title: Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease.
abstract: Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Eleonor
authors.initials: E
authors.lastname: Olsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Christof
authors.initials: C
authors.lastname: Winter
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Anthony
authors.initials: A
authors.lastname: George
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Yilun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Jillian
authors.initials: J
authors.lastname: Howlin
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Man-Hung Eric
authors.initials: MH
authors.lastname: Tang
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Dahlgren
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden SCIBLU Genomics, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Ralph
authors.initials: R
authors.lastname: Schulz
authors.affiliation: Department of Pathology, Skåne University Hospital, Lund, Sweden.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Grabau
authors.affiliation: Department of Radiology, Skåne University Hospital, Lund, Sweden.
authors.forename: Danielle
authors.initials: D
authors.lastname: van Westen
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Department of Surgery, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Lund University Cancer Center, Lund, Sweden Department of Immunotechnology, Lund University, Lund, Sweden CREATE Health Strategic Centre for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rose
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Lund University Cancer Center, Lund, Sweden Department of Surgery, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rydén
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden SCIBLU Genomics, Department of Clinical Sciences, Lund University, Lund, Sweden CREATE Health Strategic Centre for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Sofia K
authors.initials: SK
authors.lastname: Gruvberger-Saal
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernström
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Lund University Cancer Center, Lund, Sweden CREATE Health Strategic Centre for Translational Cancer Research, Lund University, Lund, Sweden lao.saal@med.lu.se.
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000150:complications* / Q000473:pathology*; D004247:DNA / Q000097:blood*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D009362:Neoplasm Metastasis / Q000175:diagnosis*; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D004247:DNA
keywords: breast carcinoma; circulating tumor DNA; early detection; liquid biopsy; metastasis