Archives of Gynecology and Obstetrics

, Volume 285, Issue 2, pp 485–492

Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients

  • Brigitte Rack
  • Julia Jückstock
  • Maria Günthner-Biller
  • Ulrich Andergassen
  • Julia Neugebauer
  • Philip Hepp
  • Alexandra Schoberth
  • Doris Mayr
  • Thomas Zwingers
  • Christian Schindlbeck
  • Klaus Friese
  • Wolfgang Janni
Gynecologic Oncology

Abstract

Purpose

Isolated tumor cells (ITC) in the bone marrow of breast cancer patients increase the risk of recurrence and decrease survival, both at primary diagnosis and during follow-up. We tested the efficacy of trastuzumab in clearing HER2/neu-positive ITC from the marrow of patients completing primary treatment.

Methods

Ten recurrence-free patients with persistent HER2/neu-positive ITC after routine adjuvant treatment received trastuzumab 6 mg/kg q3w for 12 months in a non-randomized pilot phase II interventional study. Bone marrow ITC HER2/neu status was evaluated at baseline, after treatment for 3, 6 and 12 months, and yearly thereafter, in combination with clinical follow-up. Median follow-up was 23 (15–64) months after baseline bone marrow aspiration.

Results

Trastuzumab for 12 months eradicated HER2/neu-positive ITC from bone marrow in all patients (P = 0.002) and significantly reduced the number of ITC-positive patients (P = 0.031). However, HER2/neu-negative ITC persisted in three patients immediately after treatment and were detected at yearly bone marrow aspiration in five patients. Two patients with ITC counts ≥5 at yearly follow-up developed metastases and one died.

Conclusion

This is the first evidence that trastuzumab is effective in clearing HER2/neu-positive cells from bone marrow during recurrence-free follow-up in breast cancer patients. It also suggests, thanks to the antigen shift phenomenon, an important prognostic role for HER2/neu expression on marrow ITC as a real-time biopsy. However, treatment was mainly effective in patients with HER2/neu-positive ITC. Given the heterogeneity of minimal residual disease, these patients might benefit from a combination of targeted treatment approaches.

Keywords

Breast cancer Recurrence-free follow-up Isolated tumor cells Minimal residual disease Trastuzumab treatment 

