ABCSG-12: Zoledronic Acid (Zometa) Reduces Recurrence of Early Breast Cancer

The Austrian Breast and Colorectal Cancer Study Group Trial 12 results were reported at the American Society of Clinical Oncology (ASCO) 2008 Annual Meeting.  The study compared treatment with zoledronic acid (Zometa) with placeo in premenopausal women who were treated with anti-estrogen therapy following surgery. 

Between 1999 and 2006, over 1800 women participated in the study. All were premenopausal, had estrogen receptor (ER)- and/or progesterone receptor (PR)-positive stage I or II (<10 positive nodes) breast cancer, and have received no chemotherapy other than neo-adjuvant (pre-operative) treatment.

Following completion of surgery (with radiotherapy in breast conservation cases), women were treated with 3.6 mg of goserelin (an ovarian suppression LHRH drug) and then randomized to one of four treatment arms: tamoxifen 20 mg/day; tamoxifen 20 mg/day plus zoledronic acid 4 mg given intravenously every 6 months; anastrozole 1 mg/day; or the AI plus the bisphosphonate at the same doses and schedule.

Dr. Gnant of the University of Vienna reported that the disease-free (DFS) and overall survival (OS) rates were very good for the whole cohort, at 94.0% and 98.2%, respectively.

A total of 137 first DFS events were reported. Of these, 72 occurred in patients treated with anastrozole, and the remaining 65 occurred in those treated with tamoxifen. Statistical analysis showed no significant difference in the primary endpoint of DFS according to the type of endocrine treatment used, but there was a significant difference according to whether or not patients had been given the bisphosphonate. Of the 137 DFS events, 54 occurred in women who had received zoledronic acid, with the remaining 83 in those who had not received the drug. This gave a hazard ratio of 0.643 (95% confidence interval: 0.46-0.91), with a p value of 0.011, in favor of bisphosphonate use over no bisphosphonate use.  This is a 35% reduction in the number of events. 

The reduction in events were not limited to bone metastasis reduction.  Reduction in other distant metastases, local recurrence, and contralateral breast cancer events was established. 

Zoledronic acid is a bisphosphonate drug which reduces bone resorption and thereby increases bone mineral density.  Bisphosphonates are approved therapies for treatment of osteoporosis.   The anticancer effect of bisphosphonates has been suggested in prior studies of other bisphosphonate drugs, e.g., oral clodronate (NSABP).  The mechanism of the anticancer effect is not known. 

These results have been called “practice changing” by some observers, but not all.  However, if the effect is confirmed in other large ongoing studies (AZURE, BIG 1-04, NATAN, GAIN, NSABP B-34), then the use of bisphosphonate therapy is likely to have a large impact on practice, as well as the design of future studies. 

Access to bisphosphonate therapy for adjuvant therapy of early breast cancer in the US is limited, because the drugs are not FDA-approved yet for breast cancer treatment.  For example, Medicare does not pay for coverage for zoledronic acid for breast cancer.  Private payors may not pay for zoledronic acid for breast cancer either, since their treatment algorithms heavily rely upon national guideline groups and current FDA approvals.  While zoledronic acid is approved for osteoporosis, the dosing of the drug at the approved frequency is yearly, and the dosing that was shown to be effective in the ABCSG study was more frequent, so therapy was more intensive. 

Patients may gain access to bisphosphonate therapy for early breast cancer by enrolling in clinical studies, such as the SWOG S0307 Study which is open at CORT.  This study compares the efficacy of three different bisphosphonate drugs (IV zoledronic acid, oral clodronate, oral ibandronate) in a randomized fashion.  All patients will receive one of the bisphosphonate therapies.  Three is no placebo group.  This study will also include a broader range of patients, including pre- and post-menopausal women, ER- and ER+ disease, and those who have receive either pre- or post-operative chemotherapy.  In addition, the use of adjuvant biologic therapy such as trastuzumab (Herceptin) or bevacizumab (Avastin) is allowed.  For more information about this study, visit the CORT website (www.CORTPA.com), or call 972-566-5588 to speak with a Study Coordinator.

Addendum (2/12/09):  The ABCSG-12 Study Results were published in the New England Journal of Medicine today.  The reference is: Gnant, M. et al., NEJM 2009; 360 (7): 679-691. 

Tags: ABCSG, ABCSG Trial 12, adjuvant therapy, bisphosphonates, Breast Cancer, Clodronate, Ibandronate, S0307, Stage I-III, SWOG, zoledronic acid, zometa