Correspondence
Circulating Epithelial Cells in Breast Cancer
N Engl J Med 2004; 351:2452-2454December 2, 2004
- Article
To the Editor:
Cristofanilli et al. (Aug. 19 issue)1 assume that the circulating epithelial cells detected by the CellSearch System are tumor cells. This may be the case in most of the blood samples examined, but a formal proof was not attempted. A recent study showed a cytogenetic relationship — that is, clonality — between circulating epithelial cells and the corresponding primary tumor cells.2 It seems mandatory that a molecular genetic characterization of circulating tumor cells be performed to validate a highly sensitive test such as the CellSearch assay.
2 ReferencesMichael Fiegl, M.D.
Hubert Denz, M.D.
Academic Natters Hospital, A-6161 Natters, Austria
michael.fiegl@uibk. ac. at 1
Cristofanilli M ,Budd GT ,Ellis MJ , et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781-791
Full Text | Web of Science | Medline2
Fehm T ,Sagalowsky A ,Clifford E , et al. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 2002;8:2073-2084
Web of Science | Medline
To the Editor:
Cristofanilli and colleagues state that the number of circulating tumor cells is an independent predictor of progression-free survival and overall survival in metastatic breast cancer. However, the distribution of the metastases is likely to have a significant effect on the number of circulating tumor cells. Circulating tumor cells are more likely to be detected in patients with breast cancer who have bone metastases.1 In Table 1 of the article by Cristofanilli et al., the patients are divided into those with visceral metastases and those with nonvisceral metastases, but patients with bone metastases are not identified as a specific group. The response of bone metastases to chemotherapy on bone scintigraphy is notoriously difficult to assess. If a fall in the level of circulating tumor cells were a predictive marker of a response to chemotherapy in patients with bone metastases, it would greatly enhance our capacity to monitor such patients in the clinic.
1 ReferencesIan H. Kunkler, M.B., B.Chir.
University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
i.kunkler@ed. ac. uk 1
Weigelt B ,Bosma AJ ,Hart AA ,Rodenhuis S ,van 't Veer LJ . Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients. Br J Cancer 2003;88:1091-1094
CrossRef | Web of Science | Medline
To the Editor:
The report by Cristofanilli et al. has several shortcomings. First, neither the sensitivity nor the specificity of the testing methods was established. Of concern is the cutoff of 5 circulating tumor cells. Cytokeratins are a family of peptides that have been used as surrogate markers for epithelial tumor cells. Although most circulating cytokeratin-positive cells carry chromosomal abnormalities, some normal cytokeratin-positive epithelial cells remain in the circulation.1
Second, there was heterogeneity of treatment. Two thirds of the patients (121 of 177) had estrogen-receptor progesterone-receptor positivity in the tumor tissue. However, only one third of the patients (54 of 172) received immunotherapy, hormone therapy, or both, which should be the standard first or second line of therapy for metastatic breast cancer. Moreover, there is no standard immunotherapy for breast cancer.
Finally, there was heterogeneity in the follow-up techniques. The authors state that “standard imaging” was performed, which suggests that computed tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomography (PET) was used; these techniques have variable sensitivity for the detection of metastases.
1 ReferencesChristopher Tang, B.A.
Albert Y. Lin, M.D., M.P.H.
Santa Clara Valley Medical Center, San Jose, CA 951281
Fehm T ,Sagalowsky A ,Clifford E , et al. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 2002;8:2073-2084
Web of Science | Medline
To the Editor:
Cristofanilli et al. did not discuss the roles of age and number of metastatic sites. Elderly patients, especially those 70 years of age or older, appear to have a lower median survival.1-3 Was there any relationship between age and the number of circulating tumor cells, and was age taken into account in the multivariate analysis?
Median survival has also been found to be associated with the number of metastatic sites.4 Multiple metastatic sites are present in 40 percent of patients with primary metastatic breast cancer.4 Did Cristofanilli et al. include patients with multiple metastatic sites? For example, the presence of metastases in bone and lungs may result in a larger number of circulating tumor cells, and adjustment for the number of metastatic sites may thus change the results.
4 ReferencesAdri C. Voogd, Ph.D.
Maastricht University, 6200 MD Maastricht, the Netherlands
adri.voogd@epid. unimaas. nl Kitty van Gestel, M.D.
