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Circulating Tumor Cells for Esophageal Cancer Prognosis

´╗┐Circulating Tumor Cells for Esophageal Cancer Prognosis

Discussion


This study proves the clinical significance of CTCs as a preoperative staging parameter in EC. Despite the availability of several preoperative diagnostic tools, for example, computed tomography, endoscopy, and endoscopic ultrasonography, pretreatment staging remains inaccurate. Furthermore, no adequate tool exists for patient stratification for multimodal treatments.

To our knowledge, this is the largest prospective study on the prognostic significance of CTCs in patients with EC judged preoperatively to be nonmetastatic. Overall and relapse-free survivals were similarly influenced by the presence of CTCs and were significantly shorter, irrespective of other risk factors such as tumor stage, LN invasion, tumor grade, and histological subtype. A similar influence of CTCs was observed in patients with AC; the impact of these cells in patients with SCC must be investigated by larger patients' cohorts with SCC. Several studies have reported that LN status is the most significant risk and prognostic factor in patients with EC. We found that CTC detection seems to be a stronger indicator of overall and relapse-free survival than pathological LN stage shown by the results of the multivariate analysis.

The release of CTCs may be an important step in the metastatic cascade. Klein showed that CTC detection in patients with early-stage tumors indicates that hematogenous spread occurs at an early stage of tumor progression, even in the absence of lymphatic spread. Our results are consistent with these findings. In 8 patients with stage I or II tumors, CTCs were found. These results contribute to our understanding of the metastatic cascade, especially that in EC, in which CTC involvement detected by an immunomagnetic system has not been reported before.

CTC detection rates in patients with EC from other studies that used different tests (eg, reverse transcriptase-polymerase chain reaction) ranged from 2% to 32.9%. Lack of methodological uniformity, nucleic acid-extraction protocols, and molecular marker selection, as well the inconsistent definition of CTC positivity in polymerase chain reaction-based methods may account for this large variation. The CellSearch system was designed to detect CTCs in peripheral blood samples by using immunomagnetic enrichment (EpCAM) and immunocytochemical (cytokeratin, CD45, DAPI) analyses, providing high accuracy, sensitivity, and reproducibility. Polymerase chain reaction-based methods lack visual confirmation of CTCs and can yield false-positive results. The clinical significance of the CellSearch system and its suitability for therapeutic monitoring has been proven for various cancer entities. Large, prospective, multicenter studies have validated CTC detection as the strongest prognostic factor for overall and recurrence-free survival, supporting our hypothesis that CTCs can be used as biomarkers to improve current preoperative tumor staging. Most studies using CellSearch used a cutoff of more than 5 CTCs. Tibbe et al reported that errors due to interobserver variability were the main reason for selecting 5 CTCs as the threshold value. Elimination of such errors may reduce the cutoff from 5 CTCs to 1 CTC per 7.5 mL of blood. Recent studies analyzing the stages of nonmetastatic tumors have reduced this cutoff to 2 or 1 CTC. We used a strict cutoff of 1 CTC or more, and found that CTC-positive patients with nonmetastatic disease had a significantly shorter overall and relapse-free survival than patients without CTCs. This finding confirms the use of CTCs as a reliable biomarker in patients with EC. Hiraiwa et al reported that 5 of 23 CTC-positive patients with metastatic EC showed a significantly shorter overall survival than CTC-negative patients. However, the number of patients with nonmetastatic tumors in their study (n = 10) was too small to indicate clinical significance.

Regardless of whether a multimodal treatment approach is used, surgery remains the only chance for curative treatment in EC, even though the operation is one of the most invasive thoracic and visceral surgical procedures, with morbidity rates exceeding 50%. Therefore, accurate preoperative diagnosis and prognostic staging are imperative before surgical treatment. The use of CTC detection might improve prognostic staging. Currently, up to two thirds of patients develop local or distant tumor recurrence after intended curative resection, and more than 90% die of tumor recurrence and distant metastases. There is a lack of validated serum biomarkers for EC that can be used for tumor staging, prognostic stratification and post-therapy tumor monitoring. Radioimaging techniques are of limited use for this purpose. Budd et al proposed that CTC assessment is superior to current imaging methods in patients with metastatic breast cancer. CTC detection could be used in the future for preoperative treatment decisions and immediate assessment of the success/failure of adjuvant treatments. However, this hypothesis needs to be tested in future clinical trials.

Although our results show that CTC detection in patients with EC is a strong, independent indicator for overall and relapse-free survival, it must be mentioned that detection systems based on epithelial markers, like the CellSearch system, may underestimate the number of CTCs in patients with cancer. The single enrichment technique of CellSearch involving antibodies against EpCAM may partially explain this underestimation. Several studies have reported EpCAM-negative tumors in different epithelial cancers. Another reason may be that most ECs are undifferentiated, which can lead to a lower expression of epithelial surface antigens. During the epithelial-to-mesenchymal transition, some tumor cells that separate from the primary tumor lose their epithelial characteristics, whereas in the bloodstream, and express mesenchymal markers like vimentin or fibronectin on their surface. Epithelial-to-mesenchymal transition is associated with a high malignant potential and chemotherapy resistance. Such tumor cells may be responsible for distant metastases and tumor relapse. Moreover, there may also be a platelet cloak phenomenon of single tumor cells or microemboli including CTCs likely to have enhanced metastatic potential. Thus, the CellSearch system may miss single cloaked CTCs due to EpCAM epitopes being physically covered. The CellSearch system may not detect all CTCs, especially those with high malignant potential. Nevertheless, the EpCAM-based system has provided significant prognostic data in several prospective trials, including this study. CTCs detected by CellSearch play a significant role in disease progression and patient survival. We found that CTC detection had a strong prognostic significance in patients with AC; the impact of these cells in squamous cell patients with carcinoma needs to be investigated. Although EpCAM expression is present in about 80% of SCCs, this expression is low or moderate in approximately 50% of these patients. In addition, cytokeratins used by the CellSearch system may not be optimal for detection of this histotype.



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