• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. Dec 1999; 81(7): 1165–1173.
PMCID: PMC2374326

Detection of circulating tumour cells in patients with breast or ovarian cancer by molecular cytogenetics

Abstract

Detection of micrometastases in patients with solid tumours may aid the establishment of prognosis and development of new therapeutic approaches. This study was designed to investigate the presence and frequency of tumour cells in the peripheral blood (PB) of patients with breast or ovarian cancer by using a combination of magnetic activated cell sorting (MACS) and fluorescence in situ hybridization (FISH). Separated tumour cell and PB-samples from 48 patients (35 breast cancers, 12 ovarian tumours, one uterine sarcoma) were analysed for the presence of numerical aberrations of chromosomes 7, 12, 17 and 17 q11.2–q12. Twenty-five patients had primary disease and 23 had relapsed. The technique allows the detection of one tumour cell in 106 normal cells. Circulating tumour cells were detected in 35/48 cases (17 patients had relapsed and 13 primary carcinoma with lymph node or solid metastases) by the expression of anti-cytokeratin and the presence of numerical chromosomal abnormalities. PB-tumour cells of patients with a primary carcinoma and without solid metastases had a significantly lower percentage of chromosomal aberrations, especially for chromosome 12 (P = 0.035; P = 0.038) compared to those with relapsed disease and solid metastases. Detection and quantification of minimal residual disease may monitor the response to cytotoxic or hormonal therapy and may identify women at risk of relapse. © 1999 Cancer Research Campaign

Keywords: circulating tumour cells, MACS, FISH

Full Text

The Full Text of this article is available as a PDF (121K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • An HX, Niederacher D, Beckmann MW, Göhring UJ, Scharl A, Picard F, van Roeyen C, Schnürch HG, Bender HG. ERBB2 gene amplification detected by fluorescent differential polymerase chain reaction in paraffin-embedded breast carcinoma tissues. Int J Cancer. 1995 Oct 20;64(5):291–297. [PubMed]
  • Berois N, Varangot M, Osinaga E, Babino A, Caignault L, Musé I, Roseto A. Detection of rare human breast cancer cells. Comparison of an immunomagnetic separation method with immunocytochemistry and RT-PCR. Anticancer Res. 1997 Jul-Aug;17(4A):2639–2646. [PubMed]
  • Bostick PJ, Chatterjee S, Chi DD, Huynh KT, Giuliano AE, Cote R, Hoon DS. Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. J Clin Oncol. 1998 Aug;16(8):2632–2640. [PubMed]
  • Cajulis RS, Kotliar S, Haines GK, Frias-Hidvegi D, O'Gorman M. Comparative study of interphase cytogenetics, flow cytometric analysis, and nuclear grade of fine-needle aspirates of breast carcinoma. Diagn Cytopathol. 1994;11(2):151–158. [PubMed]
  • Datta YH, Adams PT, Drobyski WR, Ethier SP, Terry VH, Roth MS. Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction. J Clin Oncol. 1994 Mar;12(3):475–482. [PubMed]
  • Devilee P, Thierry RF, Kievits T, Kolluri R, Hopman AH, Willard HF, Pearson PL, Cornelisse CJ. Detection of chromosome aneuploidy in interphase nuclei from human primary breast tumors using chromosome-specific repetitive DNA probes. Cancer Res. 1988 Oct 15;48(20):5825–5830. [PubMed]
  • Cote RJ, Rosen PP, Lesser ML, Old LJ, Osborne MP. Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. J Clin Oncol. 1991 Oct;9(10):1749–1756. [PubMed]
  • Cote RJ, Beattie EJ, Chaiwun B, Shi SR, Harvey J, Chen SC, Sherrod AE, Groshen S, Taylor CR. Detection of occult bone marrow micrometastases in patients with operable lung carcinoma. Ann Surg. 1995 Oct;222(4):415–425. [PMC free article] [PubMed]
