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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3656-3657 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.0356
Circulating Tumor Cells in Breast Cancer: Fiction or Reality?Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX
Department of Hematopathology, University of Texas, M.D. Anderson Cancer Center, Houston, TX
Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX To the Editor: We read with interest the recent manuscript from Pachmann et al,1 published in Journal Of Clinical Oncology, reporting on the monitoring of circulating tumor cells (CTCs) to evaluate the efficacy of adjuvant therapy in patients with primary breast cancer. However, we have significant issues with the overall study design and the conclusions derived from this study. Counting and characterizing CTCs in the common solid tumors represent a relatively recent approach to prognosis, prediction, determining response to therapy, monitoring genetic changes associated with tumor progression, and exposing the heterogeneity of carcinomas. This includes the recent demonstration of tumorigenic cancer stem cells with intrinsic resistance to standard therapies that may represent the key population to eliminate or control.2 However, enumeration and characterization of epithelial cells in the peripheral blood of patients with solid malignancies represents a constant challenge because of the relative paucity of these cells and stringent criteria for detection. Numerous techniques for enrichment of these cells have been described as well as the criteria for determining their malignancy, but as yet, there is little evidence that they can be detected routinely in early disease. The paper from Pachmann et al1 challenges several of the established paradigms in these fields and raises several serious concerns. Approximately 90% of patients with relatively early primary carcinomas and without detectable metastases possessed a high number of mononuclear cells that were CD45 negative and cytokeratin positive. Those mononuclear cells were not derived by any enrichment method and were not further characterized for other epithelial cell markers. It is well known that even with the use of enrichment technologies, the detection of CTCs can vary between 10% and 15% in primary breast cancer and between 45% and 50% in metastatic breast cancer.3,4 In the current report by Pachmann et al, patients with metastatic disease were not included as an additional control group. It would have been of interest to evaluate if disease stage and, therefore, tumor volume had any effect on detection rate and number of such cells. Monitoring of response to treatment in breast cancer is commonly done in a neoadjuvant setting using a pathological complete response as an end point.5 In metastatic breast cancer, the response is typically assessed by Response Evaluation Criteria in Solid Tumors Group criteria in patients with measurable disease. In the adjuvant setting, there are currently no tools to predict disease failure and existing American Society of Clinical Oncology guidelines do not recommend the routine use of serum biomarkers to monitor response for early disease but only for advanced breast cancer.6 Furthermore, persistence of micrometastatic disease in the bone marrow of patients with primary breast cancer that have completed adjuvant therapy identifies patients with high-risk of recurrence.7 However, this is not routinely used in clinical practice. Nevertheless, Pachmann et al1 appear to introduce a new concept of complete response in a clinical scenario in which measurable or detectable disease by standard imaging techniques is not present. Therefore, it must be assumed, even though not clearly stated, that patients in whom detectable mononuclear cells disappear with treatment have achieved a complete response. Moreover, other response categories are based on criteria that lack supportive validation data, such as a) marginal changes (< 10-fold decrease or > 10-fold increase) b) increase in mononuclear cells. Other problems with the manuscript include the relatively small size of the patient group (91 patients), the variety of different therapies that were employed, and the inability to prognosticate from the presence of the mononuclear cells since 90% of the patients had them. Finally, the lack of decrease of CTCs at completion of therapy was claimed to identify different prognostic groups even though their relationship to standard prognostic factors is not clearly stated. In summary, those results raise many issues and concerns among clinicians and researchers in this field. How should we interpret and use this information? Are CTCs readily detectable in every patient with breast cancer that has completed adjuvant therapy or is the interpretation of those cells as CTCs incorrect? We suggest that classification of mononuclear cells as CTCs demands rigorous scrutiny through the conduct of well-designed protocols with defined cytomorphology, expression of epithelial markers without hematopoietic cell markers, and genetic analysis whenever possible.8-10 The major effort should then be to define the molecular pathways in these cells and their potential biologic/clinical impact. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Pachmann K, Camara O, Kavallaris A, et al: Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 26:1208-1215, 2008 2. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983-3988, 2003 3. Pierga JY, Bonneton C, Vincent-Salomon A, et al: Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10:1392-1400, 2004 4. Cristofanilli M, Budd GT, Ellis M, Stopeck A, Matera J, Miller MC, et al: Circulating tumor cells predict progression free survival and overall survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004 5. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathological primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999 6. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for their use of tumor markers in breast cancer. J Clin Oncol 25:5287-5312, 2007 7. Janni W, Rack B, Schindlbeck C, et al: Persistence of isolated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse. Cancer 103:884-891, 2005[CrossRef][Medline] 8. Riethdorf S, Fritsche H, Mueller V, et al: Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: A validation study of the CellSearch system. Clin Cancer Res 13:920-928, 2007 9. Fehm T, Morrison L, Saboorian H, et al: Patterns of aneusomy for three chromosomes in individual cells from breast cancer tumors. Breast Cancer Res Treat 75:227-239, 2002[CrossRef][Medline] 10. Meng S, Tripathy D, Shete S, et al: HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 101:9393-9398, 2004
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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