Detection of disseminated tumor cells (DTCs) in bone marrow is an independent prognostic factor in primary breast cancer. Here, we conducted a proof-of-principle study to evaluate whether this tumor cell spread occurs already in patients with ductal carcinoma in situ (DCIS). After preoperative screening by stereotactic core biopsy, 30 consecutive women with DCIS were included. Bone marrow aspirates, taken at the time of primary surgery, were subjected to DTC detection by a standardized immunoassay using the established monoclonal anti-cytokeratin antibodies A45-B/B3 and AE1/AE3. DTCs were detected in 4 of 19 cases of pure DCIS (21.1%) and in four of seven cases of DCIS with microinvasion (57.1%). After a median follow-up time of 22 months, two initially DTC-positive patients suffered from contralateral carcinoma and contralateral DCIS at months 12 and 30, respectively, whereas the remaining patients were relapse free. Thus, hematogenous tumor cell dissemination into bone marrow is an early event in breast cancer development.Breast cancer is the most common malignant disease in women. According to a meta-analysis including 4,703 Stage I-III breast cancer patients, the detection of disseminated tumor cells (DTCs) in bone marrow is associated with poor prognosis.1,2 Interestingly, DTC detection is seen in small primary carcinomas and is not only a predictor for metastatic relapse in bone and other organs but also for local relapse, 2 supporting recent experimental data that breast tumor cells may recirculate from bone marrow back to the primary site where they might contribute to local relapse and even primary tumor growth.3 Thus, bone marrow might be a reservoir for breast tumor cells in which they may survive for an extended period of time. 4,5 Thus far, the time point of the onset of breast tumor cell spread is unclear. A DCIS is a nonobligate precursor of invasive breast cancer. However, 1-2% of all primary DCIS patients present positive axillary lymph node metastases. 6 Indeed, classification of DCIS is based on histopathological criteria and on the growth dimensions. 7,8 Remarkably, DCIS patients may relapse with invasive breast cancer, whereas patients with large, high-grade DCIS with necrosis are at higher risk of developing recurrence. Furthermore, DCIS patients with poorly differentiated histological types are associated with higher rates of distant metastases and death within a long follow-up period. 9 The rate of metastases increases after invasive local recurrence.10 Free surgical margins and postoperative radiotherapy are the most important and significant prognostic factors for local disease control, 11 but none of them can reliably predict the risk of invasive recurrence.
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Material and MethodsOur proof-of-principle investigation focused on the search for DTC in bone marrow aspirates from 30 patients who were treated with the suspicion of DCIS at the Goethe-University hospital and the Diakonie Medical Center, Frankfurt, Germany. Written informed consent was provided by all patients, and the stud...