Open Access Highly Accessed Research article

Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial

Malgorzata Banys13, Erich-Franz Solomayer2, Gerhard Gebauer3, Wolfgang Janni4, Natalia Krawczyk1, Hans-Joachim Lueck5, Sven Becker6, Jens Huober1, Bernhard Kraemer7, Birgit Wackwitz8, Peter Hirnle9, Diethelm Wallwiener7 and Tanja Fehm1*

Author Affiliations

1 Department of Gynecology and Obstetrics, Heinrich-Heine University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany

2 Department of Gynecology and Obstetrics, University Hospital of Saarland, Homburg, Germany

3 Department of Gynecology and Obstetrics, Marienkrankenhaus Hamburg, Hamburg, Germany

4 Department of Gynecology and Obstetrics, University of Ulm, Ulm, Germany

5 Department of Gynecologic Oncology, Hannover Medical School, Hannover, Germany

6 Department of Gynecology and Obstetrics, University of Frankfurt, Frankfurt, Germany

7 Department of Gynecology and Obstetrics, University of Tuebingen, Tuebingen, Germany

8 Novartis Oncology, Nuremberg, Germany

9 Central Academic Hospital, Department of Radiation Oncology, Bielefeld, Germany

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BMC Cancer 2013, 13:480  doi:10.1186/1471-2407-13-480

Published: 15 October 2013

Abstract

Background

The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068).

Methods

Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated.

Results

86 patients could be included into survival analysis (median follow-up: 88 months, range: 8–108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011).

Conclusions

Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC.

Trial registration

ClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].

Keywords:
Breast cancer; Bisphosphonates; Zoledronate; Disseminated tumor cells; Survival