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Journal of Clinical Oncology, Vol 23, No 8 (March 10), 2005: pp. 1623-1626 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.10.073
Circulating and Disseminated Tumor Cells
From the Department of Obstetrics and Gynecology, University of Innsbruck, Innsbruck, Austria; and Department of Oncology, The Norwegian Radium Hospital, Oslo, Norway Address reprint requests to Stephan Braun, MD, Innsbruck Medical University, Department of Obstetrics and Gynecology, Breast Health Center, Anichstrasse 35 A-6020 Innsbruck Austria; e-mail: stephan.braun{at}uklibk.ac.at.
The genesis of overt metastases in breast cancer is based on the idea that tumor cells that dissociate from the primary cancer get access to circulation either directly into blood vessels or after transit in lymphatic channels. Thus, detection of such cells in patients with newly diagnosed solid tumors has been an appealing strategy to provide evidence of future metastases.1 Overall, the existence of circulating tumor cells (CTC) and the settlement of these cells in secondary organs, such as liver, bone, and lungs, as disseminated metastatic tumor cells (DTC), is generally accepted. These cells are believed to be rare members among the cellular population of primary tumor cells.2 This model, viewing CTC and DTC as rare and late events during primary tumor progression, has been challenged by recent expression profiling studies, in which a more ubiquitous "metastatic phenotype" that can be assessed by gene expression analysis was proposed.3-5 On the other hand, genome and transcriptome analyses of single disseminated tumor cells demonstrated that the majority of DTCs are cells with genetic abberations compatible with malignancy, and therefore most likely direct descendants of the primary tumor, although the genetic changes generally were incongruent with the dominant genotype of the corresponding primary tumor.6-8 These observations support the hypothesis of a breast cancer stem cell: a progenitor cell with self-renewing properties that gives rise to most of the tumor mass that is dealt with clinically. Thus, genotyping or phenotyping of tumor tissue provides heterogeneous information about the more terminally differentiated cells that make up the lion's share of the cancer, but, because stem cells comprise such a small portion of the cell mass, they do not provide information about the key cell that is driving the malignant progression.9,10 However, beyond the discussion of such models and opinions, the actual presence of tumor cells outside the primary tumor and in organs relevant for subsequent metastasis formation, such as bone and bone marrow, would serve three purposes that could be clinically useful: (1) as unambiguous evidence for an early occult spread of tumor cells; (2) as a relevant risk factor for subsequent metastasis and, thus, a poor prognosis; and (3) as a marker for monitoring treatment susceptibility. Finally, and perhaps as importantly in the long run, genotyping and phenotyping of CTC and DTC should provide detailed insight into the metastatic process and permit direct exploration of targeted treatment strategies.1 Is detection of CTC or DTC prognostic in early-stage breast cancer? The currently available literature regarding the prognostic relevance of the presence of DTC in bone marrow is controversial, and without clear conclusions if viewed globally. However, a substantial number of studies do not meet essential criteria for quality assurance, (such as thorough validation of the detection antibody and detection system), adequate controls, and/or clinical trial design (such as ensuring a sufficient number of individuals enrolled on the study to be representative and adequately powered), and therefore should be excluded from our debate. To date, sufficient data are available from several large studies that unambiguously demonstrate the independent poor prognostic influence of DTC present in bone marrow on outcome in patients with stage I to III breast cancer (Table 1).11-17
In contrast to the simplicity of the technology, the influence of confounding variables of the immunocytochemical assay on detection of DTC in bone marrow should not be underestimated.18-20 Thorough and critical evaluation of each process step of sample preparation, immunostaining, and analysis is required to avoid severe misinterpretation. Before unrestricted routine use of the technology, results of an ongoing process of methodologic improvement (eg, optimization of the standard protocol, implementation of automated devices for sample preparation, staining, and screening) have to be awaited. Thus, the immunocytochemical technology, which ultimately has turned out to be technically demanding, has induced implementation of seemingly easier molecular solutions, such as the reverse-transcriptase polymerase-chain reaction technique.21-24 However, the same quality