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  • Review Article
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Emerging targeted agents in metastatic breast cancer

Abstract

Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents.

Key Points

  • Breast cancer cells are heterogeneous, with a multitude of molecular alterations supporting their malignant progression

  • Besides the epithelial compartment of the disease, the functional importance of the tumour microenvironment and of breast cancer stem cells has been recognized

  • A high number of emerging targeted agents against all the compartments of breast cancer are being developed in genotype-driven clinical trials

  • Rationally chosen combination targeted therapies hold promise for improving the clinical outcome of patients with metastatic breast cancer

  • Despite their refined mode of molecular action, targeted therapies are associated with diverse toxicities, which clinicians should be aware of and treat patients accordingly

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Figure 1: Emerging targeted agents against breast cancer cells under clinical development.
Figure 2: Emerging targeted agents against breast cancer stem cells under clinical development.

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The authors thank Ahmad Awada for valuable scientific discussions before writing this manuscript.

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All authors researched data for the article and made a substantial contribution to the discussion of the content. D. Zardavas wrote the article, and all authors edited the manuscript prior to submission.

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J. Baselga acts as a consultant for AstraZeneca, Chugai, Genentech, Merck, Novartis, Roche. M. Piccart acts as a consultant for Amgen, Bayer, Roche-Genentech, PharmaMar and SanofiAventis. She receives honoraria from Amgen, Bayer, Novartis, Roche-Genentech, PharmaMar and SanofiAventis. D. Zardavas declares no competing interests.

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Zardavas, D., Baselga, J. & Piccart, M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol 10, 191–210 (2013). https://doi.org/10.1038/nrclinonc.2013.29

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