Open Access Research article

Prognostic relevance of induced and spontaneous apoptosis of disseminated tumor cells in primary breast cancer patients

Natalia Krawczyk1, Andreas Hartkopf2, Malgorzata Banys1, Franziska Meier-Stiegen1, Annette Staebler3, Markus Wallwiener4, Carmen Röhm2, Juergen Hoffmann1, Markus Hahn2 and Tanja Fehm1*

Author Affiliations

1 Department of Obstetrics and Gynecology, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany

2 Department of Obstetrics and Gynecology, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany

3 Department of Pathology, University of Tuebingen, Liebermeisterstr. 8, 72076 Tuebingen, Germany

4 Department of Obstetrics and Gynecology, University of Heidelberg, Voßstr. 9, 69115 Heidelberg, Germany

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BMC Cancer 2014, 14:394  doi:10.1186/1471-2407-14-394

Published: 3 June 2014

Abstract

Background

An imbalance between cell proliferation and programmed cell death can result in tumor growth. Although most systemic cytotoxic agents induce apoptosis in tumor cells, a high apoptotic rate in primary breast cancer correlates with poor prognosis. The aim of this study was to investigate the incidence and the prognostic significance of apoptotic disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients who either underwent primary surgery or primary systemic chemotherapy (PST).

Methods

A total of 383 primary breast cancer patients with viable DTC in the BM were included into this study. Eighty-five patients were initially treated with primary systemic chemotherapy whereas 298 patients underwent surgery first. Detection of apoptotic DTC were performed by immunocytochemistry using the M30 antibody which detects a neo-epitope expressed after caspase cleavage of cytokeratin 18 during early apoptosis. The median follow up was 44 months (range 10–88 months).

Results

Eighty-two of 298 (27%) primary operated patients and 41 of 85 (48%) patients treated with primary systemic systemic therapy had additional apoptotic DTC (M30 positive). In the neoadjuvant group M30-positive patients were less likely to suffer relapse than those without apoptotic DTC (7% vs. 23% of the events, p = 0.049). In contrast, the detection of apoptotic DTC in patients treated by primary surgery was significantly associated with poor overall survival (5% vs. 12% of the events, p = 0.008).

Conclusions

Apoptotic DTC can be detected in breast cancer patients before and after systemic treatment. The presence of apoptotic DTC in patients with PST may be induced by the cytotoxic agents. Thus, both spontaneous and chemotherapy-induced apoptosis may have different prognostic significance.

Keywords:
Apoptosis; M30; Breast cancer; Survival; Disseminated tumor cell