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

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Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

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Abbreviations

1C:

One cycle of systemic chemotherapy

aCTC:

Apoptotic circulating tumor cell(s)

BL:

Baseline

CHT:

Chemotherapy

CI:

Confidence interval

CTC:

Circulating tumor cell(s)

DTC:

Disseminated tumor cell(s)

EMT:

Epithelial–mesenchymal transition

EpCAM:

Epithelial cell adhesion molecule

iCTC:

Intact circulating tumor cell(s)

KIN:

Kinetics

MBC:

Metastatic breast cancer

NA:

Not available/not applicable

NCT:

National Center for Tumor Diseases, Heidelberg, Germany

NST:

Neoadjuvant systemic therapy

OS:

Overall survival

PFS:

Progression-free survival

STD:

Standard deviation

References

  1. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791

    Article  CAS  PubMed  Google Scholar 

  2. Giordano A, Gao H, Anfossi S, Cohen E, Mego M, Lee BN, Tin S, De Laurentiis M, Parker CA, Alvarez RH et al (2012) Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol Cancer Ther 11(11):2526–2534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wallwiener M, Riethdorf S, Hartkopf AD, Modugno C, Nees J, Madhavan D, Sprick MR, Schott S, Domschke C, Baccelli I et al (2014) Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients. BMC Cancer 14:512

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12(14 Pt 1):4218–4224

    Article  CAS  PubMed  Google Scholar 

  5. Giuliano M, Giordano A, Jackson S, Hess KR, De Giorgi U, Mego M, Handy BC, Ueno NT, Alvarez RH, De Laurentiis M et al (2011) Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res 13(3):R67

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dawood S, Broglio K, Valero V, Reuben J, Handy B, Islam R, Jackson S, Hortobagyi GN, Fritsche H, Cristofanilli M (2008) Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system? Cancer 113(9):2422–2430

    Article  PubMed  Google Scholar 

  7. Fehm T, Sagalowsky A, Clifford E, Beitsch P, Saboorian H, Euhus D, Meng SD, Morrison L, Tucker T, Lane N et al (2002) Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 8(7):2073–2084

    CAS  PubMed  Google Scholar 

  8. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M et al (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544

    Article  CAS  PubMed  Google Scholar 

  9. Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, Matera J, Repollet M, Doyle GV, Terstappen LW et al (2006) Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res 12(21):6403–6409

    Article  CAS  PubMed  Google Scholar 

  10. Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, Marme F, Sohn C, Trumpp A, Rack B et al (2013) The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat 137(2):503–510

    Article  PubMed  Google Scholar 

  11. Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O’Rourke MA, Lew DL et al (2014) Circulating tumor cells and response to chemotherapy in metastatic breast cancer: sWOG S0500. J Clin Oncol 32(31):3483–3489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hartkopf AD, Wagner P, Wallwiener D, Fehm T, Rothmund R (2011) Changing levels of circulating tumor cells in monitoring chemotherapy response in patients with metastatic breast cancer. Anticancer Res 31(3):979–984

    PubMed  Google Scholar 

  13. Fehm T, Hoffmann O, Aktas B, Becker S, Solomayer EF, Wallwiener D, Kimmig R, Kasimir-Bauer S (2009) Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res 11(4):R59

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wallwiener M, Hartkopf AD, Riethdorf S, Nees J, Sprick MR, Schonfisch B, Taran FA, Heil J, Sohn C, Pantel K et al (2015) The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients. BMC Cancer 15:403

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mehes G, Witt A, Kubista E, Ambros PF (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159(1):17–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rossi E, Basso U, Celadin R, Zilio F, Pucciarelli S, Aieta M, Barile C, Sava T, Bonciarelli G, Tumolo S et al (2010) M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by Cell Search analysis. Clin Cancer Res 16(21):5233–5243

    Article  CAS  PubMed  Google Scholar 

  17. Kallergi G, Konstantinidis G, Markomanolaki H, Papadaki MA, Mavroudis D, Stournaras C, Georgoulias V, Agelaki S (2013) Apoptotic circulating tumor cells in early and metastatic breast cancer patients. Mol Cancer Ther 12(9):1886–1895

