Cytokeratin-Positive Cells in the Bone Marrow and Survival of Patients with Stage I, II, or III Breast Cancer
Stephan Braun, M.D., Klaus Pantel, M.D., Peter Müller, M.D., Wolfgang Janni, M.D., Florian Hepp, M.D., Christina R.M. Kentenich, Stephan Gastroph, Artur Wischnik, M.D., Thomas Dimpfl, M.D., Günter Kindermann, M.D., Gert Riethmüller, M.D., and Günter Schlimok, M.D.
Background Cytokeratins are specific markers of epithelial cancercells in bone marrow. We assessed the influence of cytokeratin-positivemicrometastases in the bone marrow on the prognosis of womenwith breast cancer.
Methods We obtained bone marrow aspirates from both upper iliaccrests of 552 patients with stage I, II, or III breast cancerwho underwent complete resection of the tumor and 191 patientswith nonmalignant disease. The specimens were stained with themonoclonal antibody A45-B/B3, which binds to an antigen on cytokeratins.The median follow-up was 38 months (range, 10 to 70). The primaryend point was survival.
Results Cytokeratin-positive cells were detected in the bonemarrow specimens of 2 of the 191 control patients with nonmalignantconditions (1 percent) and 199 of the 552 patients with breastcancer (36 percent). The presence of occult metastatic cellsin bone marrow was unrelated to the presence or absence of lymph-nodemetastasis (P=0.13). After four years of follow-up, the presenceof micrometastases in bone marrow was associated with the occurrenceof clinically overt distant metastasis and death from cancer-relatedcauses (P<0.001), but not with locoregional relapse (P=0.77).Of 199 patients with occult metastatic cells, 49 died of cancer,whereas of 353 patients without such cells, 22 died of cancer-relatedcauses (P<0.001). Among the 301 women without lymph-nodemetastases, 14 of the 100 with bone marrow micrometastases diedof cancer-related causes, as did 2 of the 201 without bone marrowmicrometastases (P<0.001). The presence of occult metastaticcells in bone marrow, as compared with their absence, was anindependent prognostic indicator of the risk of death from cancer(relative risk, 4.17; 95 percent confidence interval, 2.51 to6.94; P<0.001), after adjustment for the use of systemicadjuvant chemotherapy.
Conclusions The presence of occult cytokeratin-positive metastaticcells in bone marrow increases the risk of relapse in patientswith stage I, II, or III breast cancer.
Source Information
From I. Frauenklinik, Klinikum Innenstadt (S.B., W.J., F.H., C.R.M.K., S.G., T.D., G.K.), and the Institut für Immunologie (G.R.), Ludwig Maximilians University, Munich; Frauenklinik, Universitätsklinikum Eppendorf, Hamburg (K.P.); and II. Medizinische Klinik (P.M., G.S.) and Frauenklinik (A.W.), Zentralklinikum Augsburg, Augsburg — all in Germany.
Address reprint requests to Dr. Braun at I. Frauenklinik, Klinikum Innenstadt, Ludwig Maximilians University, Maistrasse 11, D-80337 Munich, Germany, or at sbraun{at}fk-i.med.uni-muenchen.de.
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Joensuu, H., Isola, J., Lundin, M., Salminen, T., Holli, K., Kataja, V., Pylkkanen, L., Turpeenniemi-Hujanen, T., von Smitten, K., Lundin, J.
(2003). Amplification of erbB2 and erbB2 Expression Are Superior to Estrogen Receptor Status As Risk Factors for Distant Recurrence in pT1N0M0 Breast Cancer: A Nationwide Population-based Study. Clin. Cancer Res.
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Schleiermacher, G., Peter, M., Oberlin, O., Philip, T., Rubie, H., Mechinaud, F., Sommelet-Olive, D., Landman-Parker, J., Bours, D., Michon, J., Delattre, O.
(2003). Increased Risk of Systemic Relapses Associated With Bone Marrow Micrometastasis and Circulating Tumor Cells in Localized Ewing Tumor. JCO
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Solomayer, E.-F., Feuerer, M., Bai, L., Umansky, V., Beckhove, P., Meyberg, G. C., Bastert, G., Schirrmacher, V., Diel, I. J.
(2003). Influence of Adjuvant Hormone Therapy and Chemotherapy on the Immune System Analysed in the Bone Marrow of Patients with Breast Cancer. Clin. Cancer Res.
9: 174-180
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Sabino, M. A. C., Ghilardi, J. R., Jongen, J. L. M., Keyser, C. P., Luger, N. M., Mach, D. B., Peters, C. M., Rogers, S. D., Schwei, M. J., de Felipe, C., Mantyh, P. W.
(2002). Simultaneous Reduction in Cancer Pain, Bone Destruction, and Tumor Growth by Selective Inhibition of Cyclooxygenase-2. Cancer Res.
62: 7343-7349
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Stathopoulou, 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. JCO
20: 3404-3412
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Klein, C. A., Wilke, M., Pool, J., Vermeulen, C., Blokland, E., Burghart, E., Krostina, S., Wendler, N., Passlick, B., Riethmueller, G., Goulmy, E.
(2002). The Hematopoietic System-specific Minor Histocompatibility Antigen HA-1 Shows Aberrant Expression in Epithelial Cancer Cells. JEM
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Yamashita, J.-i., Matsuo, A., Kurusu, Y., Saishoji, T., Hayashi, N., Ogawa, M.
