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Breast Cancer Research
Published in: Breast Cancer Research 5/2009

Open Access 01-10-2009 | Research article

Comparative evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer

Authors: Heidi Schwarzenbach, Klaus Pantel, Birthe Kemper, Cord Beeger, Friedrich Otterbach, Rainer Kimmig, Sabine Kasimir-Bauer

Published in: Breast Cancer Research | Issue 5/2009

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Abstract

Introduction

The origin and clinical relevance of circulating cell-free tumor DNA in the blood of cancer patients is still unclear. Here we investigated whether the detection of this DNA is related to bone marrow (BM) micrometastasis and tumor recurrence in breast cancer patients.

Methods

BM aspirates of 81 primary breast cancer patients were analyzed for the presence of disseminated tumor cells (DTC) by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. PCR-based fluorescence microsatellite analysis was performed for detection of loss of heterozygosity (LOH) at 6 polymorphic markers using cell-free serum DNA. The data were correlated with established risk factors, and patients were followed-up over 6-10 years.

Results

LOH was detected in 33.5% of blood samples. The occurrence of LOH at the entire microsatellite marker set correlated with histopathology (P = 0.05) and grading (P = 0.006) of the primary tumor. The genomic region characterized by marker D9S171 was only affected by LOH in patients with increased tumor stages (pT2-4, P < 0.05) and older age (≥ 55 years, P = 0.05). Kaplan-Meier analysis showed that LOH at D3S1255 (P = 0.009) and D9S171 (P = 0.001) were significantly associated with tumor relapse. In BM, DTC were detected in 39.5% of the patients, and this finding correlated with distant metastases (P < 0.05). Patients with DTC-positive BM had higher DNA yields in their blood than patients with DTC-negative BM (P < 0.05). However, no significant correlations were found between the presence of DTC in BM and the detection of marker-specific LOH on blood DNA.

