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Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

Author

Listed:
  • Pascal Gellert

    (Breast Cancer Now Research Centre at The Institute of Cancer Research)

  • Corrinne V. Segal

    (Breast Cancer Now Research Centre at The Institute of Cancer Research)

  • Qiong Gao

    (Breast Cancer Now Research Centre at The Institute of Cancer Research)

  • Elena López-Knowles

    (Breast Cancer Now Research Centre at The Institute of Cancer Research)

  • Lesley-Ann Martin

    (Breast Cancer Now Research Centre at The Institute of Cancer Research)

  • Andrew Dodson

    (Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital)

  • Tiandao Li

    (McDonnell Genome Institute, Washington University School of Medicine)

  • Christopher A. Miller

    (McDonnell Genome Institute, Washington University School of Medicine)

  • Charles Lu

    (McDonnell Genome Institute, Washington University School of Medicine)

  • Elaine R. Mardis

    (McDonnell Genome Institute, Washington University School of Medicine)

  • Alexa Gillman

    (Clinical Trials and Statistics Unit at The Institute of Cancer Research)

  • James Morden

    (Clinical Trials and Statistics Unit at The Institute of Cancer Research)

  • Manuela Graf

    (Breast Cancer Now Research Centre at The Institute of Cancer Research)

  • Kally Sidhu

    (Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital)

  • Abigail Evans

    (Poole General Hospital)

  • Michael Shere

    (Southmead Hospital, Westbury-on-Trym)

  • Christopher Holcombe

    (Royal Liverpool University Hospital)

  • Stuart A. McIntosh

    (Queen’s University Belfast)

  • Nigel Bundred

    (University Hospital of South Manchester, Education and Research Centre)

  • Anthony Skene

    (Royal Bournemouth Hospital, Castle Ln E)

  • William Maxwell

    (Withybush General Hospital)

  • John Robertson

    (University of Nottingham)

  • Judith M. Bliss

    (Clinical Trials and Statistics Unit at The Institute of Cancer Research)

  • Ian Smith

    (Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital)

  • Mitch Dowsett

    (Breast Cancer Now Research Centre at The Institute of Cancer Research
    Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital)

Abstract

Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

Suggested Citation

  • Pascal Gellert & Corrinne V. Segal & Qiong Gao & Elena López-Knowles & Lesley-Ann Martin & Andrew Dodson & Tiandao Li & Christopher A. Miller & Charles Lu & Elaine R. Mardis & Alexa Gillman & James Mo, 2016. "Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation," Nature Communications, Nature, vol. 7(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13294
    DOI: 10.1038/ncomms13294
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    Cited by:

    1. Eugene F. Schuster & Elena Lopez-Knowles & Anastasia Alataki & Lila Zabaglo & Elizabeth Folkerd & David Evans & Kally Sidhu & Maggie Chon U. Cheang & Holly Tovey & Manuel Salto-Tellez & Perry Maxwell , 2023. "Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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