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Disseminated tumor cells as a monitoring tool for adjuvant therapy in patients with primary breast cancer

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Abstract

The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of early breast cancer patients at initial surgery as well as during follow-up predicts an unfavorable outcome. This study aimed to assess whether adjuvant systemic therapy has the ability to eradicate DTC and to determine the clinical impact of DTC-persistence. Between 12 and 24 months after an initial BM aspiration during primary surgery (BMA1) a second and third bone marrow aspiration (BMA2 and BMA3, respectively) was performed. DTC were identified by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology. A total of 190 patients who were DTC-positive at BMA1 were eligible for this retrospective analysis. DTC persisted in 35 of 190 (19 %) patients at BMA2 and in 11 of 71 (16 %) patients at BMA3. DTC-persistence at BMA3 was significantly lower in patients that received adjuvant endocrine therapy (p = 0.017). At BMA2, DTC-positive patients were at an increased risk of disease recurrence (HR: 4.17, 95 % CI: 1.51–11.50, p = 0.003) and death (HR: 5.02, 95 % CI: 1.156–21.83, p = 0.031). At BMA3, the presence of DTC was associated with shorter disease free survival (HR: 3.20, 95 % CI: 1.05–9.78, p = 0.010). In conclusion, a majority of initially DTC-positive primary breast cancer patients turned negative during adjuvant treatment. As DTC-persistence predicted an adverse outcome, serial DTC-determination can identify patients that will probably benefit from additional or a switch of adjuvant therapy.

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References

  1. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802

    Article  CAS  PubMed  Google Scholar 

  2. Diel IJ, Kaufmann M, Costa SD, Holle R, von Minckwitz G, Solomayer EF, Kaul S, Bastert G (1996) Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 88(22):1652–1658

    Article  CAS  PubMed  Google Scholar 

  3. Gebauer G, Fehm T, Merkle E, Beck EP, Lang N, Jager W (2001) Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-up. J Clin Oncol 19(16):3669–3674

    CAS  PubMed  Google Scholar 

  4. Mansi JL, Gogas H, Bliss JM, Gazet JC, Berger U, Coombes RC (1999) Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study. Lancet 354(9174):197–202

    Article  CAS  PubMed  Google Scholar 

  5. Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342(8):525–533

    Article  CAS  PubMed  Google Scholar 

  6. Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland JM, Qvist H, Schlichting E, Sauer T, Janbu J, Harbitz T, Naume B (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 21(18):3469–3478

    Article  CAS  PubMed  Google Scholar 

  7. Molino A, Pelosi G, Turazza M, Sperotto L, Bonetti A, Nortilli R, Fattovich G, Alaimo C, Piubello Q, Pavanel F, Micciolo R, Cetto GL (1997) Bone marrow micrometastases in 109 breast cancer patients: correlations with clinical and pathological features and prognosis. Breast Cancer Res Treat 42(1):23–30

    Article  CAS  PubMed  Google Scholar 

  8. Harbeck N, Untch M, Pache L, Eiermann W (1994) Tumour cell detection in the bone marrow of breast cancer patients at primary therapy: results of a 3-year median follow-up. Br J Cancer 69(3):566–571

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Pierga JY, Bonneton C, Vincent-Salomon A, de Cremoux P, Nos C, Blin N, Pouillart P, Thiery JP, Magdelenat H (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10(4):1392–1400

    Article  CAS  PubMed  Google Scholar 

  10. Hartkopf AD, Taran FA, Brucker S, Hahn M, Wallwiener D, Becker S, Solomayer EF, Wallwiener M, Fehm T (2013) The prognostic relevance of disseminated tumor cells (DTC) form the bone marrow (BM) in different molecular subtypes of primary breast cancer (PBC) patients. San Antonio Breast Cancer Symposium Abstract PD6-7

