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Detection of Isolated Tumor Cells in Bone Marrow Is an Independent Prognostic Factor in Breast Cancer

G. Wiedswang, E. Borgen, R. Kåresen, G. Kvalheim, J.M. Nesland, H. Qvist, E. Schlichting, T. Sauer, J. Janbu, T. Harbitz, B. Naume

From the Departments of Surgery and Pathology, Ullevål University Clinic; Departments of Pathology, Oncology, and Surgery, The Norwegian Radium Hospital; Department of Surgery, Baerum Hospital; and Department of Surgery, Aker University Hospital, Oslo, Norway.

Address reprint requests to Gro Wiedswang, MD, Surgical Department, Ullevål University Hospital, Kirkeveien 165, N-0407 Oslo, Norway; email: gro.wiedswang{at}ulleval.no.

Purpose: This study was performed to disclose the clinical impact of isolated tumor cell (ITC) detection in bone marrow (BM) in breast cancer.

Patients and Methods: BM aspirates were collected from 817 patients at primary surgery. Tumor cells in BM were detected by immunocytochemistry using anticytokeratin antibodies (AE1/AE3). Analyses of the primary tumor included histologic grading, vascular invasion, and immunohistochemical detection of c-erbB-2, cathepsin D, p53, and estrogen receptor (ER)/progesterone receptor (PgR) expression. These analyses were compared with clinical outcome. The median follow-up was 49 months.

Results: ITC were detected in 13.2% of the patients. The detection rate rose with increasing tumor size (P = .011) and lymph node involvement (P < .001). Systemic relapse and death from breast cancer occurred in 31.7% and 26.9% of the BM-positive patients versus 13.7% and 10.9% of BM-negative patients, respectively (P < .001). Analyzing node-positive and node-negative patients separately, ITC positivity was associated with poor prognosis in the node-positive group and in node-negative patients not receiving adjuvant therapy (T1N0). In multivariate analysis, ITC in BM was an independent prognostic factor together with node, tumor, and ER/PgR status, histologic grade, and vascular invasion. In separate analysis of the T1N0 patients, histologic grade was independently associated with both distant disease-free survival (DDFS) and breast cancer–specific survival (BCSS), ITC detection was associated with BCSS, and vascular invasion was associated with DDFS.

Conclusion: ITC in BM is an independent predictor of DDFS and BCSS. An unfavorable prognosis was observed for node-positive patients and for node-negative patients not receiving systemic therapy. A combination of several independent prognostic factors can classify subgroups of patients into excellent and high-risk prognosis groups.

Supported by the Norwegian Cancer Society and the Norwegian Foundation of Health and Rehabilitation, Oslo, Norway.

Presented in part at the San Antonio Breast Cancer Conference, December 2002, and the International Conference on Tumor Cell Dissemination in Breast Cancer, Tuebingen, Germany, January 2003.

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