Correspondence
Bone Marrow Metastases in Breast Cancer
N Engl J Med 2000; 343:577-578August 24, 2000
- Article
To the Editor:
In their study of the histochemical detection of metastases from breast cancer to bone marrow, Braun et al. (Feb. 24 issue)1 found that multivariate analysis identified the presence of cytokeratin-positive cells in the bone marrow as an independent predictor of survival. What do the authors think about the use of flow cytometry after cytokeratin staining? Their results clearly demonstrate that the presence of cytokeratin-positive cells in the bone marrow of patients with breast carcinoma is associated with shorter survival. However, because cytokeratin-positive cells were detected in control patients with nonmalignant disease and stage I tumors had fewer than 5 cytokeratin-positive cells per 2×106 bone marrow cells, the authors should also clarify the threshold of positivity needed to avoid false positive results. Braun et al. found a median of 3 cytokeratin-positive cells per 2×106 bone marrow cells, but the exclusion of patients with fewer than 3 cytokeratin-positive cells per 2×106 bone marrow cells would not be enough, because the confidence interval for each stage is not mentioned.
1 ReferencesSalvador J. Diaz-Cano, M.D., Ph.D.
St. Bartholomew's and the Royal London School of Medicine and Dentistry, London E1 1BB, United Kingdom1
Braun S ,Pantel K ,Muller P , et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525-533
Full Text | Web of Science | Medline
To the Editor:
Thanks to improved screening procedures, the average diameter of most newly diagnosed breast tumors is 1.5 cm, and tumors larger than 5 cm are rare.1-3 Hence, the tumor-size variable (≤5 cm vs. >5 cm) chosen by Braun et al. for multivariate analysis does not reflect the clinical situation. Analysis of the preliminary results of our own study of 905 patients with a median follow-up of 53 months (range, 7 to 112) revealed that lymph-node status and tumor size are independent prognostic features of breast cancer. We used anticytokeratin antibodies to detect isolated epithelial cells in bone marrow. When we dichotomized tumor size as ≤2 cm or >2 cm in multivariate analysis, bone marrow status was not an independent prognostic factor in breast cancer. This result reflects the strongest multivariate model according to scoring and goodness of fit. However, when we dichotomized tumor size as ≤5 cm or >5 cm, we confirmed the independent prognostic effect of the bone marrow status reported by Braun et al. Notably, in the study by Braun et al., this large size had no effect on overall survival, although it was associated with the development of distant metastases, an event that is evidently correlated with a poor prognosis.
3 ReferencesIlona Funke, M.D.
Winfried Schraut, M.D., M.P.H.
Klinikum Grosshadern, 81377 Munich, Germany1
Braun S ,Pantel K ,Muller P , et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525-533
Full Text | Web of Science | Medline2
Smith BL . Approaches to breast-cancer staging. N Engl J Med 2000;342:580-581
Full Text | Web of Science | Medline3
Cady B ,Stone MD ,Schuler JG ,Thakur R ,Wanner MA ,Lavin PT . The new era in breast cancer: invasion, size, and nodal involvement dramatically decreasing as a result of mammographic screening. Arch Surg 1996;131:301-308
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To the Editor:
It is possible that the cytokeratin-positive cells identified by Braun et al. represent cells in the circulation1 that were aspirated together with the bone marrow and that were not derived from bone marrow. This distinction is important, since circulating cells are one rung below cells that have transmigrated through the target tissue's endothelial, basement-membrane, and connective-tissue barriers.
We therefore believe that the designation “micrometastasis” is too restrictive. It is obvious that finding such cells does not change the stage of cancer to stage IV, because many such cases of cancer can be cured, a goal that is currently not achievable with stage IV cancer. If, indeed, this protocol does become part of clinical practice, then a less-alarming designation should be used, possibly microdissemination, or MD. Adding the designation MD to the stage without changing the stage of the cancer may reduce the patient's anxiety as well as the risk of overtreatment by physicians.
1 ReferencesEli Pikarsky, M.D.
Tamar Peretz, M.D.
Hadassah Medical Center, 91120 Jerusalem, Israel1
Mori M ,Mimori K ,Ueo H , et al. Clinical significance of molecular detection of carcinoma cells in lymph nodes and peripheral blood by reverse transcription-polymerase chain reaction in patients with gastrointestinal or breast carcinomas. J Clin Oncol 1998;16:128-132
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Author/Editor Response
The authors reply:
To the Editor: Although defining the threshold of positivity would help to avert a few false positive results (in our series the rate was 1 percent), it would also increase the rate of false negative findings, because 90 of 199 patients with positive cells (45 percent) had only 1 or 2 cytokeratin-positive cells per bone marrow sample. The statement that patients with stage I breast cancer “had fewer than 5 cytokeratin-positive cells” is wrong, since we wrote that “patients with stage I cancer had a mean of 5 tumor cells per 2×106 bone marrow cells.” Because of the low numbers of immunostained cells, flow cytometry is not an adequate approach, unless an efficient and reproducible tumor-cell–enrichment procedure can be used.
We recalculated our multivariate statistics, with tumor size dichotomized as ≤2 cm or >2 cm, and found that the bone marrow status remained an independent prognostic factor, with hazard ratios of 5.80 (95 percent confidence interval, 3.74 to 9.00; P<0.001) for survival free of distant disease and 3.76 (95 percent confidence interval, 2.25 to 6.27; P<0.001) for overall survival. Tumor size became an independent prognostic indicator of the risk of death from cancer, with the remaining values (as shown in Table 2 of our article) essentially unchanged. The discrepancy between our findings and those of Funke and Schraut may reflect the fact that they used the monospecific anti–cytokeratin-18 antibody CK2, which is less sensitive1 than the broad-spectrum monoclonal antibody A45-B/B3 that we used in our study.
With current aspiration techniques, the possibility that circulating tumor cells are obtained with bone marrow tumor cells cannot be excluded. Nevertheless, the frequency of tumor cells in the circulation of patients with stage I, II, or III breast cancer is considerably lower than that of disseminated tumor cells in bone marrow, which decreases the likelihood that a major fraction of the tumor cells identified in our study stemmed from the peripheral blood.
We agree with Drs. Pikarsky and Peretz that the term “micrometastases” may be misleading; “occult metastatic cells” or “isolated tumor cells”2 may be better alternatives.
2 ReferencesStephan Braun, M.D.
Technische Universität München, D-81675 Munich, GermanyGünter Schlimok, M.D.
Zentralklinikum Augsburg, D-86165 Augsburg, GermanyKlaus Pantel, M.D.
Universitätsklinikum Eppendorf, D-20246 Hamburg, Germany1
Braun S ,Muller M ,Hepp F ,Schlimok G ,Riethmuller G ,Pantel K . Re: Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1998;90:1099-1101
CrossRef | Web of Science | Medline2
Hermanek P ,Hutter RV ,Sobin LH ,Wittekind C . International Union Against Cancer: classification of isolated tumor cells and micrometastasis. Cancer 1999;86:2668-2673
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