'New Standard of Care' for Some Premenopausal Breast Cancer

But Not Treatment of Choice

Nick Mulcahy

December 12, 2011

December 12, 2011 (San Antonio, Texas) — There is level 1 evidence supporting the value of zoledronic acid (Zometa, Novartis) as an adjuvant treatment for premenopausal women with endocrine-responsive breast cancer, researchers reported here at the 34th Annual San Antonio Breast Cancer Symposium.

That means that a prospective clinical trial has met its end points, so the studied agent qualifies for use in standard clinical practice, said presenter James Ingle, MD, from the Mayo Clinic in Rochester, Minnesota.

However, this adjuvant use of zoledronic acid is limited to estrogen-receptor-positive and/or progesterone-receptor-positive premenopausal women receiving the ovarian function suppressant goserelin, along with antiestrogens.

However, Dr. Ingle does not anticipate going home and using this treatment approach in these young women with endocrine-responsive breast cancer. At the Mayo Clinic, tamoxifen alone is the treatment of choice, he said, meaning that ovarian suppression is not used.

Nonetheless, zoledronic acid is "a new standard of care" for goserelin-treated patients, said Dr. Ingle. He was the discussant of a study update from a phase 3 clinical trial of zoledronic acid in such patients.

The study, the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, was the first to indicate that zoledronic acid had an effect on breast cancer progression.

New 84-month data from the ABCSG-12 trial confirm the disease-free survival and death-risk reduction benefits seen with zoledronic acid at 48 and 62 months of follow-up, said the lead investigator Michael Gnant, MD, professor of surgery at the Medical University of Vienna, Austria.

He told the symposium audience that the trial involved 1803 premenopausal women with stage 1 (76.3%) or stage 2 or higher (21.4%) endocrine-responsive breast cancer; most (67%) were node-negative. After surgery, they received ovarian suppression with goserelin plus adjuvant endocrine treatment with either tamoxifen or the aromatase inhibitor anastrozole (Arimidex, AstraZeneca) for 3 years.

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

At 84 months, the patients receiving zoledronic acid had a statistically significant 29% reduction in the risk for disease-free survival events (multivariate hazard ratio [HR], 0.71; = .01) and a significant 36% reduction in the risk for death (HR, 0.64; = .03), compared with those receiving no zoledronic acid. Zoledronic acid "eliminated more than one third of the breast cancer deaths," summarized Dr. Gnant.

The addition of zoledronic acid resulted in an absolute increase in overall survival of 1.2%, according to the latest data.

There was no osteonecrosis of the jaw or serious renal events in patients receiving the injectable bisphosphonate at 84 months, said Dr. Gnant. However, zoledronic acid was associated with bone pain, arthralgias, and fever.

Not Many Americans Treated With Ovarian Suppression

Dr. Ingle's declaration that zoledronic acid is now a standard of care does not influence the treatment of many American women, suggested another breast cancer expert.

The patient population in the Austrian trial was very specific (premenopausal women treated with goserelin), and goserelin is not widely used in the United States, said Peter Ravdin, MD, PhD, a codirector of the symposium, in a previous interview with Medscape Medical News. Dr. Ravdin is director of the comprehensive breast health clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio.

But Dr. Ingle said that this recommendation to use zoledronic acid will be "more widely applicable" if SOFT (the Suppression of Ovarian Function Trial) shows that ovarian function suppression plus endocrine therapy is more effective than tamoxifen alone in this population.

Dr. Ingle explained that there are a number of questions that remain about the adjuvant use of zoledronic acid in premenopausal women, including the impact of age (the combination therapy was more effective in women older than 40 years) and optimal duration.

Zoledronic acid is approved by the US Food and Drug Administration for the prevention of skeletal fractures, not for use in patients with cancer. But the drug evidently has a positive effect on the progression of disease in some women with breast cancer.

This difference and benefit persists and lasts long term.

Dr. Gnant does not believe that that the drug directly affects solid tumors; instead, it works in the bone. "We believe we can effectively silence dormant micrometastases," he told an audience of journalists at a press conference. The ability to target the bone microenvironment is "exciting news for our patients," Dr. Gnant said.

He also pointed out that the effect of combining antiestrogen therapy and bone microenvironment therapy was long-lasting; the 2 therapies stopped at 3 years and the positive results have now continued to 7 years. "The benefit is persisting way after treatment stopped," said Dr. Gnant. "We obviously can make a difference early on in the course of treatment and this difference and benefit persists and lasts long term."

The study was funded by AstraZeneca, which markets anastrozole (Arimidex), and by Novartis, which markets zoledronic acid (Zometa and Reclast).

34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-2. Presented December 7, 2011

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