    Article  CAS  PubMed  Google Scholar 

  18. Krawczyk N, Hartkopf A, Banys M, Meier-Stiegen F, Staebler A, Wallwiener M, Rohm C, Hoffmann J, Hahn M, Fehm T (2014) Prognostic relevance of induced and spontaneous apoptosis of disseminated tumor cells in primary breast cancer patients. BMC Cancer 14:394

    Article  PubMed  PubMed Central  Google Scholar 

  19. Russo A, Terrasi M, Agnese V, Santini D, Bazan V (2006) Apoptosis: a relevant tool for anticancer therapy. Ann Oncol 17(Suppl 7 vii):115–123

    Google Scholar 

  20. Smerage JB, Budd GT, Doyle GV, Brown M, Paoletti C, Muniz M, Miller MC, Repollet MI, Chianese DA, Connelly MC et al (2013) Monitoring apoptosis and Bcl-2 on circulating tumor cells in patients with metastatic breast cancer. Mol Oncol 7(3):680–692

    Article  CAS  PubMed  Google Scholar 

  21. Fehm T, Becker S, Becker-Pergola G, Sotlar K, Gebauer G, Durr-Storzer S, Neubauer H, Wallwiener D, Solomayer EF (2006) Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer. Breast Cancer Res 8(5):R60

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hartkopf AD, Taran FA, Wallwiener M, Hagenbeck C, Melcher C, Krawczyk N, Hahn M, Wallwiener D, Fehm T (2013) The presence and prognostic impact of apoptotic and nonapoptotic disseminated tumor cells in the bone marrow of primary breast cancer patients after neoadjuvant chemotherapy. Breast Cancer Res 15(5):R94

    Article  PubMed  PubMed Central  Google Scholar 

  23. Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I et al (2010) Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 16(9):2634–2645

    Article  CAS  PubMed  Google Scholar 

  24. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  CAS  PubMed  Google Scholar 

  25. Riethdorf S, Pantel K (2008) Disseminated tumor cells in bone marrow and circulating tumor cells in blood of breast cancer patients: current state of detection and characterization. Pathobiology 75(2):140–148

    Article  PubMed  Google Scholar 

  26. Cristofanilli M (2009) The biological information obtainable from circulating tumor cells. Breast 18(Suppl 3):S38–S40

    Article  PubMed  Google Scholar 

  27. R: A Language and environment for statistical computing. http://www.r-project.org

  28. http://www.ago-online.de/en/guidelines-mamma/March-2015/

  29. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D et al (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162

    Article  PubMed  Google Scholar 

  30. Fehm T, Muller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, Lattrich C, Lohberg CR, Solomayer E, Rack B et al (2010) HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 124(2):403–412

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

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Author notes

    Authors and Affiliations

    1. National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

      Thomas M. Deutsch, Juliane Nees & Andreas Schneeweiss

    2. Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

      Sabine Riethdorf & Klaus Pantel

    3. Department of Obstetrics and Gynecology, University of Tübingen, Calwerstraße7, 72076, Tübingen, Germany

      Andreas D. Hartkopf, Birgitt Schönfisch & Sara Y. Brucker

    4. Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany

      Christoph Domschke, Florian Schütz, Stefan Stefanovic, Christof Sohn, Andreas Schneeweiss & Markus Wallwiener

    5. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGMBH), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

      Martin R. Sprick & Andreas Trumpp

    6. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

      Andreas Trumpp

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    1. Thomas M. Deutsch
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    Correspondence to Markus Wallwiener.

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    The authors declare that they have no competing interests.

    Additional information

    Thomas M. Deutsch and Sabine Riethdorf are joint first authors. Andreas Schneeweiss and Markus Wallwiener are joint senior authors.

    Thomas M. Deutsch, Sabine Riethdorf, Andreas Schneeweiss, and Markus Wallwiener have contributed equally to this work.

    Electronic supplementary material

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    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)

    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)

    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)

    Supplementary material 4 (DOCX 23 kb)

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    Deutsch, T.M., Riethdorf, S., Nees, J. et al. Impact of apoptotic circulating tumor cells (aCTC) in metastatic breast cancer. Breast Cancer Res Treat 160, 277–290 (2016). https://doi.org/10.1007/s10549-016-3997-3

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