Abstract
Purpose. The immunocytochemical detection of epithelial cells in the bone marrow (BM) of breast cancer (BC) patients has been shown to have prognostic importance in several studies. We conducted a systematic review of the literature and a meta-analysis to assess the specificity, rate of positivity and correlation with known prognostic variables as well as with disease free (DFS) and overall survival (OS). Design. We performed a systematic review from the published literature. We included studies with at least 20 previously untreated BC patients as well as non-BC controls that evaluated the presence of epithelial cells in BM using immunocytochemistry (IC). Results. We identified 14 eligible studies with 3253 BC patients and 532 controls. Our results showed that IC has an overall rate of positivity of 31%(95%CI: 30–33%), and specificity of 96%(compared to normal patients) (95%CI: 0.94–0.98). We observed significant direct correlations between IC BM positivity and the primary tumor's presence with expression of estrogen receptors, larger size and higher histologic grade as well as with the presence of more than 3 positive axillary lymph nodes. At 5 years of follow up IC positivity correlated directly with a lower DFS (relative risk=1.60; 95%CI: 1.39–1.83) and OS (relative risk=1.73; 95%CI: 1.29–2.31). The prognostic impact of BM positivity seemed to decrease with time. Conclusions. We conclude that the finding of epithelial cells in BM of BC patients correlates with several known prognostic factors and has adverse impact in the DFS and OS of these patients that seems, however, to decrease with time.
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Early Breast Cancer Trialists' Collaborative Group:Poly-chemotherapy for early breast cancer:an overview of the randomised trials.Lancet 352:930–942,1998
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimp T, Kindermann G, Riethmuller 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 342:525–533,2000
Mansi JL, Easton D, Berger U, Gazet JC, Ford HT, Dearnaley D, Coombes RC:Bone marrow micrometastases in primary breast cancer:prognostic signi cance after 6 years' follow-up.Eur J Cancer 27:1552–1555,1991
Molino A, Pelosi G, Turazza M, Sperotto L, Bonetti A, Nortilli R, Fattovich G, Alaimo C, Piubello Q, Pavanel F, Micciolo R, Cetto GL:Bone marrow micrometastases in 109 breast cancer patients:correlations with clinical and pathological features and prognosis.Breast Cancer Res Treat 42:23–30,1997
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 dor-mant tumor cells in bone marrow of high-risk breast cancer patients.J Clin Oncol 18:80–86,2000
Funke I, Schraut W:Meta-analyses of studies on bone marrow micrometastases:an independent prognostic im-pact remains to be substantiated.J Clin Oncol 16:557–566, 1998
Gerber B, Krause A, Muller H, Richter D, Reimer T, Makovitzky J, Herrnring C, Jeschke U, Kundt G, Friese K: Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. J Clin Oncol 19:960–971,2001
Naume B, Borgen E, Kvalheim G, Karesen R, Qvist H, Sauer T, Kumar T, Nesland JM: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 7: 4122–4129,2001
Mansi JL, Gogas H, Bliss JM, Gazet JC, Berger U, Coombes RC:Outcome of primary-breast-cancer patients with micrometastases:a long-term follow-up study.Lancet 354:197–202,1999
Molino A, Pelosi G, Micciolo R, Turazza M, Nortilli R, Pavanel F, Cetto GL:Bone marrow micrometastases in breast cancer patients.Breast Cancer Res Treat 58:123–130,1999
Solomayer EF, Diel IJ, Salanti G, Hahn M, Gollan C, Schutz F, Bastert G:Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.Clin Cancer Res 7:4102–4108,2001
Yusuf S, Peto R, Lewis J, Collins R, Sleight P:Beta blockade during and after myocardial infarction:an overview of the randomized trials.Prog Cardiovasc Dis 27:335–371,1985
