Advertisement

Detection of disseminated tumor cells in bone marrow and circulating tumor cells in blood of patients with early-stage male breast cancer

  • Mitra TewesEmail author
  • Sabine Kasimir-Bauer
  • Anja Welt
  • Martin Schuler
  • Rainer Kimmig
  • Bahriye Aktas
Original Article – Cancer Research

Abstract

Background

Male breast cancer (MBC) is a rare malignant disease, accounting for <1 % of all breast cancers (BCs). Treatment of men with early-stage BC is based on standards established in female BC. Prognostic or predictive markers to guide therapeutic decisions, in particular in early-stage male BC, are missing. Here, we explored whether disseminated tumor cells (DTC) in bone marrow (BM) and circulating tumor cells (CTC) in blood could be suitable biomarkers in male BC.

Patients and methods

Five male patients (pT2–4, pN0–2, M0) with hormone receptor-positive, HER2-negative, and ductal primary BC (median age 70 years, range 51–73) were enrolled in a prospective study of patients with early-stage breast cancer. Here, we analyze the male subgroup. DTC in BM were analyzed before therapy and identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. Blood samples (10 ml) were analyzed for CTC using the AdnaTest BreastCancer (AdnaGen AG, Langenhagen, Germany).

Results

DTC were found in three out of five male patients (60 %) with two DTC detected in one patient and one DTC detected in each of the other two patients. This is compared to a detection rate of 25–40 % in pooled analyses of female patients. CTC were only found in one of five patients. After a median follow-up time of 3 years (range 1–10 years), all patients were still alive and free of relapse.

Conclusion

The prevalence of DTC and CTC in male BC seems comparable with female BC. No prognostic relevance could be documented in this small population. A prospective study or at least larger cases series will be required to assess the prognostic or predictive value of DTC and CTC in this rare disease.

Keywords

Male breast cancer Early-stage breast cancer Disseminated tumor cells Circulating tumor cells 