  11. Janni W, Vogl FD, Wiedswang G, Synnestvedt M, Fehm T, Juckstock J, Borgen E, Rack B, Braun S, Sommer H, Solomayer E, Pantel K, Nesland J, Friese K, Naume B (2011) Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse—a European pooled analysis. Clin Cancer Res 17(9):2967–2976

    Article  PubMed  Google Scholar 

  12. Wiedswang G, Borgen E, Karesen R, Qvist H, Janbu J, Kvalheim G, Nesland JM, Naume B (2004) Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 10(16):5342–5348

    Article  PubMed  Google Scholar 

  13. Becker S, Becker-Pergola G, Wallwiener D, Solomayer EF, Fehm T (2006) Detection of cytokeratin-positive cells in the bone marrow of breast cancer patients undergoing adjuvant therapy. Breast Cancer Res Treat 97(1):91–96

    Article  CAS  PubMed  Google Scholar 

  14. Janni W, Rack B, Schindlbeck C, Strobl B, Rjosk D, Braun S, Sommer H, Pantel K, Gerber B, Friese K (2005) The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 103(5):884–891

    Article  PubMed  Google Scholar 

  15. Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8(5):329–340

    Article  CAS  PubMed  Google Scholar 

  16. Hartkopf AD, Banys M, Fehm T (2012) HER2-positive DTCs/CTCs in breast cancer. Recent Results Cancer Res 195:203–215

    Article  PubMed  Google Scholar 

  17. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2009) Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20(8):1319–1329

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Bauer KD, de la Torre-Bueno J, Diel IJ, Hawes D, Decker WJ, Priddy C, Bossy B, Ludmann S, Yamamoto K, Masih AS, Espinoza FP, Harrington DS (2000) Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging. Clin Cancer Res 6(9):3552–3559

    CAS  PubMed  Google Scholar 

  19. Borgen E, Naume B, Nesland JM, Kvalheim G, Beiske K, Fodstad O, Diel I, Solomayer EF, Theocharous P, Coombes RC, Smith BM, Wunder E, Marolleau JP, Garcia J, Pantel K (1999) Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. establishment of objective criteria for the evaluation of immunostained cells. Cytotherapy 1(5):377–388

    Article  CAS  PubMed  Google Scholar 

  20. Fehm T, Braun S, Muller V, Janni W, Gebauer G, Marth C, Schindlbeck C, Wallwiener D, Borgen E, Naume B, Pantel K, Solomayer E (2006) A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 107(5):885–892

    Article  PubMed  Google Scholar 

  21. Synnestvedt M, Borgen E, Wist E, Wiedswang G, Weyde K, Risberg T, Kersten C, Mjaaland I, Vindi L, Schirmer C, Nesland JM, Naume B (2012) Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study. BMC Cancer 12(1):616

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Kuukasjarvi T, Kononen J, Helin H, Holli K, Isola J (1996) Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14(9):2584–2589

    CAS  PubMed  Google Scholar 

  23. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757

    Article  PubMed  Google Scholar 

  24. Fehm T, Krawczyk N, Solomayer EF, Becker-Pergola G, Durr-Storzer S, Neubauer H, Seeger H, Staebler A, Wallwiener D, Becker S (2008) ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients. Breast Cancer Res 10(5):R76

    Article  PubMed Central  PubMed  Google Scholar 

  25. Hartkopf AD, Banys M, Meier-Stiegen F, Hahn M, Rohm C, Hoffmann J, Helms G, Taran FA, Wallwiener M, Walter C, Neubauer H, Wallwiener D, Fehm T (2013) The HER2 status of disseminated tumor cells in the bone marrow of early breast cancer patients is independent from primary tumor and predicts higher risk of relapse. Breast Cancer Res Treat 138(2):509–517

    Article  CAS  PubMed  Google Scholar 

  26. Ditsch N, Mayer B, Rolle M, Untch M, Schildberg FW, Funke I (2003) Estrogen receptor expression profile of disseminated epithelial tumor cells in bone marrow of breast cancer patients. Recent Results Cancer Res 162:141–147

