Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies

  • Mitra Tewes
  • Bahriye Aktas
  • Anja Welt
  • Siemke Mueller
  • Siegfried Hauch
  • Rainer Kimmig
  • Sabine Kasimir-Bauer
Clinical Trial

Abstract

Purpose We analyzed circulating tumor cells (CTC) in blood of metastatic breast cancer patients (n = 42) and determined the ability of this method to predict therapy response. Methods CTC from blood were analyzed before and during therapy for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer. The estrogen (ER) and progesterone (PR) receptor expression was assessed by RT-PCR. Results The overall detection rate for CTC was 52% (thereof 86% EpCAM; 86% MUC1; 32% HER2; 35% ER; 12% PR). CTC were ER, PR and HER2 negative in 45% (ER), 78% (PR) and 60% (HER-2) of patients with steroid receptor-positive tumors. 29% of patients with HER2-negative tumors had HER2-positive CTC. The test predicted therapy response in 78% of all cases. Persistence of CTC significantly correlated with shorter overall survival (P = 0.005). Conclusions Molecular profiling of CTC may offer superior prognostic information with regard to risk assessment for recurrence and predictive judgement of therapeutical regimens.

Keywords

Circulating tumor cells Molecular profiling Therapy monitoring Metastatic breast cancer 

References

  1. 1.
    Goldhirsch A, Glick JH, Gelber RD et al (2005) Meeting highlights: international expert consensus conference on the primary therapy of early breast cancer. Ann Oncol 16:1569–1583PubMedCrossRefGoogle Scholar
  2. 2.
    Braun S, Hepp F, Sommer HL et al (1999) Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer 84:1–5PubMedCrossRefGoogle Scholar
  3. 3.
    Pantel K, Schlimok G, Braun S et al (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85:1419–24PubMedCrossRefGoogle Scholar
  4. 4.
    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
  5. 5.
    Kasimir-Bauer S, Mayer S, Bojko P et al (2001) Survival of tumor cells in stem cell preparations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy. Clin Cancer Res 7:1582–1588PubMedGoogle Scholar
  6. 6.
    Braun S, Kentenich C, Janni W et al (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
  7. 7.
    Wiedswang G, Borgen E, Schirmer C et al (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
  8. 8.
    Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 53:793–802CrossRefGoogle Scholar
  9. 9.
    Stathopoulou A, Vlachonikolis I, Mavroudis D et al (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 20:3404–3412PubMedCrossRefGoogle Scholar
  10. 10.
    Giatromanolaki A, Koukourakis MI, Kakolyris S et al (2004) Assessment of highly angiogenic and disseminated in the peripheral blood disease in breast cancer patients predicts for resistance to adjuvant chemotherapy and early relapse. Int J Cancer 108:620–627PubMedCrossRefGoogle Scholar
  11. 11.
    Gaforio J-J, Serrano M-J, Sanchez-Rovira P et al (2003) Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer 107:984–990PubMedCrossRefGoogle Scholar
  12. 12.
    Jotsuka T, Okumura Y, Nakano S et al (2004) Persistent evidence of circulating tumor cells detected by means of RT-PCR for CEA mRNA predicts early relapse: a prospective study in node-negative breast cancer. Surgery 135:419–426PubMedCrossRefGoogle Scholar
  13. 13.
    Pierga J-Y, Bonneton Ch, Vincent-Salomon A et al (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
  14. 14.
    Benoy IH, Elst H, Philips M et al (2006) Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer 94:672–680PubMedGoogle Scholar
  15. 15.
    Mehes G, Witt A, Kubista E et al (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159:17–20PubMedGoogle Scholar
  16. 16.
    Cristofanilli M, Budd GT, Ellis MJ et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791PubMedCrossRefGoogle Scholar
  17. 17.
    Cristofanilli M, Broglio KR, Guarneri V et al (2007) Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clin Breast Cancer 7(6):471–479PubMedCrossRefGoogle Scholar
  18. 18.
    Hayes DF, Walker TM, Singh B et al (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.
    Bosma AJ, Weigelt B, Lambrechts AC et al (2002) Detection of circulating breast tumor cells by differential expression of marker genes. Clin Cancer Res 8:1871–1877PubMedGoogle Scholar
  20. 20.
    Ring AE, Zabaglo L, Ormerod MG et al (2005) Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques. Br J Cancer 92:906–912PubMedCrossRefGoogle Scholar