Abbreviations

CTC

Circulating tumor cells

DTC

Disseminating tumor cells

ER

Estrogen receptor

PR

Progesterone receptor

HR

Hormone receptor

BM

Bone marrow

Pt

Patient

MBC

Male breast cancer

Notes

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Abraham BK, Fritz P, Mc Clellan M, Hauptvogel P, Athelogou M, Brauch H (2005) Prevalence of CD44+//CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11:1154–1159PubMedGoogle Scholar
  2. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are freuently expressed in metastatic breast cancer patients with circulating tumor cells. Breast Cancer Res 11:R46PubMedCentralPubMedCrossRefGoogle Scholar
  3. Aktas B, Müller V, Schumacher K, Tewes M, Zeitz J, Kasimir-Bauer S, Rack B, Janni W, Solomayer E, Fehm T, behalf of the DETECT study group (2011) Comparison of ER and PR status of circulating tumor cells and the primary tumor in metastatic breast cancer patients. Gynecol Oncol 122(2):356–360PubMedCrossRefGoogle Scholar
  4. Anderson WF, Jatoi I, Tse J et al (2010) Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol 28(2):232–239PubMedCentralPubMedCrossRefGoogle Scholar
  5. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12:5615–5621PubMedCrossRefGoogle Scholar
  6. Banys M, Solomayer EF, Gebauer G, Janni W, Krawczyk N, Lueck HJ, Becker S, Huober J, Kraemer B, Wackwitz B, Hirnle P, Wallwiener D, Fehm T (2013) Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 15(13):480. doi: 10.1186/1471-2407-13-480 CrossRefGoogle Scholar
  7. 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 97:91–96PubMedCrossRefGoogle Scholar
  8. Benoy IH, Elst H, Philips M, Wuyts H, Van Dam P, Scharpe S, Van Marck E, Vermeulen PB, Dirix LY (2006) Real-time RT-PCR detection of disseminated tumor cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer 94:672–680PubMedCentralPubMedGoogle Scholar
  9. Borgen PI, Senie RT, Mc Kinnon WM, Rosen PP (1997) Carcinoma of the male breast: analysis of prognosis compared with matched female patients. Ann Surg Oncol 4:385–388PubMedCrossRefGoogle Scholar
  10. 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: The European ISHAGE Working Group for Standardization of Tumor Cell Detection. Cytotherapy 5:377–388CrossRefGoogle Scholar
  11. Braun S, Müller P, Hepp F, Schlimok G, Riethmüller G, Pantel K (1998) Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 90:1099–1101PubMedCrossRefGoogle Scholar
  12. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber G, 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):793–802PubMedCrossRefGoogle Scholar
  13. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M Boyle P (2007) Cancer incidence in five continents, vol IX. IARC Scientific Publications, Lyon, IARCGoogle Scholar
  14. Demel U, Tilz GP, Foeldes-Papp Z, Gutierrez B, Albert WH, Böcher O (2004) Detection of tumour cells in the peripheral blood of patients with breast cancer. Development of a new sensitive and specific immunomolecular assay. J Exp Clin Cancer Res 23:465–468PubMedGoogle Scholar
  15. Donegan WL, Redlich PN, Lang PJ, Gall MT (1998) Carcinoma of the breast in males: a multi-institutional survey. Cancer 83:498–509PubMedCrossRefGoogle Scholar
  16. Ellis IO, Schnitt SJ, Sastre-Garau X, Bussolati G, Tavassoli FA (2003) Invasive breast carcinoma. In: von Devilee P, Tavassoli FA (eds) World Health Organization classification of tumours. Tumours of the breast and female genital organs. IARC Press, Lyon, pp 13–59Google Scholar
  17. Fehm T, Braun S, Müller V, Janni W, Gebauer G, Marth C, Schindlbeck C, Wallwiener D, Borgen E, Naume B, Pantel K (2006) A concept for the standardized detection of disseminated tumor cells in bone marrow of patients with primary breast cancer and its clinical implementation. Cancer 197:885–892CrossRefGoogle Scholar
  18. Fehm T, Hoffmann O, Aktas B, 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:R59PubMedCentralPubMedCrossRefGoogle Scholar
  19. Gazzaniga P, Naso G, Raimondi C, Gradilone A, Palazzo A, Gandini O, Petracca A, Nicolazzo C, Cortesi E, Frati L (2011) Circulating tumor cells count and characterization in a male breast cancer patient. Cancer Biol Ther 12(5):379–382PubMedCrossRefGoogle Scholar
  20. Hauch S, Zimmermann S, Lankiewicz S, Ziegelschmid V, Böcher O, Albert WH (2007) The clinical significance of circulating tumour cells in breast cancer and colorectal cancer patients. Anticancer Res 27:1337–1341PubMedGoogle Scholar
  21. Hoffmann O, Aktas B, Goldnau C, Oberhoff C, Kimmig R, Kasimir-Bauer S (2011) Effect of ibandronate on disseminated tumor cells in the bone marrow of patients with primary breast cancer: a pilot study. Anticancer Res 31(10):3623–3628PubMedGoogle Scholar
  22. Ignatiadis M, Georgoulias V, Mavroudis D (2008) Micrometastatic disease in breast cancer: clinical implications. Eur J Cancer 44:2726–2736PubMedCrossRefGoogle Scholar
  23. Janni W, Vogl FD, Wiedswang G, Synnestved 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):2967–2976PubMedCrossRefGoogle Scholar
  24. Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T (2012) Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res 14:R15PubMedCentralPubMedCrossRefGoogle Scholar
