Breast Cancer Research and Treatment

, Volume 178, Issue 1, pp 63–73 | Cite as

Plasma cell-free DNA chromosomal instability analysis by low-pass whole-genome sequencing to monitor breast cancer relapse

  • Huanhuan Zhou
  • Xiao-Jia Wang
  • Xiyi Jiang
  • Ziliang Qian
  • Tianhui Chen
  • Yue Hu
  • Zhan-Hong Chen
  • Yun Gao
  • Rong Wang
  • Wei-Wu Ye
  • Wen-Ming CaoEmail author
Preclinical study



Chromosomal instabilities (CIN) of plasma cell-free DNA (cfDNA) are common in breast cancer. We aimed to investigate the value of cfDNA CIN in monitoring the breast cancer relapse and additionally to compare it with the traditional biomarkers (CA15-3 and CEA).


Overall 62 recurrent breast cancer patients and 20 healthy controls were recruited. Low-pass whole-genome sequencing (LPWGS) was performed to detect cfDNA CIN. A CIN score was calculated. The performance of CA15-3, CEA, and CIN score in monitoring the recurrence was investigated with receiver operating characteristic (ROC) curve and the area under curve (AUC). Multivariable Cox proportional hazard model was established to analyze the correlations between copy number gain/loss and disease-free survival (DFS).


cfDNA CIN achieved the positive rate of 77.6% [(95% confidence interval (CI) 73.4–95.3%)] among recurrent breast cancer patients, with an AUC value of 0.933, superior to CA15-3 (positive rate: 38.7%; AUC: 0.864) and CEA (positive rate: 41.93%; AUC: 0.878) (P < 0.01). The combination of cfDNA CIN with two biomarkers further increased the positive rate to 88.7% (95% confidence interval 77.5–95.0%). cfDNA CIN achieved better performance in patients with shorter DFS (≤ 41 months), with an AUC value of 0.975.


cfDNA CIN yields a higher accuracy in monitoring breast cancer recurrence compared to traditional biomarkers (CA15-3 and CEA), especially for biomarker-negative patients. The combination of cfDNA CIN to traditional biomarkers further improved the detection rate of recurrence, which may provide a new method for monitoring the early relapse of breast cancer, though further investigations are warranted.


Cell-free DNA CIN CA153 CEA Recurrent breast cancer 



We would like to express special thanks to all participating patients and their families.


This trial was funded by grants from National Natural Science Foundation of China (Grant Number: 81672597), Natural Science Foundation of Zhejiang Province, China (Grant Number: LY17H160038, LY14H160030), Key Research-Development Program of Zhejiang Province [Grant Number: 2019C04001, 2017C03013], Science and Technology Program offered by the Health Bureau of Zhejiang Province, China (Grant Number: 2017RC014), and Joint Key Program of Zhejiang Province-Ministry of Health [Grant Number: WKJ-ZJ-1714], and Qianjiang Talents Fund of Zhejiang Province [Grant Number: QJD1602026].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the Clinical Research Ethics Committee of Zhejiang Cancer Hospital. All experiments comply with the current China laws.

Informed Consent

Written informed consent was obtained from all individual participants included in the study.

Supplementary material

10549_2019_5375_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1056 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Breast Medical OncologyZhejiang Cancer HospitalHangzhouChina
  2. 2.Group of Molecular Epidemiology & Cancer Precision PreventionZhejiang Academy of Medical SciencesHangzhouChina
  3. 3.Prophet Genomics IncSan JoseUSA
  4. 4.Department of Breast SurgeryThe Second Affiliated Hospital, Zhejiang UniversityHangzhouChina

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