Breast Cancer Research and Treatment

, Volume 169, Issue 1, pp 69–82 | Cite as

Circulating free DNA integrity and concentration as independent prognostic markers in metastatic breast cancer

  • Jie Cheng
  • Tim Holland-Letz
  • Markus Wallwiener
  • Harald Surowy
  • Katarina Cuk
  • Sarah Schott
  • Andreas Trumpp
  • Klaus Pantel
  • Christof Sohn
  • Andreas Schneeweiss
  • Barbara Burwinkel
Clinical trial
First Online:
Received:
Accepted:

Abstract

Purpose

Non-invasive blood-based molecular markers have been investigated for cancer diagnosis and prognosis. Circulating free or cell-free DNA (cfDNA) variables have been shown to be putative markers in breast cancer prognosis.

Methods

Here, we investigated the potential prognostic ability of cfDNA concentration and cfDNA integrity (cfDI) in a study cohort of 268 patients by quantitative PCR. We compared cfDNA concentration and cfDI at baseline and after one cycle of therapy in metastatic breast cancer (MBC) patients.

Results

A significantly increased cfDI (P = 1.21E-7 for ALU and P = 1.87E-3 for LINE1) and decreased cfDNA concentration (P = 1.17E-3 for ALU and P = 1.60E-2 for LINE1) in both repetitive DNA elements after one cycle of therapy was observed. A multiple Cox regression model indicated that cfDI and cfDNA concentration can serve as independent prognostic markers in patients at baseline with HR (95% CI) of 0.70 (0.48–1.01) for ALU cfDI, 0.63 (0.44–0.92) for LINE1 cfDI, 2.44 (1.68–3.53) for ALU cfDNA concentration, and 2.12 (1.47–3.06) for LINE1 cfDNA concentration and after one cycle of therapy with HR (95% CI) of 0.59 (0.42–0.84) for ALU cfDI, 0.51 (0.36–0.74) for LINE1 cfDI, 1.59 (1.31–1.92) for ALU cfDNA concentration, and 1.30 (1.17–1.45) for LINE1 cfDNA concentration, respectively. By comparing integrated prediction error of different models, cfDNA variables were shown to improve the prognostic power of the CTC status.

Conclusions

We hereby show that cfDNA variables, especially in combination with other markers, can serve as attractive prognostic markers for MBC patients at baseline and during the systematic therapy.

Keywords

Metastatic breast cancer Circulating DNA concentration Circulating DNA integrity Circulating tumor cells Prognostic marker 

Abbreviations

AUC

Area under the curve

BL

Baseline

cfDI

Circulating free or cell-free DNA integrity

cfDNA

Circulating free or cell-free DNA

CI

Confidence interval

CTC

Circulating tumor cell

HR

Hazard ratio

IPE

Integrated prediction errors

MBC

Metastatic breast cancer

NCT

National Center for Tumor Diseases, Heidelberg, Germany

PFS

Progression-free survival

OS

Overall survival

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Notes

Acknowledgements

We thank the study participants and all our colleagues who helped us with patient recruitment, blood collection, and processing. The study has been supported by cellgene.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2018_4666_MOESM1_ESM.docx (1.3 mb)
Supplementary material 1 (DOCX 1312 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jie Cheng
    • 1
    • 2
  • Tim Holland-Letz
    • 3
  • Markus Wallwiener
    • 4
    • 5
  • Harald Surowy
    • 1
    • 2
  • Katarina Cuk
    • 1
    • 2
  • Sarah Schott
    • 4
  • Andreas Trumpp
    • 6
    • 7
  • Klaus Pantel
    • 8
  • Christof Sohn
    • 4
  • Andreas Schneeweiss
    • 4
    • 5
  • Barbara Burwinkel
    • 1
    • 2
  1. 1.Division of Molecular EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Molecular Biology of Breast Cancer, Department of Gynecology and ObstetricsUniversity of HeidelbergHeidelbergGermany
  3. 3.Department of BiostatisticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Department of Gynecology and ObstetricsUniversity Women’s ClinicHeidelbergGermany
  5. 5.National Center for Tumor DiseasesUniversity of HeidelbergHeidelbergGermany
  6. 6.Division of Stem Cells and CancerGerman Cancer Research Center (DKFZ)HeidelbergGermany
  7. 7.Hi-STEM-Heidelberg Institute for Stem Cell Technology and Experimental Medicine, GmbHHeidelbergGermany
  8. 8.Department of Tumor BiologyUniversity Hospital Hamburg-EppendorfHamburgGermany

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