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Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival

Randi R Mathiesen12, Elin Borgen3, Anne Renolen3, Erik Løkkevik2, Jahn M Nesland103, Gun Anker45, Bjørn Østenstad2, Steinar Lundgren67, Terje Risberg8, Ingvil Mjaaland9, Gunnar Kvalheim2, Per Eystein Lønning45 and Bjørn Naume102*

Author Affiliations

1 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Radium Hospital, Ullernchausseen 70, Oslo, 0310, Norway

2 Division of Surgery and Cancer Medicine, Department of Oncology, Oslo University Hospital, Ullernchausseen 70, Oslo, 0310, Norway

3 Department of Pathology, Oslo University Hospital, The Radium Hospital, Ullernchausseen 70, Oslo, 0310, Norway

4 Section of Oncology, Institute of Medicine, University of Bergen, Jonas Lies vei 65, Bergen, 5020, Norway

5 Department of Oncology, Haukeland University Hospital, Jonas Lies vei 65, Bergen, 5020, Norway

6 Department of Oncology, St. Olav University Hospital, Olav Kyrres gate 17, Trondheim, 7006, Norway

7 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Hogskoleringen 1, Trondheim, 7491, Norway

8 Department of Oncology, University Hospital of Northern Norway and Institute of Clinical Medicine, University of Tromsø, Sykehusvegen 38, Tromsø, 9037, Norway

9 Division of Hematology and Oncology, Stavanger University Hospital, Armauer Hansens vei 20, Stavanger, 4011, Norway

10 Institute of Clinical medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, Oslo, 0450, Norway

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Breast Cancer Research 2012, 14:R117  doi:10.1186/bcr3242

Published: 14 August 2012



Presence of disseminated tumor cells (DTCs) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood (PB) predicts reduced survival in early breast cancer. The aim of this study was to determine the presence of and alterations in DTC- and CTC-status in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy (NACT) and to evaluate their prognostic impact.


Bone marrow and peripheral blood were collected before NACT (BM1: n = 231/PB1: n = 219), at surgery (BM2: n = 69/PB2: n = 71), and after 12 months from start of NACT (BM3: n = 162/PB3: n = 141). Patients were included from 1997 to 2003 and followed until 2009 (or ten years follow-up). DTC- and CTC-status were determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. The prognostic significance of DTCs/CTCs was assessed by univariate and multivariate Cox-regression analyses.


Before NACT, DTCs and CTCs were detected in 21.2% and 4.9% of the patients, respectively. At surgery, 15.9% and 1.4% had DTC- and CTC-presence, compared to 26.5% and 4.3% at 12 months from start of NACT. Of patients for whom DTC results both before NACT and at 12 months were available, concordant results were observed in 68%, and 14 out of 65 had positive DTC-status at both time points. Presence of ≥ 1 DTC 12 months from start of NACT, but not at other time points, predicted reduced disease-free survival (DFS; HR 2.3, p = 0.003), breast cancer-specific survival (BCSS; HR 3.0, p < 0.001) and overall survival (OS; HR 2.8, p < 0.001). Before NACT, presence of ≥ 3 DTCs was also associated with unfavorable outcome, and reduced BCSS was observed for CTC-positive patients (HR 2.2, p = 0.046). In multivariate analysis, DTC status (</≥ 1 DTC) at 12 months after start of NACT remained as a prognostic factor for both DFS (HR 2.2, p = 0.005), BCSS (HR 2.6, p = 0.002) and OS (HR 2.6, p = 0.002). The survival for patients with change in DTC-status was determined by the DTC-status at 12 months.


Presence of DTCs after NACT indicated high risk for relapse and death, irrespective of the DTC-status before treatment. The results supports the potential use of DTC analysis as a monitoring tool during follow up, for selection of patients to secondary treatment intervention within clinical trials.