  • Cote RJ, Houchens DP, Hitchcock CL, Saad AD, Nines RG, Greenson JK, Schneebaum S, Arnold MW, Martin EW., Jr Intraoperative detection of occult colon cancer micrometastases using 125 I-radiolabled monoclonal antibody CC49. Cancer. 1996 Feb 15;77(4):613–620. [PubMed]
  • Diel IJ, Kaufmann M, Costa SD, Holle R, von Minckwitz G, Solomayer EF, Kaul S, Bastert G. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst. 1996 Nov 20;88(22):1652–1658. [PubMed]
  • Dutrillaux B, Gerbault-Seureau M, Zafrani B. Characterization of chromosomal anomalies in human breast cancer. A comparison of 30 paradiploid cases with few chromosome changes. Cancer Genet Cytogenet. 1990 Oct 15;49(2):203–217. [PubMed]
  • Eaton MC, Hardingham JE, Kotasek D, Dobrovic A. Immunobead RT-PCR: a sensitive method for detection of circulating tumor cells. Biotechniques. 1997 Jan;22(1):100–105. [PubMed]
  • Engel H, Friedrich J, Kleespies C, Kurbacher CM, Schöndorf T, Grecu O, Kolhagen H, Mallmann P. Detection of chromosomal aberrations in tumor cells and tumor infiltrating lymphocytes by molecular cytogenetics in patients with gynecological cancer. Cancer Genet Cytogenet. 1998 Oct 15;106(2):159–165. [PubMed]
  • Fernández JL, Goyanes V, López-Fernández C, Buño I, Gosálvez J. Quantification of C-ERB-B2 gene amplification in breast cancer cells using fluorescence in situ hybridization and digital image analysis. Cancer Genet Cytogenet. 1996 Jan;86(1):18–21. [PubMed]
  • Fiegl M, Tueni C, Schenk T, Jakesz R, Gnant M, Reiner A, Rudas M, Pirc-Danoewinata H, Marosi C, Huber H, et al. Interphase cytogenetics reveals a high incidence of aneuploidy and intra-tumour heterogeneity in breast cancer. Br J Cancer. 1995 Jul;72(1):51–55. [PMC free article] [PubMed]
  • Franklin WA, Shpall EJ, Archer P, Johnston CS, Garza-Williams S, Hami L, Bitter MA, Bast RC, Jones RB. Immunocytochemical detection of breast cancer cells in marrow and peripheral blood of patients undergoing high dose chemotherapy with autologous stem cell support. Breast Cancer Res Treat. 1996;41(1):1–13. [PubMed]
  • Geleick D, Müller H, Matter A, Torhorst J, Regenass U. Cytogenetics of breast cancer. Cancer Genet Cytogenet. 1990 Jun;46(2):217–229. [PubMed]
  • Hardingham JE, Kotasek D, Farmer B, Butler RN, Mi JX, Sage RE, Dobrovic A. Immunobead-PCR: a technique for the detection of circulating tumor cells using immunomagnetic beads and the polymerase chain reaction. Cancer Res. 1993 Aug 1;53(15):3455–3458. [PubMed]
  • Hardingham JE, Kotasek D, Sage RE, Eaton MC, Pascoe VH, Dobrovic A. Detection of circulating tumor cells in colorectal cancer by immunobead-PCR is a sensitive prognostic marker for relapse of disease. Mol Med. 1995 Nov;1(7):789–794. [PMC free article] [PubMed]
  • Helfrich W, ten Poele R, Meersma GJ, Mulder NH, de Vries EG, de Leij L, Smit EF. A quantitative reverse transcriptase polymerase chain reaction-based assay to detect carcinoma cells in peripheral blood. Br J Cancer. 1997;76(1):29–35. [PMC free article] [PubMed]
  • Hildebrandt M, Mapara MY, Körner IJ, Bargou RC, Moldenhauer G, Dörken B. Reverse transcriptase-polymerase chain reaction (RT-PCR)-controlled immunomagnetic purging of breast cancer cells using the magnetic cell separation (MACS) system: a sensitive method for monitoring purging efficiency. Exp Hematol. 1997 Jan;25(1):57–65. [PubMed]
