Prognostic significance of micrometastatic bone marrow involvement

The present review focuses on the methodology and clinical significance of new diagnostic approaches to identify micrometastatic breast cancer cells p resent in bone marrow (BM), as a frequent site of overt metastases. Using m onoclonal antibodies (mAbs) to epithelial cytokeratins (CK) or tumor-associ ated cell membrane glycoproteins, individual carcinoma cells can be detecte d on cytologic BM preparations at frequencies of 10(-5) to 10(-6). Prospect ive clinical studies have shown that the presence of these immunostained ce lls is prognostically relevant with regard to relapse-free and overall surv ival. The current interest in autologous bone marrow transplantation in pat ients with solid tumors further underlines the need for screening methods t hat allow the detection of minute numbers of residual tumor cells in the tr ansplant. Although the development of new molecular detection methods based on the amplification of a marker mRNA species by the polymerase chain reac tion technique is a very exciting area of research, the clinical significan ce of this approach needs to be demonstrated in prospective studies. The im munocytochemical assays may be, therefore, used to improve tumor staging wi th potential consequences for adjuvant therapy. Another promising clinical application is monitoring the response of micrometastatic cells to adjuvant therapies, which, at present, can only be assessed retrospectively after a n extended period of clinical follow-up. The extremely low frequency of BM tumor cells greatly hampers approaches to obtain more specific information on their biological properties. The available data indicate that these cell s represent a selected population of cancer cells which, however, still exp ress a considerable degree of heterogeneity with regard to the expression o f MHC class I antigens, adhesion molecules (EpCAM), growth factor receptors (EGF receptor, erb-B2, transferrin receptor), or proliferation-associated markers (Ki-67, p120). Regardless of the detection technique applied, there is an urgent demand for large multicentre trials, in which standardized me thods are related to specified clinical outcomes.