Long-term outcome of (neo)adjuvant zoledronic acid therapy in locally advanced breast cancer



The role of zoledronic acid (ZOL), a bone-targeted bisphosphonate, in the treatment of patients with breast cancer remains an active area of study. Here, we report the long-term outcomes of a randomized placebo-controlled phase II clinical trial in which ZOL treatment was added to neoadjuvant chemotherapy in women with locally advanced breast cancer.


120 women with clinical stage II–III (≥ T2 and/or ≥ N1) newly diagnosed breast cancer were randomized to receive either 4 mg intravenous ZOL every 3 weeks for 1 year (17 total doses) beginning with the first dose of neoadjuvant chemotherapy, or chemotherapy alone. Clinical endpoints included time to recurrence (TTR), time to bone recurrence (TTBR), time to non-bone recurrence (TTNBR), breast cancer survival (BCS) and overall survival (OS).


With a median follow-up interval of 14.4 years, there were no significant differences in any of the clinical endpoints studied between the control and ZOL groups in the overall study population. However, ER+/HER2− patients younger than age 45 who were treated with ZOL had significantly worse TTR and TTNBR with a trend towards worse TTBR, BCS and OS (TTR: P = 0.024, HR 6.05 [1.26–29.1]; TTNBR: P = 0.026, HR 6.94 [1.26–38.1]; TTBR: P = 0.054, HR 6.01 [0.97–37.1]; BCS: P = 0.138, HR 4.43 [0.62–31.7]; OS: P = 0.138, HR 4.43 [0.62–31.7]). These differences were not seen in older ER+/HER2− patients or triple-negative patients of any age.


Addition of ZOL to neoadjuvant therapy did not significantly affect clinical outcomes in the overall study population but was associated with increased extra-skeletal recurrence and a trend towards worse survival in ER+/HER2− patients younger than age 45. These findings suggest caution when using zoledronic acid in young, premenopausal women with locally advanced breast cancer and warrant further investigation.

Clinical Trial Registration Number NCT00242203, Date of Registration: 10/17/2005

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Data availability

Deidentified datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.


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This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number TL1TR002344. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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AJ, KW and RA contributed to the study conception and design. Material preparation, data collection and analysis were performed by AJ and SP. The first draft of the manuscript was written by AJ and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Rebecca L. Aft.

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The Institutional Review Board of Washington University approved the study. The Siteman Cancer Center’s quality assurance and safety monitoring committee oversaw patient safety and all aspects of the study were conducted in accordance with the Declaration of Helsinki.

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Jallouk, A.P., Paravastu, S., Weilbaecher, K. et al. Long-term outcome of (neo)adjuvant zoledronic acid therapy in locally advanced breast cancer. Breast Cancer Res Treat (2021). https://doi.org/10.1007/s10549-021-06100-2

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  • Breast cancer
  • Zoledronic acid
  • Bisphosphonate
  • Neoadjuvant
  • Premenopausal