DTCs in breast cancer: clinical research and practice

Minimal residual disease (MRD), i.e., isolated tumor cells (ITC) in bone marrow, may be the source of potentially fatal overt distant metastases in solid tumors even years after primary treatment. MRD can be detected by immunohistochemical methods using antibodies directed against cytokeratins, cell-surface markers, or molecular PCR-based techniques. Among solid tumors, the clinical relevance of MRD has been most extensively studied in breast cancer patients. The highest level of evidence for the prognostic impact of MRD in primary breast cancer was reached by a pooled analysis comprising more than 4,000 patients, showing poor outcome in patients with MRD at primary therapy. Yet, clinical application of MRD detection is hampered by the lack of a standardized detection assay. Moreover, clinical trial results demonstrating the benefit of a therapeutic interference derived from bone marrow status are still missing. Recent results suggest that in addition to its prognostic impact, MRD can be used for therapy monitoring or as a potential therapeutic target after phenotyping of the tumor cells. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. In a pooled analysis bone marrow aspirates of 726 patients from academic breast cancer units in Oslo (n=356), Munich (n=228), and Tuebingen (n=142) were analyzed during recurrence-free follow-up at a mean interval of 31.7 months after primary diagnosis of breast cancer pT1-4, pN0-3 pM0. Persistent ITC was detected in 15.4% of the patients (n=112). The Kaplan-Meier estimate for mean distant relapse-free survival estimate was 163.6 months in patients with negative and 105.2 months in patients with positive BM status. Patients without evidence of persistent ITC had a significantly longer overall survival (165.6), than patients with positive bone marrow status (103.3 months, p < .0001). Given these inspiring results on ITC in the bone marrow, several trials currently analyze the prognostic relecance of circulating tumor cells (CTC) in peripheral blood in the adjuvant setting. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. However, until clinical consequences of MRD detection in solid tumors and particularly in breast cancer have been validated, the detection of isolated tumor cells in bone marrow should be performed mainly in clinical trials.