References

  1. 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 353:793–802PubMedCrossRefGoogle Scholar
  2. 2.
    Janni W, Vogl FD, Wiedswang G, Synnestvedt M, Fehm T, Jückstock 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 Google Scholar
  3. 3.
    Simmons C, Miller N, Geddie W, Gianfelice D, Oldfield M, Dranitsaris G, Clemons MJ (2009) Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol 20:1499–1504PubMedCrossRefGoogle Scholar
  4. 4.
    Santinelli A, Pisa E, Stramazzotti D, Fabris G (2008) HER-2 status discrepancy between primary breast cancer and metastatic sites. Impact on target therapy. Int J Cancer 122:999–1004PubMedCrossRefGoogle Scholar
  5. 5.
    Yonemori K, Tsuta K, Shimizu C, Hatanaka Y, Hashizume K, Ono M, Nakanishi Y, Hasegawa T, Miyakita Y, Narita Y, Shibui S, Fujiwara Y (2008) Immunohistochemical profiles of brain metastases from breast cancer. J Neurooncol 90:223–228PubMedCrossRefGoogle Scholar
  6. 6.
    Vincent-Salomon A, Pierga JY, Couturier J, d’Enghien CD, Nos C, Sigal-Zafrani B, Lae M, Freneaux P, Dieras V, Thiery JP, Sastre-Garau X (2007) HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management? Br J Cancer 96:654–659PubMedCrossRefGoogle Scholar
  7. 7.
    Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C, Polzer B, Petronio M, Eils R, Klein CA (2005) Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8:227–239PubMedCrossRefGoogle Scholar
  8. 8.
    Fehm T, Muller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, Lattrich C, Lohberg CR, Solomayer E, Rack B, Riethdorf S, Klein C, Schindlbeck C, Brocker K, Kasimir-Bauer S, Wallwiener D, Pantel K (2010) HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 124(2):403–412PubMedCrossRefGoogle Scholar
  9. 9.
    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 101:9393–9398PubMedCrossRefGoogle Scholar
  10. 10.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  11. 11.
    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 107:885–892PubMedCrossRefGoogle Scholar
  12. 12.
    Janni W, Hepp F, Rjosk D, Kentenich C, Strobl B, Schindlbeck C, Hantschmann P, Sommer H, Pantel K, Braun S (2001) The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence. Cancer 92:46–53PubMedCrossRefGoogle Scholar
  13. 13.
    Stigbrand T, Andres C, Bellanger L, Bishr OM, Bodenmuller H, Bonfrer H, Brundell J, Einarsson R, Erlandsson A, Johansson A, Leca JF, Levi M, Meier T, Nap M, Nustad K, Seguin P, Sjodin A, Sundstrom B, van Dalen A, Wiebelhaus E, Wiklund B, Arlestig L, Hilgers J (1998) Epitope specificity of 30 monoclonal antibodies against cytokeratin antigens: the ISOBM TD5-1 Workshop. Tumour Biol 19:132–152PubMedCrossRefGoogle Scholar
  14. 14.
    Pantel K, Felber E, Schlimok G (1994) Detection and characterization of residual disease in breast cancer. J Hematother 3:315–322PubMedCrossRefGoogle Scholar
  15. 15.
    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 342:525–533PubMedCrossRefGoogle Scholar
  16. 16.
    Lang JE, Mosalpuria K, Cristofanilli M, Krishnamurthy S, Reuben J, Singh B, Bedrosian I, Meric-Bernstam F, Lucci A (2009) HER2 status predicts the presence of circulating tumor cells in patients with operable breast cancer. Breast Cancer Res Treat 113:501–507PubMedCrossRefGoogle Scholar
  17. 17.
    Solomayer EF, Becker S, Pergola-Becker G, Bachmann R, Kramer B, Vogel U, Neubauer H, Wallwiener D, Huober J, Fehm TN (2006) Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat 98:179–184PubMedCrossRefGoogle Scholar
  18. 18.
    Hayes DF, Walker TM, Singh B, Vitetta ES, Uhr JW, Gross S, Rao C, Doyle GV, Terstappen LW (2002) Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer. Int J Oncol 21:1111–1117PubMedGoogle Scholar
  19. 19.
    Pestrin M, Bessi S, Galardi F, Truglia M, Biggeri A, Biagioni C, Cappadona S, Biganzoli L, Giannini A, Di Leo A (2009) Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Res Treat 118:523–530PubMedCrossRefGoogle Scholar
  20. 20.
    Wulfing P, Borchard J, Buerger H, Heidl S, Zanker KS, Kiesel L, Brandt B (2006) HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res 12:1715–1720PubMedCrossRefGoogle Scholar
  21. 21.
    Solomayer E, Gebauer G, Hirnle P, Janni W, Lück HJ, Becker S, Huober J, Kraemer B, Wackwitz B, Fehm T (2008) Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Cancer Res 69(Suppl 2):170s–171sGoogle Scholar
  22. 22.
    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 18:80–86PubMedGoogle Scholar
  23. 23.
    Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmuller G (1999) Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci USA 96:4494–4499PubMedCrossRefGoogle Scholar
  24. 24.
    Pantel K, Muller V, Auer M, Nusser N, Harbeck N, Braun S (2003) Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin Cancer Res 9:6326–6334PubMedGoogle Scholar
  25. 25.
    Rack B, Schindlbeck C, Strobl B, Sommer H, Friese K, Janni W (2008) Efficacy of zoledronate in treating persisting isolated tumor cells in bone marrow in patients with breast cancer. A phase II pilot study. Dtsch Med Wochenschr 133:285–289PubMedCrossRefGoogle Scholar
  26. 26.
    Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R (2010) Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol 21(11):2188–2194Google Scholar
  27. 27.
    Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R (2011) Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12(7):631–641Google Scholar
  28. 28.
    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 19:2007–2011PubMedCrossRefGoogle Scholar
  29. 29.
    Braun S, Hepp F, Kentenich CR, Janni W, Pantel K, Riethmuller G, Willgeroth F, Sommer HL (1999) Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res 5:3999–4004PubMedGoogle Scholar
  30. 30.
    Hempel P, Muller P, Oruzio D, Behr W, Brockmeyer C, Wochner M, Ehnle S, Riethmuller R, Schlimok G (2000) Combination of high-dose chemotherapy and monoclonal antibody in breast-cancer patients: a pilot trial to monitor treatment effects on disseminated tumor cells. Cytotherapy 2:287–295PubMedCrossRefGoogle Scholar
  31. 31.
    Kirchner EM, Gerhards R, Voigtmann R (2002) Sequential immunochemotherapy and edrecolomab in the adjuvant therapy of breast cancer: reduction of 17-1A-positive disseminated tumour cells. Ann Oncol 13:1044–1048PubMedCrossRefGoogle Scholar
  32. 32.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  33. 33.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  34. 34.
    Bozionellou V, Mavroudis D, Perraki M, Papadopoulos S, Apostolaki S, Stathopoulos E, Stathopoulou A, Lianidou E, Georgoulias V (2004) Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer. Clin Cancer Res 10:8185–8194PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Brigitte Rack
    • 1
  • Julia Jückstock
    • 1
  • Maria Günthner-Biller
    • 1
  • Ulrich Andergassen
    • 1
  • Julia Neugebauer
    • 1
  • Philip Hepp
    • 6
  • Alexandra Schoberth
    • 2
  • Doris Mayr
    • 5
  • Thomas Zwingers
    • 4
  • Christian Schindlbeck
    • 3
  • Klaus Friese
    • 1
  • Wolfgang Janni
    • 6
  1. 1.Department of Gynecology and Obstetrics, Klinikum InnenstadtLudwig-Maximilians-Universitaet MuenchenMunichGermany
  2. 2.TRION Research GmbHMartinsriedGermany
  3. 3.Klinikum TraunsteinTraunsteinGermany
  4. 4.Estimate GmbHAugsburgGermany
  5. 5.Pathologisches InstitutLudwig-Maximilians-UniversitaetMunichGermany
  6. 6.Department of Gynecology and Obstetrics, Heinrich-Heine-UniversitaetDüsseldorfGermany

Personalised recommendations