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

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 Morden, Manuela Graf, Kally Sidhu, Abigail Evans, Michael Shere, Christopher Holcombe, Stuart A. McIntosh, Nigel Bundred, Anthony Skene, William Maxwell, John Robertson, Judith M. Bliss, Ian Smith and Mitch Dowsett ()
Additional contact information
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

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13294

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