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

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

doi:10.1186/1471-2407-13-480

Abstract

BackgroundThe 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).MethodsPatients 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.Results86 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).ConclusionsBisphosphonate 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 registrationClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].

Highlights

The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome
Patients’ characteristics of all patients were presented previously by Solomayer et al [12]. In this manuscript we focus on survival analysis
For 86 patients a follow-up of at least 8 months was available. 64 per cent of these patients had T1 tumors and 88% were node negative. 40 out of 86 patients were assigned to receive adjuvant therapy plus intravenous zoledronic acid every 4 weeks. 46 patients were randomized into control group

Summary

Introduction

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). It has been shown that tumor cells are able to Recently, two large randomized clinical trials demonstrated zoledronic acid (ZOL) to significantly prolong disease-free survival in breast cancer patients undergoing adjuvant hormonal therapy (ABCSG-12, ZO-FAST). In contrast to these two trials, interim analysis from the AZURE trial did not show a benefit from adding ZOL to adjuvant therapy in the overall patient population [4]. Limited data are available on the in vivo effects of ZOL on DTC

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Conclusion