Genomic profile of advanced breast cancer in circulating tumour DNA

Kingston, B. et al. (2021) Genomic profile of advanced breast cancer in circulating tumour DNA. Nature Communications, 12, 2423. (doi: 10.1038/s41467-021-22605-2) (PMID:33893289) (PMCID:PMC8065112)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:MacPherson, Professor Iain
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, A. 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., and Turner, N. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12: 2423
Publisher Policy:Reproduced under a Creative Commons licence

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