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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
  • 340 Downloads

Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

Keywords

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

Abbreviations

MBC

Metastatic breast cancer

CTCs

Circulating tumor cells

PFS

Progression-free survival

OS

Overall survival

CEA

Carcinoembryonic antigen

CA15-3

Cancer antigen 15-3

iCTCs

Intact circulating tumor cells

aCTCs

Apoptotic circulating tumor cells

fCTCs

Enucleated fragments of circulating tumor cells

NCT

National Center for Tumor Diseases

REMARK

Reporting recommendations for tumor marker prognostic studies

RECIST

Response Evaluation Criteria in Solid Tumors

SD

Stable disease

PR

Partial response

CR

Complete response

PD

Progressive disease

BL

Baseline/study inclusion

CTCBL

CTC status at baseline

CTCPD

CTC status within 4 weeks of tumor progression

FDA

US Food and Drug Administration

anti-EpCAM

Anti-epithelial cellular adhesion molecule antibody

DAPI

4,2-Diamidino-2-phenylindole

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

Negative/positive CTC status at baseline

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

Negative/positive CTC status within 4 weeks of tumor progression

iKineticsBL–PD

Course of intact CTCs from BL to PD

aKineticsBL–PD

Course of apoptotic CTCs from BL to PD

fKineticsBL–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 \({\text {CTC}_\text {PD}}^-\)

rs

Spearman correlation coefficient

CI

Confidence interval

BIC

Bayesian information criterion

HR

Hormone receptor or hazard ratio

HER2

Human epidermal growth factor receptor 2

ER

Estrogen receptor

PR

Progesterone receptor

TNBC

Triple-negative breast cancer

ctDNA

Circulating tumor DNA

Notes

Acknowledgements

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.

Funding

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

10549_2018_4972_MOESM1_ESM.tif (8.1 mb)
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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