    Article  CAS  PubMed  Google Scholar 

  27. Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH, Riethmuller G (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360(9334):683–689

    Article  CAS  PubMed  Google Scholar 

  28. Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen LW, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 101(25):9393–9398

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Becker S, Solomayer E, Becker-Pergola G, Wallwiener D, Fehm T (2007) Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 106(2):239–243

    Article  PubMed  Google Scholar 

  30. Banys M, Hartkopf A, Krawczyk N, Kaiser T, Meier-Stiegen F, Fehm T, Neubauer H (2012) Dormany in beast cancer. Breast Cancer Targets Ther 4:183–191

    CAS  Google Scholar 

  31. Diel IJ, Jaschke A, Solomayer EF, Gollan C, Bastert G, Sohn C, Schuetz F (2008) Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 19(12):2007–2011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Rack B, Juckstock J, Genss EM, Schoberth A, Schindlbeck C, Strobl B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese K, Janni W (2010) Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 30(5):1807–1813

    CAS  PubMed  Google Scholar 

  33. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M, Bastert G (1998) Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339(6):357–363

    Article  CAS  PubMed  Google Scholar 

  34. Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K (2000) Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J Clin Oncol 18(1):80–86

    CAS  PubMed  Google Scholar 

  35. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162

    Article  PubMed  Google Scholar 

  36. Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I, Hilfrich J, Holms F, Tesch H, Eidtmann H, Untch M, von Minckwitz G, Pantel K (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 

  37. Rack B, Juckstock J, Gunthner-Biller M, Andergassen U, Neugebauer J, Hepp P, Schoberth A, Mayr D, Zwingers T, Schindlbeck C, Friese K, Janni W (2012) Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients. Arch Gynecol Obstet 285(2):485–492

    Article  CAS  PubMed  Google Scholar 

  38. Georgoulias V, Bozionelou V, Agelaki S, Perraki M, Apostolaki S, Kallergi G, Kalbakis K, Xyrafas A, Mavroudis D (2012) Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK-19mRNA-positive circulating tumor cells: results of a randomized phase II study. Ann Oncol 23(7):1744–1750

    Article  CAS  PubMed  Google Scholar 

  39. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (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 

  40. Pierga JY, Bidard FC, Mathiot C, Brain E, Delaloge S, Giachetti S, de Cremoux P, Salmon R, Vincent-Salomon A, Marty M (2008) Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res 14(21):7004–7010

    Article  CAS  PubMed  Google Scholar 

  41. Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis C, Apostolaki S, Malamos N, Kakolyris S, Kotsakis A, Xenidis N, Reppa D, Georgoulias V (2002) Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol 20(16):3404–3412

    Article  CAS  PubMed  Google Scholar 

  42. Molloy TJ, Bosma AJ, Baumbusch LO, Synnestvedt M, Borgen E, Russnes HG, Schlichting E, van’t Veer LJ, Naume B (2011) The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients. Breast Cancer Res 13(3):R61

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Tuebingen, Calwerstrasse 7, 72076, Tübingen, Germany

    Ines Gruber, Florin Andrei Taran, Markus Hahn, Diethelm Wallwiener & Andreas Daniel Hartkopf

  2. Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany

    Tanja Fehm, Natalia Krawzyck & Juergen Hoffmann

  3. Department of Obstetrics and Gynecology, University of Duesseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany

    Markus Wallwiener

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  1. Ines Gruber
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  2. Tanja Fehm
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  3. Florin Andrei Taran
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Correspondence to Ines Gruber.

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Ines Gruber and Tanja Fehm contributed equally to this publication.

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Gruber, I., Fehm, T., Taran, F.A. et al. Disseminated tumor cells as a monitoring tool for adjuvant therapy in patients with primary breast cancer. Breast Cancer Res Treat 144, 353–360 (2014). https://doi.org/10.1007/s10549-014-2853-6

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  • DOI: https://doi.org/10.1007/s10549-014-2853-6

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