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Clinical management of breast cancer heterogeneity

Key Points

  • Breast cancer is a heterogeneous group of diseases with different histological, prognostic and clinical aspects

  • Heterogeneous expression of the oestrogen, progesterone, and HER2 receptors has been observed among different patients with breast cancer, as well as between matched samples from primary tumours and their metastases

  • Powerful technologies, such as DNA microarrays and next-generation sequencing, are providing further insight into intertumour and intratumour heterogeneity

  • Intratumour heterogeneity is documented at both spatial and temporal levels, with breast cancer cells behaving similarly to an evolving ecosystem, showing a molecular evolution in response to selective pressures

  • Heterogeneity poses impediments to the successful clinical development of molecularly targeted agents

  • Innovative approaches are urgently needed to overcome the hurdle of tumour heterogeneity and improve clinical outcomes for patients with breast cancer

Abstract

Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. Results of high-throughput molecular profiling studies have subsequently revealed the true extent of this heterogeneity. Further complicating this scenario, the heterogeneous expression of the oestrogen receptor (ER), progesterone receptor (PR), and HER2 has been reported in different areas of the same tumour. Furthermore, discordance, in terms of ER, PR and HER2 expression, has also been reported between primary tumours and their matched metastatic lesions. High-throughput molecular profiling studies have confirmed that spatial and temporal intratumour heterogeneity of breast cancers exist at a level beyond common expectations. We describe the different levels of tumour heterogeneity, and discuss the strategies that can be adopted by clinicians to tackle treatment response and resistance issues associated with such heterogeneity, including a rationally selected combination of agents that target driver mutations, the targeting of deleterious passenger mutations, identifying and eradicating the 'lethal' clone, targeting the tumour microenvironment, or using adaptive treatments and immunotherapy. The identification of the most-appropriate strategies and their implementation in the clinic will prove highly challenging and necessitate the adoption of radically new practices for the optimal clinical management of breast malignancies.

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Figure 1: Schematic depiction of intertumour and intratumour heterogeneity in breast cancer.
Figure 2: The AURORA study design.

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Acknowledgements

C.S. is a senior Cancer Research UK clinical research fellow and is funded by Cancer Research UK, the Rosetrees Trust, EU FP7 (projects PREDICT and RESPONSIFY, ID:259,303), the Prostate Cancer Foundation, the European Research Council and the Breast Cancer Research Foundation. This research is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

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All authors researched data for the article, reviewed and edited the manuscript before submission and substantially contributed to discussion of content. D.Z. wrote the manuscript.

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M.P. is a board member for PharmaMar and receives consultant honoraria from Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, sanofi Aventis, Symphogen, Synthon, Verastem. The other authors declare no competing interests

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Zardavas, D., Irrthum, A., Swanton, C. et al. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol 12, 381–394 (2015). https://doi.org/10.1038/nrclinonc.2015.73

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