St. Elisabeth Hospital, 5022 CG Tilburg, the NetherlandsMiranda F. Ernst, Ph.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands1
Coleman RE ,Smith P ,Rubens RD . Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 1998;77:336-340
CrossRef | Web of Science | Medline2
Chang J ,Clark GM ,Allred DC ,Mohsin S ,Chamness G ,Elledge RM . Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 2003;97:545-553
CrossRef | Web of Science | Medline3
Ryberg M ,Nielsen D ,Osterlind K ,Skovsgaard T ,Dombernowsky P . Prognostic factors and long-term survival in 585 patients with metastatic breast cancer treated with epirubicin-based chemotherapy. Ann Oncol 2001;12:81-87
CrossRef | Web of Science | Medline4
Andre F ,Slimane K ,Bachelot T , et al. Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004;22:3302-3308
CrossRef | Web of Science | Medline
Author/Editor Response
Drs. Fiegl and Denz pose the question of whether the circulating cells detected with the use of the CellSearch assay are malignant. The work they cite by Fehm et al., which was conducted with the use of CellSearch technology in collaboration with Immunicon, supports the hypothesis that they are.1 The CellSearch assay only rarely detects circulating epithelial cells in normal subjects. Since the data in our report pertain exclusively to the use of the CellSearch assay to predict outcomes in patients with metastatic disease, one can assume that most, if not all, circulating epithelial cells in such patients are malignant.
All patients had measurable disease (according to the World Health Organization Response Evaluation Criteria in Solid Tumors). A prospective study of the CellSearch assay in patients with bone-only metastatic breast cancer is ongoing.
Both age and the number of metastatic sites were evaluated as continuous and categorical variables with the use of univariate and multivariate Cox regression analyses, and neither variable was significantly associated with outcomes. In all models, the level of circulating tumor cells remained the strongest predictor of progression-free survival and overall survival. Only 39 women older than 70 years of age were enrolled in the study — too small a number for a meaningful analysis. No association was found between an age of 50 years or older and the likelihood of elevated levels of circulating tumor cells; among patients with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood at baseline, 54 percent (26 of 48 patients) were younger than 50 years of age and 48 percent (61 of 127 patients) were 50 years of age or older (P=0.501).
In response to Drs. Tang and Lin, the sensitivity and specificity of the CellSearch assay in patients with metastatic disease were established in our report2 and in a subsequent, more detailed description of the methods published elsewhere.3 Table 1 in our report2 provides data on the prevalence of circulating tumor cells at baseline in 145 healthy subjects, 200 subjects with benign conditions, and 177 patients with metastatic breast cancer. The threshold of 5 or more circulating tumor cells per 7.5 ml of whole blood was established in the training set and was prospectively validated in the second set of patients (Fig. 2 and 3 of our article2). Patients were enrolled if they were starting any new systemic regimen, at any time in the clinical course, on the basis of the hypothesis that the CellSearch assay would be accurate in patients receiving any type of therapy. Patients with estrogen-receptor positivity received chemotherapy if their clinicians judged that it was the appropriate standard therapy. Immunotherapy consisted exclusively of trastuzumab. The study design dictated that imaging (bone scintigraphy, CT, or MRI only; PET was not used for study purposes) be performed prospectively in all patients, and lesions seen at baseline were followed with the use of the same technique while the patient remained in the study. All imaging was digitized, and the quality was monitored by a core laboratory.
3 ReferencesMassimo Cristofanilli, M.D.
M.D. Anderson Cancer Center, Houston, TX 77030Leon W.M.M. Terstappen, M.D., Ph.D.
Immunicon, Huntingdon Valley, PA 19006Daniel F. Hayes, M.D.
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
hayesdf@umich.edu 1
Fehm T ,Sagalowsky A ,Clifford E , et al. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 2002;8:2073-2084
Web of Science | Medline2
Cristofanilli M ,Budd GT ,Ellis MJ , et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781-791
Full Text | Web of Science | Medline3
Allard WJ ,Matera J ,Miller MC , et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004;10:6897-6904
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Katherine H. Rak Tkaczuk, Olga Goloubeva, Nancy S. Tait, Faye Feldman, Ming Tan, Zhao-Ping Lum, Stephen A. Lesko, David A. Echo, Paul O. P. Ts’o. (2008) The significance of circulating epithelial cells in Breast Cancer patients by a novel negative selection method. Breast Cancer Research and Treatment 111:2, 355-364
CrossRef
