Cytokeratin-Positive Cells in the Bone Marrow and Survival of Patients with Stage I, II, or III Breast Cancer

Braun, Stephan; Pantel, Klaus; Müller, Peter E.; Janni, Wolfgang; Hepp, Florian; Kentenich, Christina; Gastroph, Stephan; Wischnik, A; Dimpfl, T.; Kindermann, G.; Riethmüller, Gert; Schlimok, Günter

doi:10.1056/nejm200002243420801

Cited by 847 publications

(618 citation statements)

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“…The detection of occult tumor cells either in the bone marrow or the peripheral blood has been demonstrated to represent an independent prognostic factor for disease relapse and reduced survival [2][3][4][5][6]. Indeed, a meta-analysis involving 4,703 patients with stage I-III breast cancer confirmed the independent prognostic value of DTCs [7].…”

Section: Introductionmentioning

confidence: 99%

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Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance

Apostolaki

Perraki

Kallergi

et al. 2008

Breast Cancer Res Treat

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Section: Introductionmentioning

confidence: 99%

“…Among these markers are cytokeratin-19 (CK19), mammaglobin, maspin, and carcinoembryonic antigen (CEA) [2][3][4][5][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance

Apostolaki

Perraki

Kallergi

et al. 2008

Breast Cancer Res Treat

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“…This assumption is apparently supported by some prospective studies suggesting that the presence of isolated tumour cells in bone marrow or peripheral blood is an independent prognostic factor (Diel et al, 1996;Braun et al, 2000;Stathopoulou et al, 2002). However, the literature reports conflicting results; so this subject is still under discussion (Jiang et al, 2002;Ozbas et al, 2003;Pantel et al, 2003).…”

Section: Discussionmentioning

confidence: 95%

“…Several studies suggest that these objectives can be achieved with the current assays (Cote et al, 1991;Harbeck et al, 1994;Diel et al, 1996;Smith et al, 2000;Terstappen et al, 2000;Gebauer et al, 2001;Jiang et al, 2002;Ozbas et al, 2003;Pantel et al, 2003) and in a few of them the presence of disseminated tumour cells in bone marrow or peripheral blood is recognised as an independent prognostic factor (Diel et al, 1996;Braun et al, 2000;Stathopoulou et al, 2002). However, the literature reports conflicting results and the clinical value of these assays remains to be proven basically because it is uncertain whether the published assays have enough sensitivity, specificity and consistency to be reliably integrated into prospective studies provided with adequate statistical power to answer the most relevant clinical questions (Jiang et al, 2002;Ozbas et al, 2003;Pantel et al, 2003).…”

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confidence: 99%

Effect of different cytokines on mammaglobin and maspin gene expression in normal leukocytes: possible relevance to the assays for the detection of micrometastatic breast cancer

et al. 2005

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In cancer patients, the ability to detect disseminated tumour cells in peripheral blood or bone marrow could improve prognosis and consent both early detection of metastatic disease and monitoring of the efficacy of systemic therapy. These objectives remain elusive mainly due to the lack of specific genetic markers for solid tumours. The use of surrogate tissue-specific markers can reduce the specificity of the assays and give rise to a clinically unacceptable false-positive rate. Mammaglobin (MAM) and maspin are two putative breast tissue-specific markers frequently used for detection of occult tumour cells in the peripheral blood, bone marrow and lymph nodes of breast cancer patients. In this study, it was evaluated whether MAM and maspin gene expression may be induced in the normal blood and bone marrow cells exposed to a panel of cytokines, including chemotactic factors (C5a, interleukin (IL)-8), LPS, proinflammatory cytokines (TNF-a, IL-1b) and growth factors (IL-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor). The experimental data show that all cytokines included in the panel, except for IL-8, were able to induce maspin expression; on the contrary, MAM gene was never induced. These results suggest that MAM is more specific than maspin and that the possible interference of cytokines should be taken into account in interpreting molecular assays for detection of isolated tumour cells.

