Genomic profile of advanced breast cancer in circulating tumour DNA

Belinda Kingston, Rosalind J. Cutts, Hannah Bye, Matthew Beaney, Giselle Walsh-Crestani, Sarah Hrebien, Claire Swift, Lucy S. Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M. Wardley, Iain R. Macpherson, Richard D. Baird, Rebecca Roylance, Jorge S. Reis-Filho, Michael Hubank, Iris Faull, Kimberly C. Banks, Richard B. Lanman, Isaac Garcia-Murillas, Judith M. Bliss, Alistair Ring () and Nicholas C. Turner ()
Additional contact information
Belinda Kingston: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Rosalind J. Cutts: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Hannah Bye: Centre for Molecular Pathology, Royal Marsden Hospital
Matthew Beaney: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Giselle Walsh-Crestani: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Sarah Hrebien: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Claire Swift: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Lucy S. Kilburn: ICR-CTSU, The Institute of Cancer Research
Sarah Kernaghan: ICR-CTSU, The Institute of Cancer Research
Laura Moretti: ICR-CTSU, The Institute of Cancer Research
Katie Wilkinson: ICR-CTSU, The Institute of Cancer Research
Andrew M. Wardley: NIHR Manchester Clinical Research Facility at The Christie, Manchester Academic Health Science Centre & Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine & Health, University of Manchester
Iain R. Macpherson: The Beatson West of Scotland Cancer Centre
Richard D. Baird: Cancer Research UK Cambridge Centre
Rebecca Roylance: University College London Hospitals NHS Foundation Trust
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Centre
Michael Hubank: Centre for Molecular Pathology, Royal Marsden Hospital
Iris Faull: Guardant Health, Inc.
Kimberly C. Banks: Guardant Health, Inc.
Richard B. Lanman: Guardant Health, Inc.
Isaac Garcia-Murillas: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
Judith M. Bliss: ICR-CTSU, The Institute of Cancer Research
Alistair Ring: Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital
Nicholas C. Turner: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22605-2

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