Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma

BACKGROUND, Using cytokeratin (CK) as a histogenetic marker of epithelial t umor cells in the bone marrow of patients with primary breast carcinoma, a subgroup of patients with decreased survival can be identified. This study was designed to evaluate the frequency and prognostic relevance of such cel ls in patients with recurrent breast carcinoma. METHODS, Bone marrow aspirates from 65 patients were analyzed immunocytoche mically for the presence of CK positive cells. A quantitative immunoassay w ith monoclonal anti-CK antibody A45-B/B3 was used and 2 x 10(6) bone marrow cells per patient were evaluated. For prognostic evaluation the authors ca lculated a cutoff value of micrometastatic tumor cells by analogy to classi fication and regression tree (CART) analysis. Patients were monitored prosp ectively for a median of 37 months (range, 11-63 months). RESULTS. Bone marrow micrometastases were present in 5 of 32 patients (16%) with locoregional recurrence and in 24 of 33 patients (73%) with distant r ecurrence. The bone marrow status yielded no prognostic indication for pati ents with locoregional recurrence. In contrast, a cutoff value of 2.5 tumor cells per 1 million bone marrow cells analyzed (2.5 x 10(-6) tumor cells) correlated with a significantly different prognosis for women with distant disease. Patients with metastatic disease and a micrometastatic tumor load of > 2.5 x 10(-6) tumor cells survived for a mean of 6 months (95% confiden ce interval [95% CI], 2.0-9.1) compared with 17 months (95% CI, 11.6-22.0) for patients with less than or equal to 2.5 x 10(-6) tumor cells (P < 0.000 1). Multivariate analysis, allowing for hormone receptor status, disease fr ee interval prior to recurrence, manifestation site of metastases, age, and micrometastases in bone marrow, revealed that bane marrow involvement was an independent risk factor, with a hazard ratio of 7.4 (95% CI, 1.6-13.3) f or disease-related death. CONCLUSIONS, An increased number of micrometastases identified in the bone marrow of patients with metastatic breast carcinoma represents an independe nt prognostic factor that may influence future therapeutic strategies for p atients with metastatic breast carcinoma. Cancer 2000;88:2252-9. (C) 2000 A merican Cancer Society.