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“…After median follow-up of 12 years, occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in postmenopausal but not in premenopausal patients. Other studies have also shown that breast cancer micrometastases in axillary lymph nodes being detected by serial sectioning and IHC have prognostic significance (Braun et al, 2000(Braun et al, , 2001. Reverse transcriptase -polymerase chain reaction (RT -PCR) has a potential of increasing the sensitivity of the pathologic processing of lymph nodes obtained from breast cancer patients.…”

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confidence: 99%

Multimarker RT–PCR assay for the detection of minimal residual disease in sentinel lymph nodes of breast cancer patients

et al. 2006

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The presence of metastases in lymph nodes is the most powerful prognostic factor in breast cancer patients. Routine histological examination of lymph nodes has limited sensitivity for the detection of breast cancer metastases. The aim of the present study was to develop a multimarker reverse transcriptase -polymerase chain reaction (RT-PCR) assay for the detection of minimal residual disease in sentinel nodes of breast cancer patients. RNA was extracted from 30 sentinel lymph nodes (SLN) obtained from 28 patients, three primary breast cancers (positive controls), three lymph nodes from patients with benign diseases, and peripheral blood lymphocytes of 10 healthy volunteers (negative controls). RT -PCR was performed using the following markers; cytokeratin (CK)-19, NY-BR-1 and mammaglobin B. RT -PCR results were compared to enhanced histopathologic examination and immunohistochemistry (IHC). All three positive controls showed strong PCR amplification for all three markers. None of the 13 negative controls was amplified by any of the three markers. Among the 30 SLN analysed, breast cancer metastases were detected in six SLNs by routine histology, in eight by IHC and in 15 by RT -PCR. We conclude that a multimarker RT -PCR assay probing for NY-BR-1, mammaglobin-B, and CK-19 is more sensitive compared to enhanced pathologic examination. This method may prove to be of value in breast cancer staging and prognosis evaluation. Although up to 80% of breast cancer patients are identified at an early stage when disease is apparently localised, 30 -35% of nodenegative patients will develop clinically detectable distant metastases within 5 years of treatment of the primary breast carcinoma and ultimately suffer tumour-related mortality (Nemoto et al, 1980). Routine histological examination of lymph nodes has limited sensitivity for the detection of breast cancer metastases. It is usually performed with a single haematoxilyn and eosin (H&E)-stained section through the examined node and therefore small metastases can go undetected. In a landmark study conducted by the International (Ludwig) Breast Cancer Group (International (Ludwig) Breast Cancer Study Group, 1990), serial sectioning of axillary lymph nodes judged to be disease free after routine histological examination revealed micrometastases in 83 (9%) of 921 breast cancer patients. These patients had a poorer disease-free (P ¼ 0.003) and overall (P ¼ 0.002) survival after 5 years' median follow-up than did patients whose nodes remained negative on serial sectioning. A later study performed by the same group (Cote et al, 1999) examined lymph nodes negative for metastases on routine histology from 736 patients by serial sectioning and by immunohistochemistry (IHC) with two anticytokeratins AE-1 and CAM 5.2. Occult nodal metastases were detected by serial sectioning and H&E in 7% of the patients and by IHC in 20%. After median follow-up of 12 years, occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in pos...

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Cytokeratin-Positive Cells in the Bone Marrow and Survival of Patients with Stage I, II, or III Breast Cancer

Abstract: The presence of occult cytokeratin-positive metastatic cells in bone marrow increases the risk of relapse in patients with stage I, II, or III breast cancer.

Cited by 847 publications

References 41 publications

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance

Effect of different cytokines on mammaglobin and maspin gene expression in normal leukocytes: possible relevance to the assays for the detection of micrometastatic breast cancer

Multimarker RT–PCR assay for the detection of minimal residual disease in sentinel lymph nodes of breast cancer patients

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