Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity

Müller, Volkmar; Stahmann, Nicole; Riethdorf, Sabine; Rau, Thomas; Zabel, T.; Goetz, Alexander; Jänicke, F.; Pantel, Klaus

doi:10.1158/1078-0432.ccr-04-2469

Cited by 369 publications

(271 citation statements)

References 32 publications

(29 reference statements)

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“…It has been shown that CTCs have a half-life of 1 -2.4 h (Meng et al, 2004) and are nonreplicating (Muller et al, 2005) and that these must be replenished by replicating cells from elsewhere. Potentially, this could be the bone marrow; however, the DTCs, when in the bone marrow, are also non-replicating in the majority of primary breast cancer patients (Pantel et al, 1993;Muller et al, 2005). In each case, we have used the best available methodologies for detecting the cells and further studies on a larger cohort of patients along with improvements in assays, for example, CellSearch applied to bone marrow aspirates, may improve the correlation between CTCs and DTCs.…”

Section: Discussionmentioning

confidence: 99%

Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment

Slade¹,

Payne²,

Riethdorf

et al. 2008

Br J Cancer

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The purpose of this study was to determine whether primary breast cancer patients showed evidence of circulating tumour cells (CTCs) during follow-up as an alternative to monitoring disseminated bone marrow tumour cells (DTCs) by immunocytochemistry and reverse transcriptase (RT) -PCR for the detection of micrometastases. We planned to compare CTC and DTC frequency in low-risk and high-risk patients. We identified two cohorts of primary breast cancer patients who were at low (group II, T 1 N 0 , n ¼ 18) or high (group III, 43 nodes positive (with one exception, a patient with two positive nodes) n ¼ 33) risk of relapse who were being followed up after primary treatment. We tested each cohort for CTCs using the CellSearch system on 1 -7 occasions and for DTCs by immunocytochemistry and RT -PCR on 1 -2 occasions over a period of 2 years. We also examined patients with confirmed metastatic disease (group IV, n ¼ 12) and 21 control healthy volunteers for CTCs (group I). All group I samples were negative for CTCs. In contrast, 7 out of 18 (39%) group II primary patients and 23 out of 33 (70%) group III patients were positive for CTCs (P ¼ 0.042). If we count only samples with 41 cell as positive: 2 out of 18 (11%) group II patients were positive compared with 10 out of 33 (30%) in group III (P ¼ 0.174). In the case of DTCs, 1 out of 13 (8%) group II patients were positive compared with 19 out of 27 (70%) in group III (Po0.001). Only 10 out of 33 (30%) patients in group III showed no evidence of CTCs in all tests over the period of testing, compared with 11 out of 18 (61%) in group II (P ¼ 0.033). A significant proportion of poor prognosis primary breast cancer patients (group III) have evidence of CTCs on follow-up. Many also have evidence of DTCs, which are more often found in patients who were lymph node positive. As repeat sampling of peripheral blood is more acceptable to patients, the measurement of CTCs warrants further investigation because it enables blood samples to be taken more frequently, thus possibly enabling clinicians to have prior warning of impending overt metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment

Slade¹,

Payne²,

Riethdorf

et al. 2008

Br J Cancer

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“…25,48 However, CTCs may play a major role in the evaluation of therapeutic efficacy because of their easier accessibility compared with bone marrow. 49,50 Currently, only 1 system for the detection of CTCs (CellSearch TM assay; Veridex) has received clearance from the U.S. Food and Drug Administration. That system has demonstrated the ability to deliver clinically relevant information for CTC detection in a prospective trial: It visualizes CTCs by using immunofluorescent micro- The presence of disseminated tumor cells in the bone marrow from patients with no evidence of disease after definitive primary and adjuvant therapy is associated with poor outcome.…”

Section: Perspectives and Unsolved Problems For The Clinical Utility mentioning

confidence: 99%

A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation

Fehm

Braun

Müller

et al. 2006

Cancer

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204

199

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Numerous single-institutional studies and a large pooled analysis have demonstrated that the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) from patients with primary, nonmetastatic breast cancer (Stages I-III) is associated with impaired prognosis. To date, sampling of BM and assessment of DTCs is not considered a routine procedure in the clinical management of breast cancer patients; however, emerging data suggest a future role for risk stratification and monitoring of therapeutic efficacy. Because these clinical options need to be evaluated in trials to verify the principle of this concept in the clinical setting, agreement on the standardized detection of DTCs is necessary. Consequently, the German, Austrian, and Swiss Societies for Senology recently formed a panel 1) to review and discuss the existing methodologies, 2) to find a consen-

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“…Over the past few years, different approaches for the detection, enumeration and isolation of CTCs in blood have been developed. Immunocytochemical analysis is usually used in combination with density-gradient centrifugation (Balic et al, 2005;Muller et al, 2005;Wiedswang et al, 2006), size filtration (Kahn et al, 2004;Wong et al, 2006) or flow cytometry (Meng et al, 2004;Allan et al, 2005) to enrich tumour cells before their detection. In addition, nucleic-acid-based approaches for cell detection have been described (Lambrechts et al, 1999;Smith et al, 2000;Aerts et al, 2001;Stathopoulou et al, 2002;Benoy et al, 2004).…”

mentioning

confidence: 99%

Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT–PCR in patients with metastatic breast cancer

Auwera

Peeters

Benoy³

et al. 2009

Br J Cancer

163

107

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BACKGROUND: The detection, enumeration and isolation of circulating tumour cells (CTCs) have considerable potential to influence the clinical management of patients with breast cancer. There is, however, substantial variability in the rates of positive samples using existing detection techniques. The lack of standardisation of technology hampers the implementation of CTC measurement in clinical routine practice. METHODS: This study was designed to directly compare three techniques for detecting CTCs in blood samples taken from 76 patients with metastatic breast cancer (MBC) and from 20 healthy controls: the CellSearch CTC System, the AdnaTest Breast Cancer Select/ Detect and a previously developed real-time qRT-PCR assay for the detection of CK-19 and mammaglobin transcripts. RESULTS: As a result, 36% of patients with MBC were positive by the CellSearch System, 22% by the AdnaTest, 26% using RT -PCR for CK-19 and 54% using RT -PCR for mammaglobin. Samples were significantly more likely to be positive for at least one mRNA marker using RT -PCR than using the CellSearch System (P ¼ 0.001) or the AdnaTest (Po0.001). CONCLUSION: We observed a substantial variation in the detection rates of CTCs in blood from breast cancer patients using three different techniques. A higher rate of positive samples was observed using a combined qRT-PCR approach for CK-19 and mammaglobin, which suggests that this is currently the most sensitive technique for detecting CTCs.

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Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity

Cited by 369 publications

References 32 publications

Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment

Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment

A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation

Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT–PCR in patients with metastatic breast cancer

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