Breast Cancer Research and Treatment

, Volume 173, Issue 1, pp 155–165 | Cite as

Sustained prognostic impact of circulating tumor cell status and kinetics upon further progression of metastatic breast cancer

  • Sarah F. JauchEmail author
  • Sabine Riethdorf
  • Martin R. Sprick
  • Florian Schütz
  • Birgitt Schönfisch
  • Sara Y. Brucker
  • Thomas M. Deutsch
  • Juliane Nees
  • Massimo Saini
  • Lisa M. Becker
  • Barbara Burwinkel
  • Peter Sinn
  • Frederik Marmé
  • Klaus Pantel
  • Dirk Jäger
  • Christof Sohn
  • Andreas Trumpp
  • Markus Wallwiener
  • Andreas Schneeweiss
Clinical trial



Serial longitudinal enumeration of circulating tumor cells (CTCs) has shown its prognostic value on progression-free survival and overall survival (OS) in patients with stage IV breast cancer. This study prospectively evaluated the role of CTCs as a prognostic marker during further progression of metastatic breast cancer (MBC).


Among 476 MBC patients recruited between 2010 and 2015, the 103 patients with a known CTC status at baseline (CTCBL) and within 4 weeks of tumor progression (CTCPD) were included. Progressive disease (PD) was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Using the CellSearch method, < 5 and ≥ 5 CTCs per 7.5 ml blood were determined as negative and positive, respectively. A shift in CTC status from baseline to progression (\({\text {CTC}_\text {BL}}^+\) to \({\text {CTC}_\text {PD}}^-\) and vice versa) was considered as alternating KineticsBL–PD.


Median follow-up was 29.9 [21.2, 40.0] months. CTCPD positivity (37%, n = 38) was associated with a significantly shorter OS than CTCPD negativity (8.0 [5.1, 10.9] vs 22.6 [15.3, 39.8] months; P < 0.001). Alternating KineticsBL–PD was observed in 24% of the patients. This significantly changed the OS prediction of \({\text {CTC}_\text {BL}}^+\) patients (\({{\text {CTC}_\text {BL}}^+}{{\text {CTC}_\text {PD}}^-}\) vs \({{\text {CTC}_\text {BL}}^+}{{\text {CTC}_\text {PD}}^+}\), 11.4 [9.7, not available (NA)] vs. 7.6 [4.4, 11.5] months; P = 0.044) and \({\text {CTC}_\text {BL}}^-\) patients (\({{\text {CTC}_\text {BL}}^-}{{\text {CTC}_\text {PD}}^+}\) vs. \({{\text {CTC}_\text {BL}}^-}{{\text {CTC}_\text {PD}}^-}\), 8.4 [4.0, NA] vs. 22.6 [18.9, NA] months, respectively; P < 0.001).

Prediction of survival was significantly improved (P = 0.002) by adding CTCPD status to clinicopathological characteristics and CTCBL status.


CTC status upon further disease progression is a prognostic factor that could significantly improve well-established models. Thus, it represents a potential additional instrument supporting treatment decision.


CTCs Circulating tumor cells Metastatic breast cancer Progressive disease Survival Prognostic marker 



Metastatic breast cancer


Circulating tumor cells


Progression-free survival


Overall survival


Carcinoembryonic antigen


Cancer antigen 15-3


Intact circulating tumor cells


Apoptotic circulating tumor cells


Enucleated fragments of circulating tumor cells


National Center for Tumor Diseases


Reporting recommendations for tumor marker prognostic studies


Response Evaluation Criteria in Solid Tumors


Stable disease


Partial response


Complete response


Progressive disease


Baseline/study inclusion


CTC status at baseline


CTC status within 4 weeks of tumor progression


US Food and Drug Administration


Anti-epithelial cellular adhesion molecule antibody



\({\text {CTC}_\text {BL}}^-/{\text {CTC}_\text {BL}}^+\)

Negative/positive CTC status at baseline

\({\text {CTC}_\text {PD}}^-/{\text {CTC}_\text {PD}}^+\)

Negative/positive CTC status within 4 weeks of tumor progression


Course of intact CTCs from BL to PD


Course of apoptotic CTCs from BL to PD


Course of enucleated fragments of CTCs from BL to PD

\({\text {Kinetics}_\text {BL-PD}}^{-/+}\)

\({\text {CTC}_\text {BL}}^-\) to \({\text {CTC}_\text {PD}}^+\)

\({\text {Kinetics}_\text {BL-PD}}^{+/-}\)

\({\text {CTC}_\text {BL}}^+\) to \({\text {CTC}_\text {PD}}^-\)