control issues that were raised for immunocytochemistry are pertinent for this technology as well, and we are concerned that many of the reported studies may overestimate the importance of the findings.25-28 In addition to appropriate clinical and statistical design, future studies should include strategies to comply with the substantial degree of genetic variability between breast carcinomas. As a hallmark and further essential requirement for upcoming studies using molecular techniques for DTC detection, comparison with a benchmark technique of DTC detection (ie, immunocytochemistry with anticytokeratin antibodies) would be essential. Although a blood test specifically designed for patients with stage I to III breast cancer would be highly desirable, preliminary data suggest that findings on CTCs and DTCs in peripheral blood and bone marrow, respectively, do not provide congruent results. In contrast to DTC detection in bone marrow of patients with early-stage disease, CTC analysis appears to be less sensitive and less prognostic.29 On the other hand, a recently reported, highly rigorous study clearly showed that, in metastatic breast cancer patients, CTCs permit prediction of progression-free and overall survival as well as response to treatment.30 The applied assay allowed prediction of progression-free and overall survival for the complete study group and in most of the investigated subgroups. As a major finding of their study, the opportunity to predict response as early as 3 to 4 weeks after initiation of treatment reflects an important step towards individualized treatment decisions in patients with metastatic disease, and will certainly stimulate similar studies in the near future. Importantly, if the cancer stem-cell theory is confirmed, from a clinical point of view it will be necessary to determine what percentages of CTC and DTC are actually capable of forming solid metastases, and which are detectable but nonviable. The ability to profile DTCs and to differentiate their biologic properties has been shown in studies using anticytokeratin antibodies in combination with antibodies against tumor-associated markers.31-36 Recently, differential gene or protein expression studies have been performed on CTCs, demonstrating heterogeneity, as expected,37,38 but supporting the malignant nature of such cells.39,40 Beyond tumor cell profiles, information on epithelial growth factor receptor,41 epithelial cell adhesion molecule,42 urokinase-type plasminogen activator,32 extracellular matrix metalloproteinase inducer,31 and HER-233 expression may have therapeutic implications for targeted therapy strategies, and may also have the potential to modify therapy due to changed antigen profiles during tumor progression.39 With regard to individualizing adjuvant treatment of breast cancer patients, we are well aware of the currently unsatisfying situation. Using existing guidelines,43 approximately 80% to 90% of early-stage breast cancer patients (those with small primary tumors and without lymph-node metastasis) receive toxic and/or potentially harmful treatment. Among these patients, however, it would be preferable to identify those 20% who will suffer recurrent distant disease and avoid unnecessarily treating the remaining 60% to 70%. Therefore, we clearly need studies that will permit us to individualize treatment based on the individual risk of harboring DTC at relevant metastasis sites. In the long run, only such studies will enable us to alter consensus treatment recommendations toward individualized therapy. Recent studies on hormone therapy of patients with a history of receptor-positive breast cancer showed evidence that both therapy prolongation beyond 5 years and alteration after 2 to 3 years are beneficial strategies that reduce the overall rate of recurrences.44,45 A diagnostic test specifically designed for the selection of patients who could benefit from either prolonged or altered hormonal treatment would be most helpful. Again, presence of CTC or DTC, or both, might be an indicator for patients who have not responded to the previous treatment and are likely to recur in the near future. These hypotheses have been investigated by two recent studies,46,47 showing that presence of DTC in bone marow some years after diagnosis and initial therapy is still an indicator of subsequent systemic treatment failure (ie, nonresponsiveness to treatment and poor prognosis). In order to individualize decision making on secondary adjuvant therapy, we need well-designed, highly powered, prospective clinical trials with appropriate surrogate markers for treatment efficacy. The currently available data strongly support the view that DTCs and CTCs are candidate surrogate markers suitable for various clinical settings and that these options should be tested in future large-scale clinical trials.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
Authors' Disclosures of...
