Detection o f I solated T umor C ells i n B one M arrow I s a n Independent P rognostic F actor i n B reast C ancer

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 BMnegative patients, respectively (P < .001). Analyzing nodepositive 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 diseasefree 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. J Clin Oncol 21:3469-3478. © 2003 by American Society of Clinical Oncology. A LARGE proportion of breast cancer patients experience systemic relapse, approximately 25% to 30% of nodenegative patients and 60% of node-positive patients. 1,2 At present, tumor, node, metastasis (TNM) classification, histopathologic tumor grade, hormone receptor status, and age are used for prognostication and treatment decisions. However, these factors are not sufficient for an accurate selection of patients into low-risk groups, with no need for adjuvant therapy, and high-risk groups for systemic relapse. Extensive work has been performed to develop methods for the assessment of risk. The presence of isolated tumor cells (ITC) in the bone marrow (BM) at the time of operation has been shown to be a predictor of early systemic relapse in nodepositive patients in several independent studies. 3-8 However, the reported results from ITC analysis of node-negative patients have been contradictory. 4,5,8-10 Most studies have used immunocytochemical (ICC) techniques for the detection of ITC. Methodologic differences between studies exist 9,11 that may cause differences in both sensitivity and specificity. Therefore, guidelines for analysis and evaluation of ITC by ICC in BM, proposed by The European Working Group for Standardization of Tumor Cell Detection, have been used in this study. 12 The aim of this study was to examine early-stage breast cancer patients for the presence of ITC in BM, clarify their prognostic value, and analyze and relate candidate prognostic factors in the primary tumors to the presence of ITC and clinical outcome in 817 unselected patients. PATIENTS AND METHODS