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Zoledronic Acid Did Not Improve Disease-Free Survival in Breast Cancer

Adapted from the NCI Cancer Bulletin.

The addition of zoledronic acid, a bisphosphonate, to standard adjuvant therapy for women with stage II or III breast cancer did not extend disease-free survival (DFS), according to results from the phase III AZURE trial presented December 9, 2010, at the San Antonio Breast Cancer Symposium (SABCS). (The results were subsequently published online Sept. 25, 2011, in the New England Journal of Medicine; see the journal abstract.) The findings run counter to those from an earlier trial, ABCSG-12, which showed improved DFS in premenopausal women with early-stage breast cancer who received zoledronic acid in addition to hormone therapy.

It is important to note, said Robert Coleman, M.D., the AZURE trial’s principal investigator, that the patient populations in the two trials were very different. AZURE enrolled both premenopausal and postmenopausal women; ABCSG-12 enrolled only premenopausal women who, as part of the trial, received the drug goserelin to induce early menopause.

The AZURE investigators enrolled 3,360 women at 174 treatment centers in the United Kingdom. The women were randomly assigned to receive either standard adjuvant treatment—chemotherapy, hormone therapy, or both, chosen by their treating physician—or to standard adjuvant treatment plus 5 years of zoledronic acid.

After almost 5 years of follow-up, no difference in DFS or overall survival (OS) was observed between the groups. However, in a preplanned subset analysis, women who had been menopausal for at least 5 years had significantly increased DFS and OS with the addition of zoledronic acid to standard treatment. Premenopausal women experienced no benefit from the addition of the bisphosphonate in the subset analysis. The updated results from ABCSG-12 presented at SABCS continued to show a statistically significant improvement in DFS and a trend toward improved OS in women who received zoledronic acid.

“Our results are strikingly different from those observed in ABCSG-12, and we need to understand why. I don’t believe one is right and one is wrong. I think we need to understand the biology as to why we’re seeing these different outcomes,” said Dr. Coleman. “Our hypothesis would be that adjuvant bisphosphonate efficacy is dependent on a low estrogen or inhibited concentration within the bone microenvironment,” he continued.

“Based on these data, I believe the routine adjuvant use of zoledronic acid to prevent recurrence is not indicated,” said Sharon Giordano, M.D., from the University of Texas M. D. Anderson Cancer Center at the press conference. “The difference in outcome by menopausal status is very intriguing but not definitive.” She continued, “the AZURE trial will not be the final word on this topic.” Ongoing large trials testing bisphosphonates for the adjuvant treatment of breast cancer include NSABP B-34, the Gain trial, the NATAN trial, and SWOG-S0307.

  • Posted: December 27, 2010
  • Updated: October 20, 2011