Conclusions

The detection of LOH on cell-free tumor DNA in blood is unrelated to BM micrometastasis and provides independent information on breast cancer progression.
Appendix
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Literature
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: A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005, 353: 793-802. 10.1056/NEJMoa050434.CrossRefPubMed
2.
Becker S, Becker-Pergola G, Wallwiener D, Solomayer EF, Fehm T: Detection of cytokeratin-positive cells in the bone marrow of breast cancer patients undergoing adjuvant therapy. Breast Cancer Res Treat. 2006, 97: 91-96. 10.1007/s10549-005-9095-6.CrossRefPubMed
3.
Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K: 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. 2000, 18: 80-86.PubMed
4.
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmüller G, Schlimok G: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000, 342: 525-533. 10.1056/NEJM200002243420801.CrossRefPubMed
5.
Kasimir-Bauer S, Mayer S, Bojko P, Borquez D, Neumann R, Seeber S: 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. 2001, 7: 1582-1589.PubMed
6.
Pantel K, Brakenhoff RH, Brandt B: Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008, 8: 329-340. 10.1038/nrc2375.CrossRefPubMed
7.
Wiedswang G, Borgen E, Karesen R, Qvist H, Janbu J, Kvalheim G, Nesland JM, Naume B: Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res. 2004, 10: 5342-5348. 10.1158/1078-0432.CCR-04-0245.CrossRefPubMed
8.
Chun FK, Muller I, Lange I, Friedrich MG, Erbersdobler A, Karakiewicz PI, Graefen M, Pantel K, Huland H, Schwarzenbach H: Circulating tumour-associated plasma DNA represents an independent and informative predictor of prostate cancer. BJU Int. 2006, 98: 544-548. 10.1111/j.1464-410X.2006.06352.x.CrossRefPubMed
9.
Fleischhacker M, Schmidt B: Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta. 2007, 1775: 181-232.PubMed
10.
Schwarzenbach H, Stoehlmacher J, Pantel K, Goekkurt E: Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer. Ann N Y Acad Sci. 2008, 1137: 190-196. 10.1196/annals.1448.025.CrossRefPubMed
11.
Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P: About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta. 2001, 313: 139-142. 10.1016/S0009-8981(01)00665-9.CrossRefPubMed
12.
Schwarzenbach H, Chun FK, Lange I, Carpenter S, Gottberg M, Erbersdobler A, Friedrich MG, Huland H, Pantel K: Detection of tumor-specific DNA in blood and bone marrow plasma from patients with prostate cancer. Int J Cancer. 2007, 120: 1465-1471. 10.1002/ijc.22470.CrossRefPubMed
13.
Schwarzenbach H, Muller V, Stahmann N, Pantel K: Detection and characterization of circulating microsatellite-DNA in blood of patients with breast cancer. Ann N Y Acad Sci. 2004, 1022: 25-32. 10.1196/annals.1318.005.CrossRefPubMed
14.
O'Connell P: Genetic and cytogenetic analyses of breast cancer yield different perspectives of a complex disease. Breast Cancer Res Treat. 2003, 78: 347-357. 10.1023/A:1023037925950.CrossRefPubMed
15.
Schwarzenbach H, Muller V, Beeger C, Gottberg M, Stahmann N, Pantel K: A critical evaluation of loss of heterozygosity detected in tumor tissues, blood serum and bone marrow plasma from patients with breast cancer. Breast Cancer Res. 2007, 9: R66-10.1186/bcr1772.CrossRefPubMedPubMedCentral
16.
Ellis IO SS, Sastre-Garau X, Bussolati G, Tavassoli FA, Eusebi V: Invasive breast carcinoma. World Health Organization Classification of Tumours. Tumours of the Breast and Female Genital Organs. Edited by: Tavassoli FA, Devilee P. 2003, Lyon: IARC Press
17.
Wittekind C, Compton CC, Greene FL, Sobin LH: TNM residual tumor classification revisited. Cancer. 2002, 94: 2511-2516. 10.1002/cncr.10492.CrossRefPubMed
18.
Muller I, Beeger C, Alix-Panabieres C, Rebillard X, Pantel K, Schwarzenbach H: Identification of loss of heterozygosity on circulating free DNA in peripheral blood of prostate cancer patients: potential and technical improvements. Clin Chem. 2008, 54: 688-696. 10.1373/clinchem.2007.099333.CrossRefPubMed
19.
Kruger S, Fahrenkrog T, Muller H: Proliferative and apoptotic activity in lobular breast carcinoma. Int J Mol Med. 1999, 4: 171-174.PubMed
20.
Mustonen M, Raunio H, Paakko P, Soini Y: The extent of apoptosis is inversely associated with bcl-2 expression in premalignant and malignant breast lesions. Histopathology. 1997, 31: 347-354. 10.1046/j.1365-2559.1997.2710877.x.CrossRefPubMed
21.
Kerangueven F, Noguchi T, Coulier F, Allione F, Wargniez V, Simony-Lafontaine J, Longy M, Jacquemier J, Sobol H, Eisinger F, Birnbaum D: Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Cancer Res. 1997, 57: 5469-5474.PubMed
22.
Lichy JH, Dalbegue F, Zavar M, Washington C, Tsai MM, Sheng ZM, Taubenberger JK: Genetic heterogeneity in ductal carcinoma of the breast. Lab Invest. 2000, 80: 291-301.CrossRefPubMed
23.
Wang Q, Larson PS, Schlechter BL, Zahid N, Finnemore E, de las Morenas A, Blanchard RA, Rosenberg CL: Loss of heterozygosity in serial plasma DNA samples during follow-up of women with breast cancer. Int J Cancer. 2003, 106: 923-929. 10.1002/ijc.11333.CrossRefPubMed
24.
Ogasawara S, Maesawa C, Tamura G, Satodate R: Frequent microsatellite alterations on chromosome 3p in esophageal squamous cell carcinoma. Cancer Res. 1995, 55: 891-894.PubMed
25.
An HX, Niederacher D, Picard F, van Roeyen C, Bender HG, Beckmann MW: Frequent allele loss on 9p21-22 defines a smallest common region in the vicinity of the CDKN2 gene in sporadic breast cancer. Genes Chromosomes Cancer. 1996, 17: 14-20. 10.1002/(SICI)1098-2264(199609)17:1<14::AID-GCC3>3.0.CO;2-5.CrossRefPubMed
26.
Fehm T, Braun S, Muller V, Janni W, Gebauer G, Marth C, Schindlbeck C, Wallwiener D, Borgen E, Naume B, Pantel K, Solomayer E: A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer. 2006, 107: 885-892. 10.1002/cncr.22076.CrossRefPubMed
27.
Bidard FC, Vincent-Salomon A, Gomme S, Nos C, de Rycke Y, Thiery JP, Sigal-Zafrani B, Mignot L, Sastre-Garau X, Pierga JY: Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res. 2008, 14: 3306-3311. 10.1158/1078-0432.CCR-07-4749.CrossRefPubMed
28.
Riethdorf S, Wikman H, Pantel K: Review: Biological relevance of disseminated tumor cells in cancer patients. Int J Cancer. 2008, 123: 1991-2006. 10.1002/ijc.23825.CrossRefPubMed
29.
Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA: Systemic spread is an early step in breast cancer. Cancer Cell. 2008, 13: 58-68. 10.1016/j.ccr.2007.12.003.CrossRefPubMed
30.
31.
Fehm T, Sagalowsky A, Clifford E, Beitsch P, Saboorian H, Euhus D, Meng S, Morrison L, Tucker T, Lane N, Ghadimi BM, Heselmeyer-Haddad K, Ried T, Rao C, Uhr J: Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res. 2002, 8: 2073-2084.PubMed
32.
Klein CA: Random mutations, selected mutations: A PIN opens the door to new genetic landscapes. Proc Natl Acad Sci USA. 2006, 103: 18033-18034. 10.1073/pnas.0609000103.CrossRefPubMedPubMedCentral
33.
Fehm T, Krawczyk N, Solomayer EF, Becker-Pergola G, Durr-Storzer S, Neubauer H, Seeger H, Staebler A, Wallwiener D, Becker S: ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients. Breast Cancer Res. 2008, 10: R76-10.1186/bcr2143.CrossRefPubMedPubMedCentral
34.
Tewes M, Aktas B, Welt A, Mueller S, Hauch S, Kimmig R, Kasimir-Bauer S: 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. Breast Cancer Res Treat. 2009, 115: 581-590. 10.1007/s10549-008-0143-x.CrossRefPubMed
35.
Pantel K, Brakenhoff R: Dissecting the metastatic cascade. Nat Rev Cancer. 2004, 4: 448-456. 10.1038/nrc1370.CrossRefPubMed
Metadata
Title
Comparative evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer
Authors
Heidi Schwarzenbach
Klaus Pantel
Birthe Kemper
Cord Beeger
Friedrich Otterbach
Rainer Kimmig
Sabine Kasimir-Bauer
Publication date
01-10-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2404

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