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Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.


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Authors

Dawson, Sarah-Jane 
Pogrebniak, Katherine 
Rueda, Oscar M 
Provenzano, Elena 

Abstract

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.

Description

Keywords

Adult, Antineoplastic Combined Chemotherapy Protocols, Bayes Theorem, Brain Neoplasms, Breast Neoplasms, Carcinoma, Ductal, Breast, Case-Control Studies, Clonal Evolution, DNA, Neoplasm, Deoxycytidine, Female, Humans, Lapatinib, Liver Neoplasms, Lung Neoplasms, Mutation, Neoplasm Metastasis, Quinazolines, Receptor, ErbB-2, Receptors, Estrogen, Sequence Analysis, DNA, Spinal Neoplasms, Tamoxifen, Trastuzumab, Gemcitabine

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

6

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research Uk (None)
Academy of Medical Sciences (unknown)
Cancer Research UK (CB4140)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cancer Research Uk (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
European Commission (260791)
European Commission FP7 Network of Excellence (NoE) (260791)
Cancer Research Uk (None)
Medical Research Council (MR/M008975/1)
Academy of Medical Sciences (ALI 01/08/14)
Pathological Society of Great Britain & Ireland (CDF 2012/01)
European Commission FP7 Collaborative projects (CP) (258967)
Cancer Research UK (C507/A16278)
European Commission (258967)
Cancer Research UK (20544)
Medical Research Council (MR/P012442/1)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (115749)
European Commission (242006)
European Research Council (694620)
Cancer Research UK (A24622)
Cancer Research UK (C14303/A17197)
European Research Council (337905)
Cancer Research UK (16942)
We thank the Human Research Tissue Bank at Addenbrooke’s Hospital which is supported by the NIHR Cambridge Biomedical Research Centre. We acknowledge the support of Cancer Research UK, the University of Cambridge, National Institute for Health Research Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre. Dr. Dawson was supported by an Australian National Breast Cancer Foundation and Victorian Cancer Agency Early Career Fellowship. Dr. Murtaza was supported by Science Foundation Arizona’s Bisgrove Scholars Early Tenure Track award.