title: Analysis of circulating tumor DNA to monitor metastatic breast cancer.
abstract: BACKGROUND
  The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.
  
  
  METHODS
  We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.
  
  
  RESULTS
  Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).
  
  
  CONCLUSIONS
  This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).
authors.affiliation: Department of Oncology, University of Cambridge and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Dawson
authors.forename: Dana W Y
authors.initials: DW
authors.lastname: Tsui
authors.forename: Muhammed
authors.initials: M
authors.lastname: Murtaza
authors.forename: Heather
authors.initials: H
authors.lastname: Biggs
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunning
authors.forename: Davina
authors.initials: D
authors.lastname: Gale
authors.forename: Tim
authors.initials: T
authors.lastname: Forshew
authors.forename: Betania
authors.initials: B
authors.lastname: Mahler-Araujo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rajan
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.forename: Jennifer
authors.initials: J
authors.lastname: Becq
authors.forename: David
authors.initials: D
authors.lastname: Halsall
authors.forename: Matthew
authors.initials: M
authors.lastname: Wallis
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics / Q000556:secondary*; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D018396:Mucin-1 / Q000097:blood*; D009154:Mutation; D009362:Neoplasm Metastasis / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics; D011379:Prognosis; D011859:Radiography; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D018396:Mucin-1