Zoledronic Acid Benefit in Breast Cancer: Data Published in NEJM

Zosia Chustecka

February 11, 2009

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February 11, 2009 — Details of a study showing a beneficial effect of zoledronic acid on breast cancer outcomes are published in the February 12 issue of the New England Journal of Medicine.

This was one of the first studies to show that the drug, a bisphosphonate used for osteoporosis and bone metastases, also has a benefit in breast cancer. Preliminary results were presented at the American Society of Clinical Oncology (ASCO) meeting last year, and reported by Medscape Oncology at the time.

The finding comes from the Austrian Breast and Colorectal Cancer Study Group (ABSCG)-12 trial, and the first author is Michael Gnant, MD, from the Medical University of Vienna, in Austria. The study was funded by AstraZeneca, which markets anastrozole (Arimidex), and Novartis, which markets zoledronic acid (Zometa, Reclast).

The trial involved 1803 premenopausal women with estrogen-responsive early breast cancer. After surgery, they received standard treatment, composed of ovarian suppression with goserelin plus adjuvant endocrine treatment with either tamoxifen or the aromatase inhibitor anastrozole for a period of 3 years. The results showed no difference in the outcomes between tamoxifen and anastrozole groups.

In addition, half of the women were randomized to receive zoledronic acid 4 mg intravenously every 6 months, also for 3 years.

The addition of zoledronic acid significantly improved disease-free survival. It resulted in an absolute reduction of 3.2% and a relative reduction of 36% in the risk for disease progression (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46 to 0.91; P = .01).

However, zoledronic acid did not improve overall survival. It did not significantly reduce the risk for death (HR, 0.60; 95% CI, 0.32 to 1.11; P = .11).

Are Results Practice-Changing?

Dr. Gnant and colleagues say the data from this trial show that ovarian suppression with endocrine therapy for 3 years "can produce excellent outcomes" in a population with low to intermediate risk.

They also suggest that the benefit seen from adding zoledronic acid is of the same order as results that, "in the past, have caused a shift in treatment standards."

The estimated number needed to treat to prevent disease progression in 1 patient in the intent-to-treat cohort was 31 in the zoledronic-acid group at median follow-up of 47.8 months.

In contrast, a meta-analysis of taxane chemotherapy in postmenopausal women with early breast cancer found the number needed to treat to prevent disease progression in 1 patient was 28 with paclitaxel (with a median follow-up of 60–69 months) and 31 with docetaxel (with a median follow-up of 43–60 months).

In addition, the researchers point out that zoledronic acid has been shown in previous studies to prevent the bone loss caused by aromatase inhibitors.

At the ASCO meeting last year, Dr. Gnant suggested that "adjuvant treatment with zoledronic acid should be considered in order to improve the standard of care in premenopausal breast cancer patients."

Discussing the results at the meeting, Eric Winer, MD, from Harvard Medical School, in Boston, Massachusetts, and Linda Vahdat, MD, from Weill Cornell Medical College, in New York City, agreed that zoledronic acid should now be considered an appropriate therapy.

However, Martine Piccart-Gebhart, MD, PhD, from the Institut Jules Bordet, in Paris, France, said these results "are not practice-changing — not yet." She said that there is a need for confirmation from other trials before the drug can be recommended for routine care.

More Results Suggesting Benefit for Zoledronic Acid

Since then, more results suggesting a benefit from zoledronic acid in breast cancer have been reported, although in different patient populations. Two studies were presented at the San Antonio Breast Cancer Symposium in December 2008, and were reported at the time by Medscape Oncology.

One set of results come from the AZURE (Neo-Adjuvant Zoledronic Acid to Reduce Recurrence) trial, conducted in 3360 patients with stage II or III breast cancer, both pre- and postmenopausal. Preliminary data from a subgroup of 205 women for whom a retrospective pathology analysis had been performed suggest that, when given before surgery, neoadjuvant zoledronic acid worked synergistically with chemotherapy and resulted in a greater shrinkage of the tumor, leading to fewer mastectomies.

The other set of results come from ZO-FAST (Zometa-Femara Adjuvant Synergy Trial), which showed that zoledronic acid can prevent bone loss associated with the aromatase inhibitor letrozole (Femara, Novartis) in postmenopausal women with early breast cancer. However, they also show that women who took zoledronic acid throughout the 3-year study had significantly lower breast cancer recurrence.

When the lead researcher, Holger Eidtmann, MD, from the University Frauenklinik, in Kiel, Germany, was asked whether he would recommend zoledronic acid for breast cancer patients who are at increased risk for relapse, he 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," he added.

Dr. Gnant told Medscape Oncology that the data from these other trials (ZO-FAST and AZURE) provide confirmation, and all the data are pointing in the same direction. These data suggest that "treatment with zoledronic acid actually changes the microenvironment in which dormant tumor cells survive, and this is fascinating," he said.

"We still don't know who benefits in particular," Dr. Gnant continued; "there may be differences between women, either in terms of their individual bone turnover or in other ways. But if a patient falls into the categories of the ABCSG-12 study, I certainly recommend that zoledronic acid treatment is considered."

The ABCSG-12 study was supported by AstraZeneca and Novartis. Both the AZURE and ZO-FAST studies were supported by Novartis. Dr. Gnant and several of the other ABSCG-12 authors report a number of relationships with various pharmaceutical companies, including consultancy and research grants from AstraZeneca and Novartis. Full details appear in the paper.

N Engl J Med. 2009;360:679-691.

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