  • Ichikawa D, Hashimoto N, Hoshima M, Yamaguchi T, Sawai K, Nakamura Y, Takahashi T, Abe T, Inazawa J. Analysis of numerical aberrations of specific chromosomes by fluorescent in situ hybridization as a diagnostic tool in breast cancer. Cancer. 1996 May 15;77(10):2064–2069. [PubMed]
  • Ishikawa T, Kobayashi M, Mai M, Suzuki T, Ooi A. Amplification of the c-erbB-2 (HER-2/neu) gene in gastric cancer cells. Detection by fluorescence in situ hybridization. Am J Pathol. 1997 Sep;151(3):761–768. [PMC free article] [PubMed]
  • Kallioniemi OP, Kallioniemi A, Kurisu W, Thor A, Chen LC, Smith HS, Waldman FM, Pinkel D, Gray JW. ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5321–5325. [PMC free article] [PubMed]
  • Kiechle-Schwarz M, Decker HJ, Berger CS, Fiebig HH, Sandberg AA. Detection of monosomy in interphase nuclei and identification of marker chromosomes using biotinylated alpha-satellite DNA probes. Cancer Genet Cytogenet. 1991 Jan;51(1):23–33. [PubMed]
  • Krüger W, Krzizanowski C, Holweg M, Stockschläder M, Kröger N, Jung R, Mross K, Jonat W, Zander AR. Reverse transcriptase/polymerase chain reaction detection of cytokeratin-19 mRNA in bone marrow and blood of breast cancer patients. J Cancer Res Clin Oncol. 1996;122(11):679–686. [PubMed]
  • Kvalheim G. Detection of occult tumour cells in bone marrow and blood in breast cancer patients--methods and clinical significance. Acta Oncol. 1996;35 (Suppl 8):13–18. [PubMed]
  • Le Beau MM. Detecting genetic changes in human tumor cells: have scientists "gone fishing?". Blood. 1993 Apr 15;81(8):1979–1983. [PubMed]
  • Luppi M, Morselli M, Bandieri E, Federico M, Marasca R, Barozzi P, Ferrari MG, Savarino M, Frassoldati A, Torelli G. Sensitive detection of circulating breast cancer cells by reverse-transcriptase polymerase chain reaction of maspin gene. Ann Oncol. 1996 Aug;7(6):619–624. [PubMed]
  • Mapara MY, Körner IJ, Hildebrandt M, Bargou R, Krahl D, Reichardt P, Dörken B. Monitoring of tumor cell purging after highly efficient immunomagnetic selection of CD34 cells from leukapheresis products in breast cancer patients: comparison of immunocytochemical tumor cell staining and reverse transcriptase-polymerase chain reaction. Blood. 1997 Jan 1;89(1):337–344. [PubMed]
  • Martin VM, Siewert C, Scharl A, Harms T, Heinze R, Ohl S, Radbruch A, Miltenyi S, Schmitz J. Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS. Exp Hematol. 1998 Mar;26(3):252–264. [PubMed]
  • Micale MA, Visscher DW, Gulino SE, Wolman SR. Chromosomal aneuploidy in proliferative breast disease. Hum Pathol. 1994 Jan;25(1):29–35. [PubMed]
  • Miltenyi S, Müller W, Weichel W, Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231–238. [PubMed]
  • Moscinski LC, Trudeau WL, Fields KK, Elfenbein GJ. High-sensitivity detection of minimal residual breast carcinoma using the polymerase chain reaction and primers for cytokeratin 19. Diagn Mol Pathol. 1996 Sep;5(3):173–180. [PubMed]
  • Müller P, Weckermann D, Riethmüller G, Schlimok G. Detection of genetic alterations in micrometastatic cells in bone marrow of cancer patients by fluorescence in situ hybridization. Cancer Genet Cytogenet. 1996 May;88(1):8–16. [PubMed]
  • Naume B, Borgen E, Beiske K, Herstad TK, Ravnås G, Renolen A, Trachsel S, Thrane-Steen K, Funderud S, Kvalheim G. Immunomagnetic techniques for the enrichment and detection of isolated breast carcinoma cells in bone marrow and peripheral blood. J Hematother. 1997 Apr;6(2):103–114. [PubMed]
  • Noguchi S, Aihara T, Motomura K, Inaji H, Imaoka S, Koyama H. Detection of breast cancer micrometastases in axillary lymph nodes by means of reverse transcriptase-polymerase chain reaction. Comparison between MUC1 mRNA and keratin 19 mRNA amplification. Am J Pathol. 1996 Feb;148(2):649–656. [PMC free article] [PubMed]
