AZURE: Zoledronic Acid Effect on Breast Cancer Is Complicated

Zosia Chustecka

December 09, 2010

December 9, 2010 ( UPDATED December 13, 2010 ) (San Antonio, Texas) — Long-awaited results from the AZURE trial in breast cancer patients show no effect from the bisphosphonate zoledronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, a subset analysis showed a significant effect on both recurrence and survival in postmenopausal women (more than 5 years after menopause), but no effect on premenopausal women.

The overall negative results from the AZURE trial have led the manufacturer to withdraw its application for zoledronic acid use in breast cancer risk reduction. But they do not appear to be deterring experts who are already using this strategy on the basis of previous positive results.

The most positive findings to date come from the Austrian ABCSG trial reported 2 years ago, and subsequently published in the New English Journal of Medicine (2009;360:679-691). This study found that zoledronic acid reduced breast cancer recurrence and breast cancer death by one third.

This Austrian trial sparked great interest from the whole medical community, and led some clinicians to prescribe zoledronic acid, which is indicated for osteoporosis, to women with breast cancer to increase their chance of survival.

Dr. Sharon Giordano

However, such use is not recommended in any clinical guidelines, and the scientific community urged physicians to wait for results from the AZURE trial, said Sharon Giordano, MD, MPH, associate professor in the Department of Breast Medical Oncology at the University of Texas M.D. Andersen Cancer Center in Houston.

She was one of several experts speaking at a press conference today here at the 33rd Annual San Antonio Breast Cancer Symposium (SABCS) to highlight the results from AZURE. They will be presented at the meeting tomorrow by principal investigator Robert Coleman, MD, professor of oncology at the University of Sheffield, United Kingdom.

Routine use of zoledronic acid to prevent breast cancer recurrence is not indicated.

In light of the new and contradictory findings from AZURE, she said, "the routine use of zoledronic acid to prevent breast cancer recurrence is not indicated." The drug has a use in osteoporosis and other bone disorders, which are approved indications.

The finding of a significant effect in postmenopausal women in a subgroup analysis is "intriguing but not definitive," she said.

However, several experts disagreed and said that they were already prescribing the drug and would continue to do so.

Michael Gnant, MD, professor of surgery at the Medical University of Vienna, who led the positive Austrian trial, said after those results came out that he would use zoledronic acid in patients who were similar to the participants of that trial (premenopausal women who were treated with goserelin to induce artificial menopause). Now, on the basis of the positive subgroup findings, he said he would also use zoledronic acid in postmenopausal women.

"Before I would say that I would treat my wife, who is 42. Now I would also treat my mother, who is 82," he said.

Dr. Rowan Chlebowski

Rowan Chlebowski, MD, PhD, medical oncologist at the Harbor-University of California in Los Angeles, told Medscape Medical News that he would also use zoledronic acid in postmenopausal women with breast cancer to reduce their risk for recurrence. "Many states cover use of zoledronic acid to prevent bone loss in the patient population, so I prescribe it for that," he said.

Last year, Dr. Chlebowski reported a large observational study that showed that women who were taking oral bisphosphonates (which did not include zoledronic acid, which is administered intravenously) for osteoporosis had a significantly lower risk for breast cancer. Two other observational studies have reported similar findings. In all of these studies, the women were postmenopausal, Dr. Chlebowski noted.

The effect of zoledronic acid on breast cancer is only seen when estrogen levels are very low, Dr. Chlebowski explained. It is seen in postmenopausal women more than 5 years after menopause (as in the AZURE subset) and in younger premenopausal women who have been pushed into artificial menopause by goserelin (as in the Austrian trial), he pointed out. Dr. Gnant noted that the best reduction effects were seen in women who were older than 40 years; younger women in whom the induced menopause was "less than perfect" had less favorable outcomes.

Zoledronic acid does not have an effect on breast cancer that is being driven by estrogen, Dr. Chlebowski said.

The latest results have led the experts to speculate that zoledronic acid does not have a direct anticancer effect — which had been suspected at one point — but rather that it has an effect on the host, specifically on the bone marrow environment, which prevents the cancer from returning.

Dr. Michael Gnant

Dr. Gnant explained that zoledronic acid is administered by injection once every 6 months, and that a healthy individual would clear the drug from the system in about 24 hours. But the drug persists in bone and changes the bone marrow environment, Dr. Gnant told Medscape Medical News. There is good reason to believe that breast cancer cells collect within the bone marrow, forming a "stem cell sanctuary," particularly in early disease. They can be dormant there, sometimes for years, before they escape and cause breast cancer recurrence, he said. It now appears that zoledronic acid is altering the bone marrow environment in such a way that the breast cancer cells are less likely to escape and cause a recurrence, he said.

Details of AZURE Results

Dr. Robert Coleman

The AZURE study was designed after the positive results from the Austrian trial came out and zoledronic acid began to be used in the wider breast cancer population, Dr. Coleman explained. It was an academic study, he emphasized, conducted in 3360 women from 174 centers worldwide (but mostly in the United Kingdom).

These women had stage II or III breast cancer. Nearly all were treated with adjuvant chemotherapy (93% anthracyclines, 23% taxanes), and some also received endocrine therapy. Half of them were randomized to receive zoledronic acid 4 mg intravenously over 3 to 4 weeks for 6 doses, and then every 3 months for 8 doses and every 6 months for 5 doses.

