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Plasma DNA integrity as a biomarker for primary and metastatic breast cancer and potential marker for early diagnosis

  • Epidemiology
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Abstract

Circulating or cell-free DNA (cfDNA) has been evaluated as a biomarker in many cancers including breast cancer. In particular, integrity of cfDNA has been shown to be altered in cancers. We have estimated the biomarker potential of cfDNA in primary (PBC) and metastatic breast cancer (MBC). cfDNA integrity (cfDI) and concentration were determined in plasma of 383 individuals, including 82 PBC and 201 MBC cases, as well as 100 healthy controls, by measuring ALU and LINE1 repetitive DNA elements using quantitative PCR. The MBC patient group was further sub-divided into patients with detectable circulating tumour cells (CTCpos-MBC, n = 100) and those without (CTCneg-MBC, n = 101). A hierarchical decrease in cfDI and increase in cfDNA concentration from healthy controls to PBC and further onto MBC patients were observed. Investigation of cfDNA in media of cell lines was in concordance with these results. Combination of cfDI and cfDNA concentration could differentiate PBC cases from controls (area under the curve, AUC = 0.75), MBC cases from controls (AUC = 0.81 for CTCneg-MBC, AUC = 0.93 for CTCpos-MBC), and CTCneg-MBC from CTCpos-MBC cases (AUC = 0.83). cfDI additionally demonstrated a positive correlation to progression-free (HR of 0.46 for ALU, P = 0.0025) and overall survival (HR of 0.15 for ALU and 0.20 for LINE1, P < 0.0001) in MBC, and had lower prediction error than CTC status. Our findings show that reduced cfDI and increased cfDNA concentration can serve as diagnostic markers for PBC and MBC, and cfDI as a prognostic marker for MBC, thereby making them attractive candidates for blood-based multi-marker assays.

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Abbreviations

AUC:

Area under the curve

cfDNA:

Circulating or cell-free DNA

cfDI:

Cell-free DNA integrity

CTC:

Circulating tumour cells

CTCpos-MBC:

Circulating tumour cells positive metastatic breast cancer

CTCneg-MBC:

Circulating tumour cells negative metastatic breast cancer

HR:

Hazard ratio

MBC:

Metastatic breast cancer

PBC:

Primary breast cancer

PFS:

Progression-free survival

OS:

Overall survival

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Acknowledgments

We thank the study participants and all our colleagues who helped us with patient recruitment, blood collection and processing. This study was funded and supported by the Dietmar-Hopp Foundation, the University Hospital of Heidelberg, the Helmholtz Society, and the German Cancer Research Center (DKFZ), Heidelberg, Germany.

Author information

Authors and Affiliations

  1. Molecular Epidemiology, C080, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Dharanija Madhavan, Katarina Cuk, Harald Surowy & Barbara Burwinkel

  2. Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany

    Dharanija Madhavan, Karin Bents, Katarina Cuk, Harald Surowy & Barbara Burwinkel

  3. Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany

    Markus Wallwiener, Juliane Nees, Sarah Schott, Christof Sohn & Andreas Schneeweiss

  4. National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany

    Markus Wallwiener, Juliane Nees & Andreas Schneeweiss

  5. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Manuela Zucknick

  6. Department of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Sabine Riethdorf & Klaus Pantel

  7. Hi-STEM-Heidelberg Institute for Stem Cell Technology and Experimental Medicine, GmbH, Heidelberg, Germany

    Andreas Trumpp

  8. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andreas Trumpp

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  1. Dharanija Madhavan
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  2. Markus Wallwiener
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  10. Klaus Pantel
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Corresponding author

Correspondence to Harald Surowy.

Additional information

H. Surowy and B. Burwinkel have contributed equally to this work.

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Madhavan, D., Wallwiener, M., Bents, K. et al. Plasma DNA integrity as a biomarker for primary and metastatic breast cancer and potential marker for early diagnosis. Breast Cancer Res Treat 146, 163–174 (2014). https://doi.org/10.1007/s10549-014-2946-2

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