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    Genomic profile of advanced breast cancer in circulating tumour DNA

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    Authors
    Kingston, B.
    Cutts, R. J.
    Bye, H.
    Beaney, M.
    Walsh-Crestani, G.
    Hrebien, S.
    Swift, C.
    Kilburn, L. S.
    Kernaghan, S.
    Moretti, L.
    Wilkinson, K.
    Wardley, Andrew M
    Macpherson, I. R.
    Baird, R. D.
    Roylance, R.
    Reis-Filho, J. S.
    Hubank, M.
    Faull, I.
    Banks, K. C.
    Lanman, R. B.
    Garcia-Murillas, I.
    Bliss, J. M.
    Ring, A.
    Turner, N. C.
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    Affiliation
    The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London
    Issue Date
    2021
    
    Metadata
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    Abstract
    The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.
    Citation
    Kingston B, Cutts RJ, Bye H, Beaney M, Walsh-Crestani G, Hrebien S, et al. Genomic profile of advanced breast cancer in circulating tumour DNA. Nat Commun. 2021 Apr 23;12(1).
    Journal
    Nature Communications
    URI
    http://hdl.handle.net/10541/624021
    DOI
    10.1038/s41467-021-22605-2
    PubMed ID
    33893289
    Additional Links
    https://dx.doi.org/10.1038/s41467-021-22605-2
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-021-22605-2
    Scopus Count
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