Elsevier

European Journal of Cancer

Volume 44, Issue 18, December 2008, Pages 2726-2736
European Journal of Cancer

Micrometastatic disease in breast cancer: Clinical implications

https://doi.org/10.1016/j.ejca.2008.09.033Get rights and content

Abstract

The presence of bone marrow disseminated tumour cells (DTCs) was shown to predict poor clinical outcome in early breast cancer. However, peripheral blood is easier to obtain and allows for serial monitoring of minimal residual disease. Towards this aim, circulating tumour cells (CTCs) in the blood are detected using either direct methods, mainly antibody-based assays (immunocytochemistry, immunofluorescence and flow cytometry), or indirect methods, mainly nucleic acid-based assays (detection of mRNA transcripts by reverse transcriptase polymerase chain reaction, RT-PCR). The detection of CTCs using RT-PCR for CK19 was shown to be an independent prognostic factor in women with early breast cancer. Furthermore, considerable progress has been accomplished in genotyping, phenotyping and profiling micrometastatic cells. The challenge now is to integrate minimal residual disease as a prognostic and predictive tool in the management of breast cancer. This requires the standardisation of micrometastatic cell detection and characterisation, which will allow the incorporation of CTCs/DTCs into prospective clinical trials testing their clinical utility.

Introduction

The TNM system used for staging breast cancer does not accurately identify prognosis for some women and especially for those with small, axillary node-negative tumours who still may relapse and die of breast cancer.1 Therefore, many investigators have hypothesised that the detection of micrometastases in the bone marrow (disseminated tumour cells, DTCs)2, 3, 4 or peripheral blood (circulating tumour cells, CTCs)5, 6, 7 might provide additional prognostic information beyond TNM system. Furthermore, the micrometastatic cells that are undetectable by the classical imaging and laboratory studies (minimal residual disease, MRD), when present after potentially curative surgery, are thought to contribute to disease relapse, and therefore are the obvious targets of adjuvant treatment strategies. Consequently, the study of these cells, apart from the impact on refining prognosis, has the exciting potential of individualising adjuvant treatment for women with breast cancer.

Bone marrow DTCs were shown to have less advanced genomic changes than primary tumour cells, suggesting that tumour cell dissemination occurs early in the course of the disease, and therefore breast cancer, even when diagnosed at an early stage, should be considered in many patients as a systemic illness.8, 9 However, the American Society of Clinical Oncology (ASCO) 2007 recommendations for breast cancer tumour markers suggested that the present data are insufficient to recommend assessment of bone marrow DTCs for the management of patients with breast cancer.10 Similarly, the panel concluded that the measurement of CTCs should not be used to make the diagnosis or to influence any treatment decisions in patients with breast cancer.10 However, this is the first time that DTCs/CTCs have been included in the ASCO guidelines, and the panel concludes that the data are intriguing and should be further evaluated in future studies.10 Here, we will critically review the literature concerning the clinical implications of DTCs/CTCs and present the potential that the study of MRD might have in changing the way we manage breast cancer. Micrometastasis in the axillary lymph nodes (included in the last TNM edition11) is beyond the scope of the present review.

Section snippets

Definition of occult tumour cells

Occult tumour epithelial cells found in the bone marrow and peripheral blood of women with breast cancer are termed as disseminated tumour cells (DTCs) and circulating tumour cells (CTCs), respectively. DTCs and CTCs are only rarely found in the bone marrow and peripheral blood of otherwise healthy women. Several investigators have provided evidence that most detectable epithelial cells in the bone marrow9, 12, 13 or peripheral blood14 of women with breast cancer harbour genomic alterations

Methods of detection of occult tumour cells

By definition, micrometastatic cells are undetectable with standard haematoxylin-eosin staining. These cells have been detected usually after an initial enrichment step (density gradients such as Ficoll/Hypaque, OncoQuick, filtration, immunomagnetic selection techniques such as magnetic affinity cell sorting or magnetic beads) using either direct methods, mainly antibody-based assays (immunocytochemistry, immunofluorescence and flow cytometry), or indirect methods, mainly nucleic acid-based

Diagnosis

Several studies have used CTCs detection as a tool to assist breast cancer diagnosis.33, 34 Reinholz et al. reported that molecular detection of CTCs can be used in combination with mammography and physical examination for the early detection of breast cancer. They used mammaglobin-A (MGB1) and B305D-C genes to construct a diagnostic test that correctly identified breast cancer in women undergoing biopsy for mammographically detected breast abnormalities with a sensitivity of 70.5% and a

Prognosis

DTCs and CTCs have been extensively studied for their impact on prognosis estimation in breast cancer (see Table 1).

Prediction

Apart from refining prognosis, the most exciting field is studying the role of MRD as a predictive tool. There is experimental evidence that the micrometastatic cells have less advanced genomic alterations than primary tumour cells.9 Since the micrometastatic cells are the true targets of adjuvant systemic treatment, it might be important to consider when choosing therapy, not only the characteristics of the primary tumour, but also those of micrometastatic cells in order to improve outcome of

DTCs/CTCs as prognostic and predictive tool. Is it ready for prime time?

CTCs can serve as a real-time biopsy to evaluate and monitor treatment response since their detection can be easily repeated at different time intervals, whereas this is not the case for bone marrow DTCs. Therefore, most ongoing and planned clinical studies use peripheral blood CTCs instead of bone marrow DTCs in order to study MRD as a prognostic and predictive tool in breast cancer. Although there are emerging data that DTCs/CTCs might be, in the near future, exciting new prognostic and

Conflict of interest statement

None declared.

Acknowledgement

We would like to apologise for not citing in the present article many studies in the field of micrometastasis due to space limitations.

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