Molecular diagnosis of metastasizing breast cancer based upon liquid biopsy

Abstract

The occurrence of distant metastases is the main cause of death for breast cancer patients. However, central factors forcing cancer cells to migrate and grow outside of the primary organ are still not well understood [1]. An association of breast cancer and bone metastasis was previously described in 1889 by Steven Paget's theory of seed and soil [2]. Rohr and Hegglin suggested the breast cancer-related metastasis in bone marrow (BM) [3] and also recognized metastatic cells in BM biopsies by hematoxylin and eosin staining. The first single disseminated tumor cells in BM smears was also screened out in nonmetastatic breast cancer patients [4], when only a few reports dealt with micrometastasis [5]. Furthermore, morphological criteria were not satisfactory to undoubtfully distinguish single epithelial tumor cells from BM cells, especially because of the extensive variety of morphologically uneven hematopoietic and mesenchymal stem as well as progenitor cells [6]. Significant progress in the field of BM micrometastasis arose from the introduction of immunocytochemical staining procedures using antibodies against epithelial-specific markers (EMA, cytokeratins) that were not expressed on the neighboring BM cells [7]. There is increasing evidence that the presence of disseminated and circulating tumor cells (DTCs/CTCs) and several novel molecular biomarkers is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. Using these methods and markers, it became more and more established during the last two decades that BM is a common homing and surviving organ for breast cancer cells [8]. These cells are likely to escape from the host immune system in a dormant state until internal and/or external signals might facilitate them to move and grow out to overt metastases at different organs [9]. In the present chapter, we will focus on recent advancements and investigations in the field of liquid biopsy-based biomarkers, especially DTCs and CTCs, along with the evolution of many fluid-based molecular biomarkers which have the capability to behave as potential biomarkers in metastasizing breast cancer.