes for the development of targeted therapies.

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Acknowledgements

Fellowship support from the National Health and Medical Research Council of Australia (B.S.P.), from the National Breast Cancer Foundation (R.L.A.) and from Susan G. Komen for the Cure (B.L.E.) is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Bedrich L. Eckhardt & Robin L. Anderson

  2. Division of Cancer Medicine and Research Division, Peter MacCallum Cancer Centre, 3002, East Melbourne, Australia

    Prudence A. Francis & Belinda S. Parker

  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, 3010, Parkville, Australia

    Belinda S. Parker & Robin L. Anderson

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  2. Prudence A. Francis
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  3. Belinda S. Parker
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  4. Robin L. Anderson
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Corresponding authors

Correspondence to Belinda S. Parker or Robin L. Anderson.

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Competing interests

During the past 2 years, Prudence Francis has received travel support from Sanofi and Amgen.

Supplementary information

Supplementary information Table 1

The identification of subtypes of breast cancer with different levels of risk of metastasis. (PDF 128 kb)

Supplementary information Table 2

Current therapies for breast cancer (PDF 141 kb)

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Peter MacCallum Cancer Centre — Metastasis Research Laboratory

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Eckhardt, B., Francis, P., Parker, B. et al. Strategies for the discovery and development of therapies for metastatic breast cancer. Nat Rev Drug Discov 11, 479–497 (2012). https://doi.org/10.1038/nrd2372

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