Breast Cancer Research and Treatment

, Volume 160, Issue 2, pp 277–290 | Cite as

Impact of apoptotic circulating tumor cells (aCTC) in metastatic breast cancer

  • Thomas M. Deutsch
  • Sabine Riethdorf
  • Juliane Nees
  • Andreas D. Hartkopf
  • Birgitt Schönfisch
  • Christoph Domschke
  • Martin R. Sprick
  • Florian Schütz
  • Sara Y. Brucker
  • Stefan Stefanovic
  • Christof Sohn
  • Klaus Pantel
  • Andreas Trumpp
  • Andreas Schneeweiss
  • Markus Wallwiener
Clinical trial



While intact circulating tumor cells (iCTC) have independent negative prognostic impact on patients with metastatic breast cancer (MBC), the prognostic relevance of apoptotic CTC (aCTC) has not been validated in larger patient cohorts. This study assessed aCTC and iCTC statuses at baseline (CTCBL) and CTC kinetics (CTCKIN) as changes from CTCBL to one completed treatment cycle for their utility in predicting response, progression-free survival (PFS), and overall survival (OS) in MBC.


Status of iCTC and aCTC was prospectively assessed in 442 patients using the CellSearch™ system. Different cutoffs were analyzed both for iCTC and aCTC (≥5, ≥10, ≥25 and ≥50 CTC/7.5 ml). CTCKIN were characterized by ≥25 % changes in CTC counts.


Numbers of iCTC and aCTC at baseline correlated strongly (r = 0.7). For iCTCBL positive patients, additional detection of aCTCBL had a significant prognostic impact on OS (aCTCBL positive 10.3 vs. aCTCBL negative 16.4 months, p = 0.012). Worst prognosis for OS was observed in patients with ≥50 iCTC/7.5 ml and simultaneously detected aCTC. Determination of aCTCKIN showed stronger discriminating power than iCTCKIN, with higher PFS and OS for the group with decreasing CTCs (PFS 7.7 vs. 6.1; OS 22.2 vs. 16.4).


Intact and aCTC are predictive of outcome in MBC. Apoptotic CTC counts ≥ 5/7.5 ml in conjunction with iCTC at baseline have an independent unfavorable prognostic impact on OS. Decreasing aCTCKIN at ≥ 5/7.5 ml in serial enumeration is associated with favorable outcome. Therefore, separate enumeration of iCTC and aCTC is useful in tailoring systemic treatment.


Metastatic breast cancer Circulating tumor cell Apoptotic circulating tumor cell Treatment response Kinetic Survival 



One cycle of systemic chemotherapy


Apoptotic circulating tumor cell(s)






Confidence interval


Circulating tumor cell(s)


Disseminated tumor cell(s)


Epithelial–mesenchymal transition


Epithelial cell adhesion molecule


Intact circulating tumor cell(s)




Metastatic breast cancer


Not available/not applicable


National Center for Tumor Diseases, Heidelberg, Germany


Neoadjuvant systemic therapy


Overall survival


Progression-free survival


Standard deviation



The authors gratefully acknowledge all patients whose data were used in this study. We also thank the medical and nursing staff, especially Martina Scharpff, at the National Center for Tumor Diseases (NCT; Heidelberg) for excellent management and care of our patients; the NCT laboratory staff; and Antje Andreas; Cornelia Coith; and Oliver Mauermann (Hamburg), who provided excellent technical assistance with the CTC determinations. This study was supported by NCT in-house funds, made available to AS and AT, and by grants to AT from the BioRN Leading Edge Cluster “Molecular and Cell Based Medicine” (BRN 02GS1893), supported by the German Federal Ministry of Education and Research (BMBF), Berlin, Germany (BMBF N02/74829), and the Dietmar Hopp Foundation. Moreover, this study was supported by the ERC-2010-AdG_20100317 DISSECT to KP. We acknowledge the financial support from the German Research Foundation (DFG) and Ruprecht-Karls-Universität Heidelberg through the funding program for Open Access Publishing.

Authors’ contributions

MW, ADH, SR, KP, AT, and AS jointly conceived the study and developed its design. MW and AS supervised the study. SR and KP developed the methodology. TMD, SR, JN, ADH, MRS, BS, CS, KP, AT, AS, and MW participated in patient recruitment, patient management, clinical data collection, sample collection, and sample analysis. BS and TMD organized and reported the data, constructed the databases, and conducted data management. BS performed the statistical analysis. TMD, JN, ADH, SS, SYB, SR, FS, CD, MRS, BS, CS, AT, AS, and MW participated in data analysis and interpretation. TMD, JN, ADH, BS, AS, and MW drafted the manuscript. MW, SR, MRS, CS, KP, SR, SS, TMD, ADH, BS, SYB, AS, and AT revised the draft manuscript for important intellectual input. MW prepared the final manuscript. All the authors read and approved the final manuscript.

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

Supplementary material

10549_2016_3997_MOESM1_ESM.eps (404 kb)
Supplementary material 1 (EPS 404 kb) Supplementary Fig. 1 Kaplan–Meier plots for OS with different cutoff values for iCTCKIN and aCTCKIN. OS by CTC status between baseline and first cycle in 252 patients with MBC: <5 CTC (<5 CTC in cells in both CTCBL and CTC1C), stable (<25 % change), decrease (≥25 % decrease), and increase (≥25 % increase)
10549_2016_3997_MOESM2_ESM.eps (342 kb)
Supplementary material 2 (EPS 342 kb) Supplementary Fig. 2 Kaplan–Meier plots for PFS with different cutoff values for iCTCKIN and aCTCKIN. PFS by CTC status between baseline and first cycle in 252 patients with MBC: <5 CTC (<5 CTC in cells in both CTCBL and CTC1C), stable (<25 % change), decrease (≥25 % decrease), and increase (≥25 % increase)
10549_2016_3997_MOESM3_ESM.eps (107 kb)
Supplementary material 3 (EPS 106 kb) Supplementary Fig. 3. Kaplan–Meier plots—Kinetic of apoptotic CTC between first cycle and progression disease. OS by CTC status between first cycle and progression disease in 189 patients with MBC: < 5 CTC (<5 CTC in cells in both CTCBL and CTC1C), stable (<25 % change), decrease (≥25 % decrease), increase (≥25 % increase)
10549_2016_3997_MOESM4_ESM.docx (23 kb)
Supplementary material 4 (DOCX 23 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Thomas M. Deutsch
    • 1
  • Sabine Riethdorf
    • 2
  • Juliane Nees
    • 1
  • Andreas D. Hartkopf
    • 3
  • Birgitt Schönfisch
    • 3
  • Christoph Domschke
    • 4
  • Martin R. Sprick
    • 5
  • Florian Schütz
    • 4
  • Sara Y. Brucker
    • 3
  • Stefan Stefanovic
    • 4
  • Christof Sohn
    • 4
  • Klaus Pantel
    • 2
  • Andreas Trumpp
    • 5
    • 6
  • Andreas Schneeweiss
    • 1
    • 4
  • Markus Wallwiener
    • 4
  1. 1.National Center for Tumor DiseasesHeidelbergGermany
  2. 2.Department of Tumor BiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Department of Obstetrics and GynecologyUniversity of TübingenTübingenGermany
  4. 4.Department of Obstetrics and GynecologyUniversity of HeidelbergHeidelbergGermany
  5. 5.Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGMBH)HeidelbergGermany
  6. 6.Division of Stem Cells and CancerGerman Cancer Research Center (DKFZ)HeidelbergGermany

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