Circulating tumor cells in breast cancer: Advanced tools for “tailored” therapy?

Abstract

Alterations in oncogenes and suppressor genes are critical steps in carcinogenesis and tumor progression in solid and hematological malignancies. The development of therapeutic strategies that interfere with the functional pathways regulated by these genes represents the most successful example of targeted therapy (e.g., imatinib in chronic myelogenous leukemia and trastuzumab in breast cancer) (1, 2). In this issue of PNAS, Meng et al. (3) raise interesting possibilities for exploring circulating tumor cells (CTCs) for personalizing targeted therapy of cancer in the future. Alterations of members of the ErbB family of receptors are frequent in breast cancer and have been extensively investigated (4). HER-2 (also known as erb B-2 or neu ) is a protooncogene that encodes a 185-kDa tyrosine kinase glycoprotein (4). Amplification of the HER-2 gene plays an important role in the pathogenesis of breast cancer and is associated with a poor prognosis in patients with axillary node-positive breast cancer (5). Treatment with trastuzumab (Herceptin), a humanized monoclonal antibody directed against the extracellular domain of HER-2/neu, has significantly improved clinical responses to chemotherapy and outcomes in primary and metastatic breast cancer (6, 7). Interestingly, several investigators have recently reported that the HER-2/neu status of tumor cells detected in metastatic sites, bone marrow, or peripheral blood of patients with advanced disease may differ from the original primary tumor, suggesting either a clonal selection or genetic instability (8, 9). Furthermore, the presence of concomitant alterations of other oncogenes [e.g., topoisomerase-2 α (TOPO-2α) and urokinase plasminogen activator (uPA)] or the truncated form of the receptor, p95HER2, appear to better define biological subsets of the disease and may contribute to decisions on treatment selection (10–13). Therefore, there is necessity for a “real time” testing of … *To whom correspondence should be addressed. E-mail: mcristof{at}mdanderson.org