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

Malgorzata Banys, Erich-Franz Solomayer, Gerhard Gebauer, Wolfgang Janni, Natalia Krawczyk, Hans-Joachim Lueck, Sven Becker, Jens Huober, Bernhard Kraemer, Birgit Wackwitz, Peter Hirnle, Diethelm Wallwiener, Tanja Fehm, Malgorzata Banys, Erich-Franz Solomayer, Gerhard Gebauer, Wolfgang Janni, Natalia Krawczyk, Hans-Joachim Lueck, Sven Becker, Jens Huober, Bernhard Kraemer, Birgit Wackwitz, Peter Hirnle, Diethelm Wallwiener, Tanja Fehm

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)].

Figures

Figure 1
Figure 1
Patient distribution diagram according to the Recommendations for Tumor Marker Prognostic Studies (REMARK).
Figure 2
Figure 2
Survival analysis. ZOL group – patients assigned to adjuvant therapy plus intravenous zoledronic acid every four weeks. Control group – patients assigned to adjuvant therapy alone (a) Overall survival (b) Relapse-free survival.
Figure 3
Figure 3
Overall survival analysis with regard to detection of persistent disseminated tumor cells at 12 months after diagnosis.
Figure 4
Figure 4
Proportion of patients with DTC-positive bone marrow at 12 and 24 months after diagnosis.

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