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Precision medicine for metastatic breast cancer—limitations and solutions

Nature Reviews Clinical Oncology volume 12, pages 693–704 (2015)Cite this article

Subjects

Key Points

  • Recent research data defining the genomic landscape of breast cancer have reinforced the notion that this disease is driven by genomic alterations

  • So far very few gene drivers validated in breast cancer have been identified, including ESR1, ERBB 2, PIK3CA and ATK1

  • Identification of drivers, characterization of resistant clones, identification of DNA repair defects and mechanisms of immune suppression are potential uses of genomics to personalize medicine

  • The development of precision medicine for the treatment of breast cancer has several major challenges that include low frequency of targetable molecular alterations, feasibility of high-throughput technologies and availability of targeted therapy

Abstract

The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The identification of driver mutational events remains the biggest challenge, because, with the few exceptions of ER, HER2, PIK3CA and AKT1, no validated oncogenic drivers of breast cancer exist. The development of bioinformatic tools to help identify driver mutations, together with assessment of pathway activation and dependency should help resolve this issue in the future. The occurrence of secondary resistance, such as ESR1 mutations, following endocrine therapy poses a further challenge. Ultra-deep sequencing and monitoring of circulating tumour DNA (ctDNA) could permit early detection of the genetic events underlying resistance and inform on combination therapy approaches. Beside these scientific challenges, logistical and operational issues are a major limitation to the development of precision medicine. For example, the low incidence of most candidate genomic alterations hinders randomized trials, as the number of patients to be screened would be too high. We discuss these limitations and the solutions, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.

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Figure 1: Possible applications of genomics to personalize therapy of MBC.
Figure 2: Limitations and solutions for precision medicine in MBC.
Figure 3: Development of MBC precision medicine.
Figure 4: Overcoming the accrual challenges of stratified medicine approaches.

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Acknowledgements

S.L. is supported by Cancer Council Victoria and the National Health and Medical Research Council of Australia (NHMRC). F.A. is supported by Grants from the ARC, Breast cancer Research Foundation, Odyssea and Operation Parrains Chercheurs.

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Authors and Affiliations

  1. Department of Medical Oncology, Gustave Roussy and Université Paris Sud, Villejuif, 94800, France

    Monica Arnedos & Fabrice Andre

  2. INSERM Unit U981, Gustave Roussy and Université Paris Sud, Villejuif, 94800, France

    Cecile Vicier & Celine Lefebvre

  3. Department of Biostatistics and Epidemiology, Gustave Roussy and Université Paris Sud, Villejuif, 94800, France

    Stefan Michiels

  4. Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Australia, 3002, VIC

    Sherene Loi

  5. Department of Medical Oncology and INSERM U916, Institut Bergonié, 229 Cours de l'Argonne, Bordeaux, 33000, France

    Herve Bonnefoi

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Contributions

H.B. and F.A. developed the outline; F.A. wrote the sections related to genomics and modalities of development. All authors made a significant contribution to writing the manuscript, reviewing and/or editing the manuscript and approved the final version before submission.

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Correspondence to Fabrice Andre.

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Competing interests

F.A. receives honourarium and has a research contract with AstraZeneca and Novartis. M.A. receives honourarium from Novartis. The other authors declare no competing interests.

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Arnedos, M., Vicier, C., Loi, S. et al. Precision medicine for metastatic breast cancer—limitations and solutions. Nat Rev Clin Oncol 12, 693–704 (2015). https://doi.org/10.1038/nrclinonc.2015.123

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