Only half of the breast cancer patients with DTC relapse, whereas the other half remain free of overt metastasis over a 10-year follow-up period (Table 7.1).56 This finding is in line with data from animal models and suggests that a significant fraction of DTC might never develop into overt metastases but might remain in a "dormant" state. However, the persistence of DTC in BM even years after primary treatment is linked to an increased risk of late metastatic relapses in breast cancer.57 Thus far, little is known about the conditions required for the escape from the dormant or quiescent phase into the dynamic phase of metastasis formation. The steady-state regulating dormancy might be disturbed by both changes in the DTC (e.g. additional mutations) and the surrounding microenvironment (e.g. decrease in immune surveillance or increased angiogenetic potential).58-60 Among the protein characteristics, expression of the tyrosine kinase receptor HER2 on DTC and CTC appears to be linked to metastatic relapse.44,61 Thus, HER2-mediated signaling might be important for the transition of DTC from a dormant to an active growth stage.
Recently, the search for breast cancer stem cells has gained increasing attention with the discovery of new stem cell markers and signa-tures.39,62-64 It is assumed that breast cancer stem cells especially can disseminate from the primary tumor to distant sites. The significant correlation between the presence of DTC in BM and metastatic relapse64 suggests that the founder cells of overt metastases might be among those DTC as metastatic stem cells. Furthermore, most DTC/CTC are nonprolif-erating (i.e. Ki-67-negative) and resistant to chemotherapy,46,65,66 as postulated for cancer stem cells. Moreover, many DTC have a
CD44+CD24-/low breast cancer stem cell phe-notype,67,68 and a subpopulation of viable DTC are CK19+MUC1-, also previously suggested as a breast stem cell phenotype.39 More recently, EpCAM has been identified as a new breast cancer stem cell marker,64 and this adhesion molecule is expressed on more than 60% of DTC in BM of breast cancer patients.52
CLINICAL RELEVANCE OF DISSEMINATED TUMOR CELLS AND CIRCULATING TUMOR CELLS FOR PREDICTING OUTCOME AND MONITORING THERAPY
The prognostic impact of DTC analysis performed at the time of primary surgery was confirmed in a large recent pooled analysis including 4703 patients with a 10-year follow-up.56 In addition to their use as prognostic factor in breast cancer, monitoring of BM postsurgery (i.e. during and after systemic adjuvant therapy) might be able to provide a unique information for the clinical management of the individual cancer patient (Table 7.1).57'65'66'69'70 The identification of patients at increased risk for recurrence after completion of adjuvant chemotherapy is an application of high clinical relevance, since these patients might benefit from an additional "second-line" treatment, e.g. bisphosphonates or targeted therapies like anti-HER2 approaches or antiangiogenetic drugs.
Sequential peripheral blood analyses should be more acceptable than BM aspirations and many research groups are currently assessing CTC in clinical studies. Depending on the detection technique used, CTC were revealed in 50-100% of patients with metastatic breast cancer.15 However, even in patients with no clinical signs of overt metastases, detection rates range from 10% to 60%.71 In contrast to one report that suggested that CTC are mostly apoptotic,72 we have recently shown that viable CTC were frequently present both in patients with early and late stage breast cancer.39
The clinical relevance of CTC measurements is still under investigation. Detection of CTC with the CellSearchTM system provided significant prognostic information before and also early (4 weeks) after initiation of chemotherapy in patients with measurable metastatic breast cancer,28 and the prognostic impact of increased CTC numbers was also maintained when repeated examinations during follow-up were performed.73 Interestingly, CTC determinations seem to be superior over conventional imaging methods for response evaluation.74 In contrast to patients with metastatic disease, the prognostic relevance of CTC in the blood of patients with early-stage disease without overt metastasis is still under investigation and needs to be demonstrated in prospective multicenter studies.75 In patients with primary breast cancer, several studies have used RT-PCR based methods and showed a prognostic impact.76-78
To date, it is not clear if CTC measurements could replace the examination of BM. Previously, two immunocytochemical studies demonstrated statistically significant correlations between DTC detection in BM and blood, but BM was more frequently positive than blood.46,79 One possible explanation is that BM is a homing organ for DTC, whereas blood analyses allow only a "snapshot" of tumor cell dissemination. Recently, it was also described that detection of DTC in BM had superior prognostic significance in comparison with CTC measurements in blood, analyzing patients with metastatic and nonmetastatic breast cancer by a quantitative RT-PCR assay for CK19 and mammaglobin mRNAs.80 In line with this, another report using immunocyto-chemistry showed that only BM but not blood analyses provided prognostic information.81 Currently, these findings do not support an exchange of DTC in BM with CTC from blood, but future studies with improved detection technologies may help to clarify this issue.
IDENTIFICATION OF THERAPEUTIC TARGETS ON DISSEMINATED TUMOR CELLS AND CIRCULATING TUMOR CELLS
A striking potential of DTC/CTC could also be to identify therapeutic targets on these cells, which might enable a more individual antimetastatic therapy in cancer patients. CTC/DTC can show properties distinct from the primary tumor and the characterization of these cells could therefore help to select cancer patients for targeted therapies.
In particular, the HER2 oncogene has become the most prominent target for biological therapies in breast cancer and a humanized anti-HER2 monoclonal antibody (trastuzumab) was recently approved by the FDA.42,82 Currently, all patients are stratified to this targeted therapy by primary tumor analysis only. However, recent reports have shown that HER2-positive DTC and CTC can also be detected in patients with HER2-negative primary tumors.44,83,84 These findings are consistent with our previous data on the high frequency and prognostic relevance of HER2 expression on DTC in BM43 and they suggest that additional patients who could benefit from HER2-directed therapies.83 Ongoing clinical studies will reveal whether the HER2 status of DTC or CTC may predict response to trastuzumab or other HER2-directed therapies.
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