(2002). Preoperative evidence of circulating tumor cells by means of reverse transcriptase-polymerase chain reaction for carcinoembryonic antigen messenger RNA is an independent predictor of survival in non-small cell lung cancer: A prospective study. J. Thorac. Cardiovasc. Surg.
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Zehentner, B. K., Dillon, D. C., Jiang, Y., Xu, J., Bennington, A., Molesh, D. A., Zhang, X., Reed, S. G., Persing, D., Houghton, R. L.
(2002). Application of a Multigene Reverse Transcription-PCR Assay for Detection of Mammaglobin and Complementary Transcribed Genes in Breast Cancer Lymph Nodes. Clin. Chem.
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Osaki, T., Oyama, T., Gu, C.-D., Yamashita, T., So, T., Takenoyama, M., Sugio, K., Yasumoto, K.
(2002). Prognostic Impact of Micrometastatic Tumor Cells in the Lymph Nodes and Bone Marrow of Patients With Completely Resected Stage I Non-Small-Cell Lung Cancer. JCO
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Fehm, T., Sagalowsky, A., Clifford, E., Beitsch, P., Saboorian, H., Euhus, D., Meng, S., Morrison, L., Tucker, T., Lane, N., Ghadimi, B. M., Heselmeyer-Haddad, K., Ried, T., Rao, C., Uhr, J.
(2002). Cytogenetic Evidence That Circulating Epithelial Cells in Patients with Carcinoma Are Malignant. Clin. Cancer Res.
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Bosma, A. J., Weigelt, B., Lambrechts, A. C., Verhagen, O. J. H. M., Pruntel, R., Hart, A. A. M., Rodenhuis, S., Veer, L. J. v.'t
(2002). Detection of Circulating Breast Tumor Cells by Differential Expression of Marker Genes. Clin. Cancer Res.
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Witzig, T. E., Bossy, B., Kimlinger, T., Roche, P. C., Ingle, J. N., Grant, C., Donohue, J., Suman, V. J., Harrington, D., Torre-Bueno, J., Bauer, K. D.
(2002). Detection of Circulating Cytokeratin-positive Cells in the Blood of Breast Cancer Patients Using Immunomagnetic Enrichment and Digital Microscopy. Clin. Cancer Res.
8: 1085-1091
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Rouzier, R., Extra, J.-M., Klijanienko, J., Falcou, M.-C., Asselain, B., Vincent-Salomon, A., Vielh, P., Bourstyn, E.
(2002). Incidence and Prognostic Significance of Complete Axillary Downstaging After Primary Chemotherapy in Breast Cancer Patients With T1 to T3 Tumors and Cytologically Proven Axillary Metastatic Lymph Nodes. JCO
20: 1304-1310
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Solakoglu, O., Maierhofer, C., Lahr, G., Breit, E., Scheunemann, P., Heumos, I., Pichlmeier, U., Schlimok, G., Oberneder, R., Kollermann, M. W., Kollermann, J., Speicher, M. R., Pantel, K.
(2002). Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc. Natl. Acad. Sci. USA
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(2002). The epistemology of epidemiology. CMAJ
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(2002). L'epistemologie de l'epidemiologie:. CMAJ
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Kufer, P., Zippelius, A., Lutterbuse, R., Mecklenburg, I., Enzmann, T., Montag, A., Weckermann, D., Passlick, B., Prang, N., Reichardt, P., Dugas, M., Kollermann, M. W., Pantel, K., Riethmuller, G.
(2002). Heterogeneous Expression of MAGE-A Genes in Occult Disseminated Tumor Cells: A Novel Multimarker Reverse Transcription-Polymerase Chain Reaction for Diagnosis of Micrometastatic Disease. Cancer Res.
62: 251-261
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Taback, B., Chan, A. D., Kuo, C. T., Bostick, P. J., Wang, H.-J., Giuliano, A. E., Hoon, D. S. B.
(2001). Detection of Occult Metastatic Breast Cancer Cells in Blood by a Multimolecular Marker Assay: Correlation with Clinical Stage of Disease. Cancer Res.
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Clark, G. M.
(2001). Interpreting and Integrating Risk Factors for Patients With Primary Breast Cancer. J Natl Cancer Inst Monogr
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Solomayer, E.-F., Diel, I. J., Salanti, G., Hahn, M., Gollan, C., Schutz, F., Bastert, G.
(2001). Time Independence of the Prognostic Impact of Tumor Cell Detection in the Bone Marrow of Primary Breast Cancer Patients. Clin. Cancer Res.
7: 4102-4108
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Naume, B., Borgen, E., Kvalheim, G., Karesen, R., Qvist, H., Sauer, T., Kumar, T., Nesland, J. M.
(2001). Detection of Isolated Tumor Cells in Bone Marrow in Early-Stage Breast Carcinoma Patients: Comparison with Preoperative Clinical Parameters and Primary Tumor Characteristics. Clin. Cancer Res.
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Zeitvogel, A., Baumann, R., Starzinski-Powitz, A.
(2001). Identification of an Invasive, N-Cadherin-Expressing Epithelial Cell Type in Endometriosis Using a New Cell Culture Model. Am. J. Pathol.
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Gebauer, G., Fehm, T., Merkle, E., Beck, E. P., Lang, N., Jager, W.
(2001). Epithelial Cells in Bone Marrow of Breast Cancer Patients at Time of Primary Surgery: Clinical Outcome During Long-Term Follow-Up. JCO
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A correction has been published: N Engl J Med 2000;343(4):308.
