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Circulating tumor cells as predictors of recurrence in primary breast cancer

Minimal residual disease (MRD) (that is, 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. Recently, 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 were 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 bone marrow status and 105.2 months in patients with positive bone marrow status. Patients without evidence of persistent ITC had a significantly longer overall survival (165.6 months), than patients with positive bone marrow status (103.3 months, P < 0.0001). In multivariate Cox regression analysis, allowing for bone marrow status, tumor size, nodal status and histopathological grading, ITC was of independent prognostic significance for subsequent reduced breast cancer specific survival (RR 6.3, 95% CI 2.3–17.6, P < 0.0001), next to nodal status at time of primary diagnosis (RR 2.9, 95% CI 1.8–4.7). Given these inspiring results on ITC in bone marrow, several trials currently analyze the prognostic relevance of circulating tumor cells (CTCs) in peripheral blood in the adjuvant setting. In Germany, for example, CTCs in peripheral blood of breast cancer patients at primary diagnosis and during adjuvant chemotherapy as well as endocrine and bisphosphonate treatment within the SUCCESS Trial (n = 3,658 patients) are currently analyzed. In this study, the CellSearchSystem (Veridex, Warren, USA) is used for isolation and enumeration of CTCs from 23 ml peripheral blood. Briefly, after immunomagnetic enrichment with an anti-Epcam antibody, cells were labelled with anticytokeratin (8,18,19) and anti-CD45 antibodies to distinguish epithelial cells and leukocytes. In an interim analysis, 456 breast cancer patients at the time of primary diagnosis before the start of systemic adjuvant treatment were analyzed. In this patient group, 28% of patients (n = 129) presented with ≥1 CTC in peripheral blood. In patients with the detection of CTCs, the mean number of cells was four (range 1–166). In 19 healthy individuals we found one CTC in the blood of two patients. The presence of CTCs did not correlate with tumor size (P = 0.18), presence of lymph node metastases (P = 0.09), histopatho-logical grading (P = 0.56), hormone receptor status (P = 0.49) or Her2/neu status of the primary tumor (P = 0.33).

Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. Until clinical consequences of MRD detection in solid tumors and particularly in breast cancer have been validated, however, the detection of isolated tumor cells in bone marrow should be performed mainly in clinical trials.

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Janni, W. Circulating tumor cells as predictors of recurrence in primary breast cancer. Breast Cancer Res 9 (Suppl 1), S2 (2007).

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