  • Pantel K. Detection of minimal disease in patients with solid tumors. J Hematother. 1996 Aug;5(4):359–367. [PubMed]
  • Persons DL, Hartmann LC, Herath JF, Keeney GL, Jenkins RB. Fluorescence in situ hybridization analysis of trisomy 12 in ovarian tumors. Am J Clin Pathol. 1994 Dec;102(6):775–779. [PubMed]
  • Press MF, Bernstein L, Thomas PA, Meisner LF, Zhou JY, Ma Y, Hung G, Robinson RA, Harris C, El-Naggar A, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997 Aug;15(8):2894–2904. [PubMed]
  • Révillion F, Bonneterre J, Peyrat JP. ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer. 1998 May;34(6):791–808. [PubMed]
  • Ross AA. Minimal residual disease in solid tumor malignancies: a review. J Hematother. 1998 Feb;7(1):9–18. [PubMed]
  • Sauter G, Feichter G, Torhorst J, Moch H, Novotna H, Wagner U, Dürmüller U, Waldman FM. Fluorescence in situ hybridization for detecting erbB-2 amplification in breast tumor fine needle aspiration biopsies. Acta Cytol. 1996 Mar-Apr;40(2):164–173. [PubMed]
  • Schildkraut JM, Collins NK, Dent GA, Tucker JA, Barrett JC, Berchuck A, Boyd J. Loss of heterozygosity on chromosome 17q11-21 in cancers of women who have both breast and ovarian cancer. Am J Obstet Gynecol. 1995 Mar;172(3):908–913. [PubMed]
  • Schoenfeld A, Luqmani Y, Smith D, O'Reilly S, Shousha S, Sinnett HD, Coombes RC. Detection of breast cancer micrometastases in axillary lymph nodes by using polymerase chain reaction. Cancer Res. 1994 Jun 1;54(11):2986–2990. [PubMed]
  • Schoenfeld A, Kruger KH, Gomm J, Sinnett HD, Gazet JC, Sacks N, Bender HG, Luqmani Y, Coombes RC. The detection of micrometastases in the peripheral blood and bone marrow of patients with breast cancer using immunohistochemistry and reverse transcriptase polymerase chain reaction for keratin 19. Eur J Cancer. 1997 May;33(6):854–861. [PubMed]
  • Smith B, Selby P, Southgate J, Pittman K, Bradley C, Blair GE. Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet. 1991 Nov 16;338(8777):1227–1229. [PubMed]
  • Traystman MD, Cochran GT, Hake SJ, Kuszynski CA, Mann SL, Murphy BJ, Pirruccello SJ, Zuvanich E, Sharp JG. Comparison of molecular cytokeratin 19 reverse transcriptase polymerase chain reaction (CK19 RT-PCR) and immunocytochemical detection of micrometastatic breast cancer cells in hematopoietic harvests. J Hematother. 1997 Dec;6(6):551–561. [PubMed]
  • Visscher DW, Wallis T, Ritchie CA. Detection of chromosome aneuploidy in breast lesions with fluorescence in situ hybridization: comparison of whole nuclei to thin tissue sections and correlation with flow cytometric DNA analysis. Cytometry. 1995 Sep 1;21(1):95–100. [PubMed]
  • Visscher DW, Wallis TL, Crissman JD. Evaluation of chromosome aneuploidy in tissue sections of preinvasive breast carcinomas using interphase cytogenetics. Cancer. 1996 Jan 15;77(2):315–320. [PubMed]
  • Vredenburgh JJ, Silva O, Tyer C, DeSombre K, Abou-Ghalia A, Cook M, Layfield L, Peters WP, Bast RC., Jr A comparison of immunohistochemistry, two-color immunofluorescence, and flow cytometry with cell sorting for the detection of micrometastatic breast cancer in the bone marrow. J Hematother. 1996 Feb;5(1):57–62. [PubMed]
  • Xu J, Wang N. Identification of chromosomal structural alterations in human ovarian carcinoma cells using combined GTG-banding and repetitive fluorescence in situ hybridization (FISH). Cancer Genet Cytogenet. 1994 May;74(1):1–7. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...