  21. 21.
    Baker MK, Mikhitarian K, Osta W et al (2003) Molecular detection of breast cancer cells in the peripheral blood of advanced-stage breast cancer patients using multimarker real-time reverse transcription-polymerase chain reaction and a novel porous barrier density gradient centrifugation technology. Clin Cancer Res 9:4865–4871PubMedGoogle Scholar
  22. 22.
    Hauch S, Zimmermann S, Lankiewicz S et al (2007) The clinical significance of circulating tumour cells in breast cancer and colorectal cancer patients. Anticancer Res (Greece) 27:1337–1341Google Scholar
  23. 23.
    Ellis IO, Schnitt SJ, Sastre-Garau X, Bussolati G, Tavassoli FA, Eusebi V (2003) Invasive breast carcinoma. In: Tavassoli FA, Devilee P (eds) World health organization classification of tumours. tumours of the breast and female genital organs. IARC Press, LyonGoogle Scholar
  24. 24.
    Sobin LH, Wittekind C (2002) International union against cancer. TNM classification of malignant tumours, 6th edn. Wiley, New YorkGoogle Scholar
  25. 25.
    Lal P, Salazar PA, Hudis CA et al (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. 26.
    Demel U, Tilz GP, Foeldes-Papp Z et al (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
  27. 27.
    Zieglschmid V, Hollmann C, Gutierrez B et al (2005) Combination of immunomagnetic enrichment with multiplex RT-PCR analysis for the detection of disseminated tumor cells. Anticancer Res 25:1803–1810PubMedGoogle Scholar
  28. 28.
    Lankiewicz S, Rivero BG, Bocher O (2006) Quantitative real-time RT-PCR of disseminated tumor cells in combination with immunomagnetic cell enrichment. Mol Biotechnol (USA) 34(1):15–27CrossRefGoogle Scholar
  29. 29.
    Braun S, Schlimok G, Heumos I et al (2001) ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I–III breast cancer patients. Cancer Res 61:1890–1895PubMedGoogle Scholar
  30. 30.
    Vincent-Salomon AJ, Couturier C, Nos X et al (2004) HER2 gene status assessment in micrometastatic cells in bone marrow (BM) of breast cancer patients by fluorescence in situ hybridization. J Clin Oncol 22:9520Google Scholar
  31. 31.
    Becker S, Becker-Pergola G, Fehm T et al (2005) HER2 expression on disseminated tumor cells from bone marrow of breast cancer patients. Anticancer Res 25:2171–2176PubMedGoogle Scholar
  32. 32.
    Solomayer EF, Becker S, Pergola-Becker G et al (2006) Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat 98(2):179–184PubMedCrossRefGoogle Scholar
  33. 33.
    Italiano A, Saint-Paul MC, Caroli-Bosc FX et al (2005) Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications. Ann Oncol 16(9):1503–1507PubMedCrossRefGoogle Scholar
  34. 34.
    Reuben JM, Lee BN, Li C et al. (2007) Genomic of circulating tumor cells in metastatic breast cancer. J Clin Oncol ASCO annual meeting proceedings part I 25(18S):1002 (June 20 Supplement)Google Scholar
  35. 35.
    Fehm T, Morrison L, Saboorian H (2002) Patterns of aneusomy for three chromosomes in individual cells from breast cancer tumors. Breast Cancer Res Treat 75(3):227–239PubMedCrossRefGoogle Scholar
  36. 36.
    Pachmann K, Oumar C, Kavallaris A et al (2008) Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 26(8):1208–1215PubMedCrossRefGoogle Scholar
  37. 37.
    Bast RC, Ravdin P, Hayes DF et al (2001) Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19(6):1865–1878PubMedGoogle Scholar
  38. 38.
    Budd GT, Cristofanilli M, Ellis MJ et al. Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin Cancer Res 12(21):6403–6409Google Scholar
  39. 39.
    Hayes DF, Cristofanilli M, Budd GT et al (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):4218–4224PubMedCrossRefGoogle Scholar
  40. 40.
    McShane LM, Altman DG, Sauerbrei W et al (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Mitra Tewes
    • 1
  • Bahriye Aktas
    • 2
  • Anja Welt
    • 1
  • Siemke Mueller
    • 3
  • Siegfried Hauch
    • 4
  • Rainer Kimmig
    • 2
  • Sabine Kasimir-Bauer
    • 2
  1. 1.Department of Internal Medicine (Cancer Research)University Hospital Essen, University of Duisburg-EssenEssenGermany
  2. 2.Department of Gynecology and ObstetricsUniversity Hospital Essen, University of Duisburg-EssenEssenGermany
  3. 3.Zentrum für Innere Medizin, Kath. Marienkrankenhaus GmbHHamburgGermany
  4. 4.AdnaGen AGLangenhagenGermany

Personalised recommendations