Abstract
Minimal residual disease (MRD), i.e., isolated tumor cells (ITC) in bone marrow, may be the source of potentially fatal overt distant metastases in solid tumors even years after primary treatment. MRD can be detected by immunohistochemical methods using antibodies directed against cytokeratins, cell-surface markers, or molecular PCR-based techniques. Among solid tumors, the clinical relevance of MRD has been most extensively studied in breast cancer patients. The highest level of evidence for the prognostic impact of MRD in primary breast cancer was reached by a pooled analysis comprising more than 4,000 patients, showing poor outcome in patients with MRD at primary therapy. Yet, clinical application of MRD detection is hampered by the lack of a standardized detection assay. Moreover, clinical trial results demonstrating the benefit of a therapeutic interference derived from bone marrow status are still missing. Recent results suggest that in addition to its prognostic impact, MRD can be used for therapy monitoring or as a potential therapeutic target after phenotyping of the tumor cells. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. In a pooled analysis bone marrow aspirates of 726 patients from academic breast cancer units in Oslo (n=356), Munich (n=228), and Tuebingen (n=142) were analyzed during recurrence-free follow-up at a mean interval of 31.7 months after primary diagnosis of breast cancer pT1-4, pN0-3 pM0. Persistent ITC was detected in 15.4% of the patients (n=112). The Kaplan–Meier estimate for mean distant relapse-free survival estimate was 163.6 months in patients with negative and 105.2 months in patients with positive BM status. Patients without evidence of persistent ITC had a significantly longer overall survival (165.6), than patients with positive bone marrow status (103.3 months, p < .0001). Given these inspiring results on ITC in the bone marrow, several trials currently analyze the prognostic relecance of circulating tumor cells (CTC) in peripheral blood in the adjuvant setting. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. However, until clinical consequences of MRD detection in solid tumors and particularly in breast cancer have been validated, the detection of isolated tumor cells in bone marrow should be performed mainly in clinical trials.
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Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802
Janni WJ, Vogl FD, Wiedswang G et al (2011) Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse—a European Pooled Analysis. Clin Cancer Res 17(9):2967–2976. [Epub 2011 March 17]
Muller V (2009) Clinical relevance of disseminated tumor cells in the bone marrow and circulating tumor cells in the blood of breast cancer patients. Breast Care 4:333–338
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 18:80–86
Naumov GN, Townson JL, MacDonald IC et al (2003) Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat 82:199–206
Braun S, Pantel K (1999) Biological characteristics of micrometastatic cancer cells in bone marrow. Cancer Metastasis Rev 18:75–90
Muller V, Stahmann N, Riethdorf S et al (2005) Circulating tumor cells in breast cancer: correlation to bone marrow DTC, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 11:3678–3685
Pantel K, Schlimok G, Braun S et al (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma-cells. J Natl Cancer Inst 85:1419–1424
Ross AA, Cooper BW, Lazarus HM et al (1993) Detection and viability of tumor-cells in peripheral-blood stem-cell collections from breast-cancer patients using immunocytochemical and clonogenic-assay techniques. Blood 82:2605–2610
Solakoglu O, Maierhofer C, Lahr G et al (2002) Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci U S A 99:2246–2251
Janni W, Hepp F, Rjosk D et al (2001) The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence. Cancer 92:46–53
Gray JW (2003) Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors. Cancer Cell 4:4–6
Sanger N, Effenberger KE, Riethdorf S et al (2011) Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ. Int J Cancer 129(10):2522–2526. doi: 10.1002/ijc.25895. [Epub 2011 Mar 25]
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 18:80–86
Hall C, Krishnamurthy S, Lodhi A et al (2010) Disseminated tumor cells in biologic subtypes of stage I–III breast cancer patients. Ann Surg Oncol 17:3252–3258
Braun S, Pantel K, Muller P et al (2000) 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
Janni W, Gastroph S, Hepp F et al (2000) Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma. Cancer 88:2252–2259
Aft R, Naughton M, Trinkaus K et al (2010) Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 11:421–428
Rack B, Juckstock J, Genss EM et al (2010) Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 30:1807–1813
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 98:179–184
Meng S, Tripathy D, Shete S et al (2004) HER2-neu gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 101:9393–9398
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 61:1890–1895
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Janni, W., Rack, B., Kasprowicz, N., Scholz, C., Hepp, P. (2012). DTCs in Breast Cancer: Clinical Research and Practice. In: Ignatiadis, M., Sotiriou, C., Pantel, K. (eds) Minimal Residual Disease and Circulating Tumor Cells in Breast Cancer. Recent Results in Cancer Research, vol 195. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28160-0_15
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DOI: https://doi.org/10.1007/978-3-642-28160-0_15
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