\({\text {Kinetics}_\text {BL-PD}}^{+/+}\)

\({\text {CTC}_\text {BL}}^+\) to \({\text {CTC}_\text {PD}}^+\)

\({\text {Kinetics}_\text {BL-PD}}^{-/-}\)

\({\text {CTC}_\text {BL}}^-\) to \({\text {CTC}_\text {PD}}^-\)


Spearman correlation coefficient


Confidence interval


Bayesian information criterion


Hormone receptor or hazard ratio


Human epidermal growth factor receptor 2


Estrogen receptor


Progesterone receptor


Triple-negative breast cancer


Circulating tumor DNA



The authors thank all the patients who participated in this study. We gratefully acknowledge the medical and nursing staff at the National Center for Tumor Diseases (NCT) Heidelberg and the University Hospital Heidelberg, especially Mirjam Becker, Bettina Mutz, and Martina Scharpff as well as Caroline Modugno for supporting patient recruitment, follow-up, and data collection. We further thank the team involved at University Medical Center Hamburg–Eppendorf for technical assistance during CTC measurement.


This work was supported by In-house Funds of the National Center for Tumor Diseases (NCT, to AS, no grant number applies). AT has received funding from Swiss Bridge (no grant number applies), the Helmholtz Initiative on Personalized Medicine (iMED, no grant number applies), Europe’s Innovative Medicines Initiative (IMI) Consortium Cancer-ID (115749), the Cancer Core Europe/Transcan Breast Project (01KT1608), the German Federal Ministry of Education and Research (BMBF N02/74829), and the Dietmar Hopp Foundation (no grant number applies).

Compliance with ethical standards

Conflict of interest

FS has served as a Consultant/Advisor for Roche and Novartis and has received Honoraria from Roche, Novartis, and Amgen. FM has served as a Consultant/Advisor for Roche, Pfizer, Novartis, AstraZeneca, and Tesara and has received travel, accommodations, and expenses from Roche, Novartis, Pfizer, AstraZeneca, and Honoraria from Roche, Pfizer, Novartis, Amgen, AstraZeneca, PharmaMar, Genomic Health, and Tesara. MW has provided Expert Testimony for Novartis, has received Honoraria from Novartis and Celgene and travel, accommodations, and expenses from Novartis. AS has received Honoraria from Roche, Celgene, AstraZeneca, Novartis, and Pfizer; research funding from Celgene; and travel, accommodations, and expenses from Roche and Celgene. All remaining authors have declared no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the Ethical Standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

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

Supplementary material

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Supplementary material 1 (TIF 8308 KB)
10549_2018_4972_MOESM2_ESM.pdf (2 kb)
Supplementary material 2 (PDF 2 KB)
10549_2018_4972_MOESM3_ESM.pdf (68 kb)
Supplementary material 3 (PDF 67 KB)


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Copyright information

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

Authors and Affiliations

  • Sarah F. Jauch
    • 1
    • 2
    • 3
    • 4
    Email author
  • Sabine Riethdorf
    • 5
  • Martin R. Sprick
    • 3
    • 4
  • Florian Schütz
    • 2
  • Birgitt Schönfisch
    • 6
  • Sara Y. Brucker
    • 6
  • Thomas M. Deutsch
    • 1
    • 2
  • Juliane Nees
    • 1
    • 2
  • Massimo Saini
    • 3
    • 4
  • Lisa M. Becker
    • 3
    • 4
  • Barbara Burwinkel
    • 2
    • 7
  • Peter Sinn
    • 8
  • Frederik Marmé
    • 1
    • 2
  • Klaus Pantel
    • 5
  • Dirk Jäger
    • 9
  • Christof Sohn
    • 2
  • Andreas Trumpp
    • 3
    • 4
    • 10
    • 11
  • Markus Wallwiener
    • 2
  • Andreas Schneeweiss
    • 1
    • 2
  1. 1.Division of Gynecologic OncologyNational Center for Tumor Diseases (NCT)HeidelbergGermany
  2. 2.Department of Obstetrics and GynecologyUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)HeidelbergGermany
  4. 4.Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ)DKFZ-ZMBH-AllianceHeidelbergGermany
  5. 5.Department of Tumor BiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.Department of Obstetrics and GynecologyUniversity Hospital TübingenTübingenGermany
  7. 7.Division of Molecular EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  8. 8.Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
  9. 9.Department of Medical OncologyNational Center for Tumor Diseases (NCT)HeidelbergGermany
  10. 10.Faculty of BiosciencesUniversity of HeidelbergHeidelbergGermany
  11. 11.German Cancer Consortium (DKTK)HeidelbergGermany

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