Chapter 27

The genesis of overt metastases in breast cancer is based on the idea that tumor cells that dissociate from the primary cancer get access to circulation either directly into blood vessels or after transit in lymphatic channels. Thus detection of such cells in patients with newly diagnosed solid tumors has been an appealing strategy to provide evidence for future metastases.

In the past, several models have been constructed to explain the presence of individual tumor cells in secondary organs and their influence on the subsequent course of the disease. Currently, according to most recent transcriptome and genome analyses, tumor cells circulating in the bloodstream (CTCs) and those already disseminated to secondary organs (DTCs) are viewed as rare and much earlier indicators of tumor cell spread than generally assumed from the typical year-long course of cancerous diseases, such as breast cancer. Despite the observation that the numerous genetic alterations found so far in such cells are rarely identical or even similar, the idea that some of these cells might be progenitor cells with self-renewing properties that give rise to most of the tumor mass that is dealt with clinically is supported by the following: (1) the long interval between dissemination and clinical manifestation of metastases, (2) the frequently observed relative resistance of some cells to chemotherapy, and (3) their significant effect on disease progression, despite their low abundance in secondary organs.

Beyond the discussion of such models and opinions, the actual presence of tumor cells outside the primary tumor and in organs relevant for subsequent metastasis formation, such as bone and bone marrow, would serve 3 purposes that could be clinically useful:

1. As unambiguous evidence for an early occult spread of tumor cells

2. As a relevant risk factor for subsequent metastasis and thus a poor prognosis

3. As a marker for monitoring treatment susceptibility

Finally, and perhaps as importantly in the long run, genotyping and phenotyping of these cells should provide detailed insight into the metastatic process and permit direct exploration of targeted treatment strategies.

The 2 main approaches for the assessment of minimal residual cancer—both for DTCs and CTCs—are immunologic assays using monoclonal antibodies directed against histogenetic proteins and polymerase chain reaction (PCR)–based molecular assays exploiting tissue-specific transcripts. In review of the last decades, the immunologic approach emerged in the first place due to the technological availability, whereas molecular techniques seem to have taken over in the last few years.

### Detection of Tumor Cell Dissemination

Tumor cells evaded or shed to the blood circulation may be detectable in peripheral venous blood and, in principle, all body organs, as shown in a few elegant experiments during the 1960s and 1970s.1,2 When specific monoclonal antibodies became broadly available in the 1980s, the interest in the identification of spread tumor cells was renewed. The first study groups,3-8 however, did not investigate peripheral blood, presumably due ...

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