Berger U, Bettelheim R, Mansi JL, Easton D,Coombes RC,Neville AM:The relationship between micrometastases in the bone marrow,histopathologic features of the primary tumor in breast cancer and prognosis.Am J Clin Pathol 90: 1–6,1988
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 micrometasta-ses.J Clin Oncol 9:1749–1756,1991
Dearnaley DP, Ormerod MG, Sloane JP:Micrometastases in breast cancer:long-term follow-up of the rst patient cohort.Eur J Cancer 27:236–239,1991
Funke I, Fries S, Rolle M, Heiss MM, Untch M, Bohmert H, Schildberg FW, Jauch KW:Comparative analyses of bone marrow micrometastases in breast and gastric cancer. Int J Cancer 65:755–761,1996
Harbeck N, Untch M, Pache L, Eiermann W:Tumour cell detection in the bone marrow of breast cancer patients at primary therapy:results of a 3-year median follow-up.Br J Cancer 69:566–571,1994
Kirk SJ, Cooper GG, Hoper M, Watt PC, Roy AD, Odling-Smee W:The prognostic signi cance of marrow micrometastases in women with early breast cancer.Eur J Surg Oncol 16:481–485,1990
Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmuller G:Differential expression of proliferation-associated molecules in individ-ual micrometastatic carcinoma cells.J Natl Cancer Inst 85: 1419–1424,1993
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 immuno-histochemistry and reverse transcriptase polymerase chain reaction for keratin 19.Eur J Cancer 33:854–861,1997
Egger M, Smith GD, Sterne JA:Uses and abuses of meta-analysis.Clin Med 1:478–484,2001
Altman DG:Systematic reviews of evaluations of prognos-tic variables.BMJ 323:224–228,2001
Deeks JJ:Systematic reviews in health care:systematic reviews of evaluations of diagnostic and screening tests. BMJ 323:157–162,2001
Manhani AR, Manhani R, Soares HP, Bendit I, Lopes F, Nicoletti AG, Fonseca FL, Novaes M, Zatta SM, Arias V, Giralt S, Del Giglio A:CK-19 expression by RT-PCR in the peripheral blood of breast cancer patients correlates with response to chemotherapy.Breast Cancer Res Treat 66: 249–254,2001
Fonseca FLA, Soares HP, Manhani AR, Bendit I, Novaes M, Zatta SM, Arias V, Pinhal MAS, Weinschenker P, Del Giglio A:Peripheral blood C-Erbb-2 expression by reverse transcriptase-polymerase chain reaction in breast cancer patients receiving chemotherapy.Clin Breast Cancer 3: 201–205,2002
Soares HP, Del Giglio A, Silva RS, Clark O, Kumar A, Djulbegovic B:Reverse transcriptase polymerase chain reaction for minimal residual disease detection in the periph-eral blood of women with breast cancer:a meta-analysis. Proceedings of ASCO.Abstract 3531,2003
Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis C, Apostolaki S, Malamos N, Kakolyris S, Kotsakis A, Xenidis N, Reppa D, Georgoulias V:Molec-ular detection of cytokeratin-19-positive cells in the periph-eral blood of patients with operable breast cancer: evaluation of their prognostic signi cance.J Clin Oncol 20:3404–3412,2002
Braun S, Cevatli BS, Assemi C, Janni W, Kentenich CR, Schindlbeck C, Rjosk D, Hepp F:Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy.J Clin Oncol 19:1468–1475,2001
Borgen E, Beiske K, Trachsel S, Nesland JM, Kvalheim G, Herstad TK, Schlichting E, Qvist H, Naume B:Immuno-cytochemical detection of isolated epithelial cells in bone marrow:non-specific staining and contribution by plasma cells directly reactive to alkaline phosphatase.J Pathol 185: 427–434,1998 Address for o.prints and correspondence:Auro Del Giglio,Av. Rebouc ¸as,3387,Sa ~;o Paulo,SP 05410-040,Brazil;Tel./Fax: +55-11-3819-5007;E-mail:sandrabr@netpoint.com.br
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Weinschenker, P., Soares, H.P., Clark, O. et al. Immunocytochemical detection of epithelial cells in the bone marrow of primary breast cancer patients: a meta-analysis. Breast Cancer Res Treat 87, 215–224 (2004). https://doi.org/10.1007/s10549-004-8691-1
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DOI: https://doi.org/10.1007/s10549-004-8691-1