  25. Lal P, Salazar PA, Hudis CA, Ladanyi M, Chen B (2004) Her-2 testing in breast cancer using immunohistochemical analysis and fluorescence in situ hybridization: a single-institution experience of 2,279 cases and comparison of dual-color and single-color scoring. Am J Clin Pathol 121:631–636PubMedCrossRefGoogle Scholar
  26. Lankiewicz S, Gutierrez RiveroB, Böcher O (2006) Quantitative real-time RT-PCR of disseminated tumor cells in combination with immunomagnetic cell enrichment. Mol Biotechnol 34:15–28PubMedCrossRefGoogle Scholar
  27. Marchal F, Salou M, Marchal C, Lesur A, Desandes E (2009) Men with breast cancer have the same disease-specific and event-free survival as women. Ann Surg Oncol 16:972–978PubMedCrossRefGoogle Scholar
  28. Mathiesen RR, Borgen E, Renolen A, Lokkevik E, Nesland JM, Anker G, Ostenstad B, Lundgren S, Risberg T, Mjaaland I, Kvalheim G, Lonning PE, Naume B (2012) Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival. Breast Cancer Res 14(4):R117PubMedCentralPubMedCrossRefGoogle Scholar
  29. Meng S, Tripathy D, Frenkel EP et al (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10:8152–8162PubMedCrossRefGoogle Scholar
  30. Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K (2005) Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogenous response to systemic therapy and low proliferative activity. Clin Cancer Res 11:3678–3685PubMedCrossRefGoogle Scholar
  31. Patten DK, Sharifi LK, Fazel M (2013) New approaches in the management of male breast cancer. Clin Breast Cancer 13(5):309–314PubMedCrossRefGoogle Scholar
  32. Pierga JY, Bonneton Ch, 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 10:1392–1400PubMedCrossRefGoogle Scholar
  33. Rack B, Schindlbeck C, Strobl B, Sommer H, Friese K, Janni W (2008) Zoledronsäure bei persistierenden isolierten Tumorzellen im Knochenmark bei Mammakarzinom Phase-II-Pilotstudie zur Evaluierung der therapeutischen Efektivität. Dtsch Med Wochenschr 133(7):285–289PubMedCrossRefGoogle Scholar
  34. Reuben JM, Lee BN, Gao H, Cohen EN, Mego M, Giordano A, Wang X, Lodhi A, Krishnamurthy S, Hortobagyi GN, Cristofanilli M, Lucci A, Woodward WA (2011) Primary breast cancer patients with high risk clinicopathologic features have high percentages of bone marrow epithelial cells with ALDH activity and SD44 (+)CD24((lo) cancer stemm cell phenotype. Eur J Cancer 47:1527–1536PubMedCentralPubMedCrossRefGoogle Scholar
  35. Ruddy KJ, Winer EP (2013) Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol 00:1–9Google Scholar
  36. Salvadori B, Saccozzi R, Manzari A, Andrealo S, Conti R et al (1994) Prognosis of breast cancer in males: an analysis of 170 cases. Eur J Cancer 30A:930–935PubMedCrossRefGoogle Scholar
  37. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29PubMedCrossRefGoogle Scholar
  38. Solomayer EF, Gebauer G, Hirnle P (2008) Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Cancer Res 69(2):170–171Google Scholar
  39. Stang A, Thomssen C (2008) Decline in breast cancer incidence in the United States: what about male breast cancer? Breast Cancer Res Treat 112:595–596PubMedCrossRefGoogle Scholar
  40. Strathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis Ch, 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 20:3404–3412CrossRefGoogle Scholar
  41. 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 10:5342–5348PubMedCrossRefGoogle Scholar
  42. Wiedswang G, Borgen E, Schirmer C, Karesen R, Kvalheim G, Nesland JM, Naume B (2006) Comparison of the clinical significance of occult tumor cells in blood and bone marrow in breast cancer. Int J Cancer 118:2013–2019PubMedCrossRefGoogle Scholar
  43. Xenidis N, Perraki M, Kafousi M, Apostolaki S, Bolonaki I, Stathopoulou A, Kalbakis K, Androulakis N, Kouroussis C, Pallis T, Christophylakis C, Argyraki K, Lianidou E, Stathopoulos S, Georgoulias V, Mavraudis D (2006) Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients. J Clin Oncol 24:3756–3762PubMedCrossRefGoogle Scholar
  44. Xenidis N, Ignatiadis M, Apostolaki S, Perraki M, Kalbakis K, Agelaki S, Stathopoulos EN, Chlouverakis G, Lianidou E, Kakolyris S, Georgoulias V, Mavroudis D (2009) Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapie in patients with early breast cancer. J Clin Oncol 27:2177–2184PubMedCrossRefGoogle Scholar
  45. Zieglschmid V, Hollmann C, Gutierrez B, Albert W, Strothoff D, Gross E, Bocher O (2005) Combination of immunomagnetic enrichment with multiplex RT-PCR analysis for the detection of disseminated tumor cells. Anticancer Res 25:1803–1810PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Mitra Tewes
    • 1
    Email author
  • Sabine Kasimir-Bauer
    • 2
  • Anja Welt
    • 1
  • Martin Schuler
    • 1
    • 3
  • Rainer Kimmig
    • 2
  • Bahriye Aktas
    • 2
  1. 1.Department of Medical Oncology, West German Cancer Center, University Hospital EssenUniversity of Duisburg-EssenEssenGermany
  2. 2.Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital EssenUniversity of Duisburg-EssenEssenGermany
  3. 3.German Cancer Consortium (DKTK)HeidelbergGermany

Personalised recommendations