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

  • Preclinical study
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Abstract

Background

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).

Methods

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).

Results

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.

Conclusions

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.

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Acknowledgements

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

Funding

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].

Author information

Author notes

  1. Huanhuan Zhou and Xiao-Jia Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China

    Huanhuan Zhou, Xiao-Jia Wang, Zhan-Hong Chen, Yun Gao, Rong Wang, Wei-Wu Ye & Wen-Ming Cao

  2. Group of Molecular Epidemiology & Cancer Precision Prevention, Zhejiang Academy of Medical Sciences, Hangzhou, 310013, China

    Xiyi Jiang & Tianhui Chen

  3. Prophet Genomics Inc, 1229 Briarcreek ct, San Jose, CA, USA

    Ziliang Qian

  4. Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University, Hangzhou, 310008, China

    Yue Hu

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  1. Huanhuan Zhou
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Correspondence to Wen-Ming Cao.

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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.

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

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Zhou, H., Wang, XJ., Jiang, X. et al. Plasma cell-free DNA chromosomal instability analysis by low-pass whole-genome sequencing to monitor breast cancer relapse. Breast Cancer Res Treat 178, 63–73 (2019). https://doi.org/10.1007/s10549-019-05375-w

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  • DOI: https://doi.org/10.1007/s10549-019-05375-w

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