title: Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.
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.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.|Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.|Mayo Clinic Center for Individualized Medicine, Scottsdale, Arizona 85259, USA.
authors.forename: Muhammed
authors.identifier: http://orcid.org/0000-0001-7557-2861
authors.initials: M
authors.lastname: Murtaza
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust and National Institute for Health Research Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0QQ, UK.|Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Dawson
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Pogrebniak
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust and National Institute for Health Research Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0QQ, UK.|Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Grant
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Dana W Y
authors.initials: DWY
authors.lastname: Tsui
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marass
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Davina
authors.initials: D
authors.lastname: Gale
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.|Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust and National Institute for Health Research Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0QQ, UK.|Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK.
authors.forename: H Raza
authors.initials: HR
authors.lastname: Ali
authors.affiliation: Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Pankti
authors.initials: P
authors.lastname: Shah
authors.affiliation: Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Contente-Cuomo
authors.affiliation: BC Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Hossein
authors.initials: H
authors.lastname: Farahani
authors.affiliation: BC Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Karey
authors.initials: K
authors.lastname: Shumansky
authors.affiliation: Illumina, Inc., Chesterford Research Park, Little Chesterford CB10 1XL, UK.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kingsbury
authors.affiliation: Illumina, Inc., Chesterford Research Park, Little Chesterford CB10 1XL, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.affiliation: Illumina, Inc., Chesterford Research Park, Little Chesterford CB10 1XL, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.affiliation: BC Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust and National Institute for Health Research Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0QQ, UK.|Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wallis
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.|Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust and National Institute for Health Research Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0QQ, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001499:Bayes Theorem; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D060965:Clonal Evolution / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D009154:Mutation; D009362:Neoplasm Metastasis; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013125:Spinal Neoplasms / Q000235:genetics* / Q000556:secondary; D013629:Tamoxifen / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D004273:DNA, Neoplasm; D003841:Deoxycytidine; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000068878:Trastuzumab; D000093542:Gemcitabine; C508053:ERBB2 protein, human