SABCS 2008: Zoledronic Acid Has Direct Effect on Breast Cancer

Zosia Chustecka

December 12, 2008

December 12, 2008 (San Antonio, Texas) — New data suggest that zoledronic acid (Zometa, Novartis) has a direct effect on breast cancer. The bisphosphonate is currently marketed for osteoporosis and bone metastasis, but there is growing evidence to suggest that it might also have a role to play in breast cancer.

Preliminary results from a clinical-trial subset presented here at the 31st Annual San Antonio Breast Cancer Symposium show that when zoledronic acid was used with chemotherapy in the neoadjuvant setting, the combination led to a significantly greater shrinkage of the primary tumor than was seen with chemotherapy alone.

Together with chemotherapy, you get this exquisite synergy.

Also, data from molecular studies presented here show that the combination produces a change in the expression of a number of genes and proteins associated with cell-cycle regulation and apoptosis, but neither produced these changes when used alone. "Zoledronic acid on its own had no appreciable effect, but together with chemotherapy, you get this exquisite synergy," commented coauthor Robert Coleman, MD, FRCP, professor of medical oncology at the University of Sheffield, United Kingdom.

These new results are the second time this year that zoledronic acid has shown an effect on breast cancer. When added to adjuvant chemotherapy, it significantly reduced the relapse rate in early breast cancer in the Austrian Breast and Colorectal Cancer Study Group trial 12. These results were presented at this year's American Society of Clinical Oncology meeting, and reported by Medscape Oncology at that time.

Neoadjuvant Use Increased Tumor Shrinkage

The latest data come from the AZURE (Neo-Adjuvant Zoledronic Acid to Reduce Recurrence) trial, conducted in 3360 patients with stage 2 or 3 breast cancer. Patients received standard neoadjuvant chemotherapy with or without the addition of zoledronic acid before surgery, and then standard adjuvant chemotherapy with or without zoledronic acid after surgery. The study was funded by the manufacturer.

The overall results of this trial are still being evaluated, but at the San Antonio meeting, Dr. Coleman presented preliminary results for a subgroup of 205 patients for whom a retrospective pathology analysis had been performed.

The results from this subgroup suggest that the addition of zoledronic acid leads to a greater shrinkage of the primary tumor. After surgery, the median residual tumor size was significantly smaller in women receiving both chemotherapy and zoledronic acid (20.5 mm vs 30.0 mm) than in those receiving chemotherapy alone (P = .002). In addition, a complete pathologic response was seen in 10.8% of women in the combination group vs 5.8% of those in the chemotherapy-alone group (P = .02).

Fewer Women Had a Mastectomy

In this neoadjuvant setting, the goal is to reduce the size of the tumor, and in doing so to potentially improve breast conservation rates and longer-term outcomes, explained coauthor Matthew Winter, MBChB, MSc, clinical research fellow at the University of Sheffield. In this analysis, fewer women in the combination group required a mastectomy (65.3% compared with 77.9% in the chemotherapy-alone group).

"The results support a potential antitumor benefit of combining zoledronic acid with chemotherapy in the neoadjuvant treatment of breast cancer," Dr. Winter commented in a statement.

Dr. Coleman emphasized that these results come from a retrospective and exploratory analysis and, hence, they should be regarded as hypothesis generating. But if the results from the overall AZURE trial confirm these findings, they could be practice changing, he suggested.

The final results from AZURE are expected in the next 2 or 3years, according to a Novartis spokesperson, who said Novartis is "committed to further exploring zoledronic acid as an anticancer treatment."

Less Bone Loss

Another presentation at the meeting reported an effect of zoledronic acid on breast cancer in yet another setting. ZO-FAST (Zometa-Femara Adjuvant Synergy Trial) assessed the effect of zoledronic acid on bone loss associated with the aromatase inhibitor letrozole in postmenopausal women with early breast cancer. The interim results at 36 months, assessed by bone-mineral-density measurements, show that the bisphosphonate is effective in preventing this bone loss, reported lead researcher Holger Eidtmann, MD, from University Frauenklinik, in Kiel, Germany.

However, the results also show an effect on breast cancer, he noted. In this study, one group of patients took zoledronic acid throughout the study (the immediate-zoledronic-acid group), and the other group took the drug only if bone-mineral density fell or they had a fracture (the delayed-zoledronic-acid group). The immediate group had a significantly lower disease recurrence than the delayed group (22 events vs 37 events; P = .0423), he reported.

When asked whether he would recommend zoledronic acid for breast cancer patients who are at increased risk for relapse, Dr. Eidtmann said: "No, I think it is too early for that; these results are only 3-year follow-up [data]. But I do believe that there is antitumor activity of zoledronic acid in breast cancer."

AZURE and ZO-FAST were funded by Novartis. Dr. Coleman reported serving on the speakers' bureau for Novartis. Dr. Eidtmann has disclosed no relevant financial relationships.

31st Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 2151, 5101, and 44. Presented December 12 and 13, 2008.

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