Genomic profile of advanced breast cancer in circulating tumour DNA.
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Date
2021-04-23ICR Author
Author
Kingston, B
Cutts, RJ
Bye, H
Beaney, M
Walsh-Crestani, G
Hrebien, S
Swift, C
Kilburn, LS
Kernaghan, S
Moretti, L
Wilkinson, K
Wardley, AM
Macpherson, IR
Baird, RD
Roylance, R
Reis-Filho, JS
Hubank, M
Faull, I
Banks, KC
Lanman, RB
Garcia-Murillas, I
Bliss, JM
Ring, A
Turner, NC
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Humans
Breast Neoplasms
Receptor, erbB-2
Receptors, Estrogen
Antineoplastic Combined Chemotherapy Protocols
Sequence Analysis, DNA
Genomics
Drug Resistance, Neoplasm
Mutation
Aged
Middle Aged
Female
Class I Phosphatidylinositol 3-Kinases
Biomarkers, Tumor
Circulating Tumor DNA
Progression-Free Survival
Research team
Molecular Oncology
Clinical Trials & Statistics Unit
Translational Genomics
Molecular Oncology
Clinical Trials & Statistics Unit
Translational Genomics
Language
eng
Date accepted
2021-03-16
License start date
2021-04-23
Citation
Nature communications, 2021, 12 (1), pp. 2423 - ?
Publisher
NATURE PORTFOLIO