BONE MARROW MICROMETASTASES AND CIRCULATING TUMOR CELLS

Circulating tumor cells (CTCs) are cells detected in the blood that possess the genetic and protein characteristics of breast cancer. These cells can be isolated from the more common leukocytes by the use of an antibody-coated immunomagnetic bead or by sorting on the basis of surface antigen expression.38 The importance of CTCs has been the subject of some debate in the literature, as a result of the observation that not all CTCs are capable of forming tumors; this phenomenon is potentially explained by tumor heterogeneity.1 Gene expression profiling using the reverse-transcriptase polymerase chain reaction (RT-PCR) process overcomes the technical limitations of IHC and can be performed on peripheral blood to aid in identification ofthe CTCs. Although some studies have used this process to provide early information regarding response to therapies,39 Assays for CTCs could potentially be more important if they are able to provide additional prognostic information in early-stage breast cancer. Several studies have tackled the use of this potential marker in early-stage breast cancer and linked CTCs to disease-free survival.40,41 Using IHC or RT-PCR methodology, most studies have correlated the presence of CTCs after surgery with adverse outcomes. However, many of the earlier studies were underpowered and used differing techniques to denote a tumor cell. Preliminary studies assessing the prognostic value of circulating cytokeratin-19 positive cells seem promising,40-42 but developing a consistent methodology and defining markers that correlates with prognosis in early-stage breast cancer has proved daunting. Much like molecular profiling of breast cancers, discussed later in this chapter, most studies demonstrate improved correlation with prognosis when several genes are assayed as opposed to one marker in isolation.

Similar to the process of detection of CTCs, the detection of microscopic disease in the bone marrow is of considerable interest with regard to refining our current staging processes. Although a meta-analysis recently reported the presence of IHC-detected tumor cells in bone marrow in patients with operable breast cancer correlated with early relapse,43 Other studies have not found a consistent association.44 Conventional assessment by routine stains, IHC and RT-PCR have been used to evaluate the presence of micrometastases in the bone marrow. The specificity of these assays however, has been unclear and importantly there appears to be considerable false-positive rates depending the on detection assay.44 Nevertheless, most studies show that detection of disseminated tumor cells in the bone marrow of patients with breast cancer is an independent risk factor for the subsequent development of metastatic disease.43

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