Detection of Breast Cancer Metastasis

Breast cancer metastasis accounts for the majority of deaths from breast cancer. Detection of breast cancer metastasis at the earliest stage is important for the management and prediction of breast cancer progression. Emerging techniques using the analysis of circulating tumor cells show promising results in predicting and identifying the early stages of breast cancer metastasis in patients. Additionally, a deeper understanding of the metastatic cascade in breast cancer will be critical for developing therapeutic interventions to combat breast cancer metastasis. In this review, the current and novel methods for detection of breast cancer metastasis, as well as the mechanisms involved in metastasis and the treatment of breast cancer metastasis, are discussed. Breast cancer is the most common type of cancer and the primary cause of cancer mortality in women (1). The majority of deaths from breast cancer are not due to the primary tumor itself, but are the result of metastasis to other organs in the body (2). Detection of Breast Cancer Metastasis Currently, detection of breast cancer metastasis relies on clinical manifestations of the spread to distant organs, biopsies of affected organs, radiological evaluations, imaging methods and serum tumor markers (3, 4). According to the American Society of Clinical Oncology (ANCO) guidelines on breast cancer follow-up and management, symptoms of breast cancer recurrence include presence of new breast lumps, pain in the bone, chest or abdomen, dyspnea and constant headaches (5). In addition, ASCO also recommends mammography for the early detection of relapse in breast cancer (5). Nicolini et al. (6) emphasized that the inclusion of serum tumor markers is an important factor in the postoperative monitoring of breast cancer patients (7, 8). Another suggestion is to have intensive postoperative follow-up which includes consultations every 4-6 months, physical examination and evaluation of serum carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and breast cancer-associated antigen 115 D8/DF3 (CA15.3), at each visit. Additionally, imaging methods such as bone scintigraphy, liver echography and chest X-ray are to be performed bianually. Computed-tomography and magnetic resonance imaging should be performed if suspicion arises from the earlier mentioned methods (6). Although mammographic screening has reduced the mortality rate associated with metastasis as a result of early diagnosis (2), the methods described above are frequently inept at detecting metastasis at the earliest stage and at accurately predicting the clinical outcome of the disease (3, 4). An emerging method to detect metastasis is the analysis of circulating tumor cells (CTCs), which has shown promise in filling the gaps left by other diagnostic methods. CTCs are tumor cells originating from primary sites or metastases that circulate in the patients’ bloodstream and are very rarely found in healthy individuals (9, 10) (Figure 1). CTCs are recognized as playing important roles in the metastasis of carcinomas (11, 12) and their analysis enables the prediction of metastatic relapse and progression (11). Generally, CTCs are firstly isolated and enriched through either morphological or immunological techniques (4). Morphological-based isolation separates CTCs according to size discrepancies, using isolation by size of epithelial tumor cells (ISET) or according to density, using density-gradient separation (4). Immunological techniques, which are the most widely used methods, employ immunomagnetic isolation (4). This method uses either epithelial cell-specific markers which are generally expressed in all tumor cells, or tumor markers expressed by specific types of cancer (13). After isolation, the source and genetic make-up of CTCs are 311 Correspondence to: Yingnan Yu, Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Blk MD10, S117 597, Singapore. E-mail: [email protected]