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Defining actionable mutations for oncology therapeutic development

Nature Reviews Cancer volume 16, pages 319–329 (2016)Cite this article

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Abstract

Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.

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Figure 1: Lollipop plot showing the distribution and classes of mutations in TP53 across pan-cancer datasets in The Cancer Genome Atlas.

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Author notes

  1. T. Hedley Carr and Robert McEwen: T.H.C. and R.M. contributed equally to this work.

Authors and Affiliations

  1. Oncology IMED, AstraZeneca, Darwin Building, Cambridge Science Park, CB4 0WG, Cambridge, UK

    T. Hedley Carr, Robert McEwen & Simon J. Hollingsworth

  2. Oncology IMED, AstraZeneca, Alderley Park, SK10 4TG, Macclesfield, UK

    Zara Ghazoui, Darren R. Hodgson & Francisco Cruzalegui

  3. Oncology IMED, AstraZeneca, Waltham, 02451, Massachusetts, USA

    Brian Dougherty, Justin H. Johnson, Jonathan R. Dry, Zhongwu Lai, Naomi M. Laing & J. Carl Barrett

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Correspondence to T. Hedley Carr or Robert McEwen.

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The authors are employees of AstraZeneca and hold shares in the company.

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Carr, T., McEwen, R., Dougherty, B. et al. Defining actionable mutations for oncology therapeutic development. Nat Rev Cancer 16, 319–329 (2016). https://doi.org/10.1038/nrc.2016.35

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