Journal
EMBO MOLECULAR MEDICINE
Volume 7, Issue 8, Pages 1034-1047Publisher
WILEY
DOI: 10.15252/emmm.201404913
Keywords
breast carcinoma; circulating tumor DNA; early detection; liquid biopsy; metastasis
Categories
Funding
- Swedish Cancer Society
- Swedish Research Council
- Swedish Foundation for Strategic Research
- Knut and Alice Wallenberg Foundation
- VINNOVA
- National Health Service
- Swedish Breast Cancer Group
- Crafoord Foundation
- Lund University Medical Faculty
- Gunnar Nilsson Cancer Foundation
- Skane University Hospital Foundation
- BioCARE Research Program, King Gustav Vth Jubilee Foundation
- Krapperup Foundation
- Mrs. Berta Kamprad Foundation
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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 11months (range 0-37months), 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.
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