Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA

Eur J Cancer. 2019 Jan;106:133-143. doi: 10.1016/j.ejca.2018.10.012. Epub 2018 Dec 4.


Background: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients.

Methods: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models.

Results: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level.

Conclusions: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients.

Keywords: Circulating cell-free DNA (ccfDNA); Circulating tumour cell (CTC); Metastatic breast cancer (MBC); Prognosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / blood
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Count
  • Circulating Tumor DNA / blood
  • Circulating Tumor DNA / genetics*
  • Disease Progression
  • Female
  • Humans
  • Liquid Biopsy
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplastic Cells, Circulating / pathology*
  • Predictive Value of Tests
  • Progression-Free Survival
  • Real-Time Polymerase Chain Reaction
  • Risk Assessment
  • Risk Factors
  • Time Factors


  • Circulating Tumor DNA