All of these details are different from the Austrian trial, Dr. Gnant noted, where all of the women were stage I, none received chemotherapy, and zoledronic acid was used once every 6 months.

Dr. Coleman explained that the more intensive administration schedule in AZURE was used because at the time the trial was designed, it was thought that zoledronic acid had a direct anticancer effect.

The differences in dosing schedule might also be related to the fact that osteonecrosis of the jaw, a known adverse effect of bisphosphonates, was not seen in the Austrian study, but was reported in 17 patients (1.16%) in the AZURE trial.

The overall results from AZURE, after a median follow-up of 59 months, show no significant effect from zoledronic acid on either disease-free or overall survival, although there was a positive trend for overall survival.

Significant Effect in Subgroup

However, in a preplanned subset analysis based on menopausal status, zoledronic acid did show a significant effect on overall survival in a subgroup of women (n = 1101) with well-established menopause (more than 5 years postmenopausal), reducing the risk for death by 29%. There were 86 deaths in the zoledronic acid groups, compared with 120 in the other group (hazard ratio, 0.71; P = .017).

There was no significant effect in younger women who were premenopausal or perimenopausal.

"To see a survival advantage like this is quite remarkable, and the difference in outcome between this group and the younger population is unlikely to be a chance finding. We will clearly want to investigate further in this population," he said.

However, he also emphasized that this result came from a subgroup analysis, so it should be considered "hypothesis-generating."

"This was an unexpected finding," he told Medscape Medical News, "and now we have to go back to see why there is an effect when there is no estrogen and why there isn't one when estrogen is present."

Dr. Gnant was more enthusiastic, and highlighted the fact the reduction in death was nearly a third, which is similar to what was reported in the Austrian study. He also pointed out that women who are in established menopause constitute a large part of the breast cancer patient population.

Dr. Coleman, however, was rather reserved in his conclusions. "Adjuvant use of bisphosphonates like zoledronic acid is widespread among women with breast cancer. The results of this trial will help answer many questions, as well as invite new ones," he said.

He also suggested that the latest findings "will likely dissuade clinicians from giving adjuvant bisphosphonates on a routine basis to younger women taking adjuvant chemotherapy because, although the drug is generally well tolerated, there is a small risk of osteonecrosis of the jaw."

In answer to questions from the audience, Dr. Coleman said that "if you are considering zoledronic acid in younger women, it should be in the presence of goserelin."

Reactions to AZURE Results

You couldn't get a more negative result.

Commenting on the findings in a talk at the end of the meeting, Alan Coates, MD, from the University of Sydney in Australia, emphasized that the results from AZURE were negative. "There was no effect on breast cancer overall" he said; "you couldn't get a more negative result."

Dr. Coates, who is cochair of the scientific committee of the International Breast Cancer Group, said that "it is irresponsible" to use results from a subset analysis to take the drug into clinical practice for the adjuvant treatment of breast cancer.

The positive results from the subset analysis in postmenopausal woman should be considered "exploratory," he added, and they need to be studied further.

Use . . . in the adjuvant treatment of breast cancer is not ready yet for prime time.

Elaborating to Medscape Medical News, Dr. Coates said that "the use of zoledronic acid in the adjuvant treatment of breast cancer is not ready yet for prime time." Bisphosphonates have a role to play in osteoporosis and bone metastases, but they are not ready for use in breast cancer, he emphasized.

"There was a tide of enthusiasm for this use" after the results of the Austrian trial, he noted. The negative result from the AZURE trial is "unwelcome," but it is also "particularly timely for countering the enthusiasm for using these drugs in breast cancer," he said.

In another talk, Peter Ravdin, MD, codirector of the SABCS, said that AZURE was the most anticipated trial and the results are "tremendously disappointing."

Dr. Ravdin, who is codirector of the SABCS and director of the Comprehensive Breast Health Clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, spoke to patient advocates at an evening session that reviewed the Hot Topics of the day. He explained that the results from the Austrian trial were "spectacular." In that trial, zoledronic acid reduced the risk for breast cancer recurrence and breast cancer death by 33%, which is similar to the benefit seen with trastuzumab (Herceptin) when it was hailed as a great advance in breast cancer.

However, he also explained that the patient population in the Austrian trial was very specific (premenopausal women treated with goserelin), and that in the United States, goserelin is not widely used. The AZURE trial set out to test zoledronic acid in a broader patient population, and included women of all ages.

"We were hoping to see a home run," Dr. Ravdin said.

Instead, there was no effect on breast cancer. Subset analyses showed that there was no benefit in premenopausal women, but there was a significant benefit on both breast cancer recurrence and breast cancer mortality in postmenopausal women.

"This is a head-scratcher," he noted. "Is this telling us something?"

"This is a really fascinating study, but it is inconclusive," Dr. Ravdin said. He added that this is not the end of the story; there several ongoing trials investigating bisphosphonates in breast cancer (including NSABP B-34 and SWOG SO307).

"Stay tuned," he urged.

Dr. Giordano has disclosed no relevant financial relationships. Dr. Coleman reports consultancy and being on the speakers' bureau for Novartis and Amgen. Dr. Gnant reports consultancy for Novartis, AstraZeneca, and Amgen, and receiving funding from Novartis and AstraZeneca. Dr. Chlebowksi reports being on the speakers' bureau of Novartis and Amgen, and receiving grants from Amgen. Dr. Coates has disclosed no relevant financial relationships.

33rd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-5. Presented December 10, 2010.

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