Role of Bisphosphonate Therapy Refined but Still More Questions

Oncology & Biotech News, January 2012, Volume 6, Issue 1

The developing theme is that bisphosphonates are most effective in postmenopausal patients with HR-positive breast cancer.

Panelists included (from left to right): Volker Möbus, PhD; Richard de Boer, MD; Alexander H.G. Paterson, MD; Michael Gnant, MD; James N. Ingle, MD

Separate studies presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium in Texas shed more light on the appropriate use of bisphosphonates in breast cancer patients. According to experts, the developing theme is that bisphosphonates are most effective in postmenopausal patients with hormone receptor (HR)-positive breast cancer—and that includes younger patients who are treated with goserelin for ovarian suppression or who have undergone oophorectomy.

In the Austrian Breast and Colorectal Cancer Study Group (ABCSG-12) trial, long-term followup showed that adjuvant use of zoledronic acid improved overall survival (OS) in premenopausal patients with endocrine-receptor-positive early breast cancer. Furthermore, in the ZO-FAST trial, an exploratory analysis suggested that the addition of zoledronic acid in women slated for endocrine therapy improved disease-free survival (DFS), but not OS, in postmenopausal women. Based on these results, expert opinion was that zoledronic acid should be considered a new standard of care in premenopausal women. Data are insufficient at this time to recommend the bisphosphonate in postmenopausal women, although mounting evidence suggested that it will become standard. Finally, 2 separate trials of clodronate and ibandronate, respectively, did not meet their primary endpoints, and were considered disappointing.

ABCSG-12 Long-Term Analysis

Longer-term analysis of the ABCSG-12 trial confirms an OS benefit of adjuvant therapy with zoledronic acid plus endocrine therapy in premenopausal women with estrogen-receptor (ER)-positive breast cancer. “We have confirmed what this trial has shown initially, which was both exciting and surprising. The continued success of this treatment means we can intervene early and still observe persistence of the benefit of treatment,” said Michael Gnant, MD, professor of Surgery, Medical University of Vienna, Austria, and president of ABCSG.

The 4-arm trial randomized 1803 premenopausal women with early stage, ER-positive breast cancer to tamoxifen or anastrozole or each of these therapies plus zoledronic acid for 3 years. Initial results presented in 2008 showed significant improvement. Long-term data reported in San Antonio this year showed that after 84 months, zoledronic acid reduced the risk of recurrence by 28% and the risk of death by 36%. No patient treated with zoledronic acid had osteonecrosis of the jaw or renal failure, said Gnant.

According to James N. Ingle, MD, Mayo Clinic, Rochester, Minnesota, formal discussant of ABCSG- 12 and other bisphosphonate trials, ABCSG-12 provides Level 1 evidence supporting use of zoledronic acid in premenopausal women requiring goserelin and anastrozole. “It is safe and effective and should be considered a new standard of care in women who have undergone ovarian suppression with goserelin,” Ingle said.

ZO-FAST Unplanned Exploratory Analysis

New data from an unplanned exploratory analysis of ZO-FAST were less robust in favor of zoledronic acid in postmenopausal women with early hormone receptor (HR)-positive breast cancer. In a subgroup of postmenopausal women, the addition of zoledronic acid to adjuvant endocrine therapy increased bone mineral density and reduced the risk of disease recurrence over the longer term.

The overall analysis, presented last year at SABCS, showed that the primary endpoint of the trial (decrease in loss of bone mineral density) was met. “The secondary endpoint of improvement in DFS was also met [in the overall trial], with a 34% decrease in recurrence in patients receiving up-front zoledronic acid,” said Richard de Boer, MD, Royal Melbourne Hospital in Victoria, Australia.

ZO-FAST randomized 1065 patients slated for treatment with letrozole, an aromatase inhibitor, to receive up-front zoledronic acid every 6 months or delayed zoledronic acid initiated at a later time only in patients who experienced a fracture or a decline in bone mineral density. In the exploratory subgroup analysis, women who were menopausal at diagnosis benefited from immediate treatment with zoledronic acid, which reduced the risk of disease recurrence by 29% and improved overall survival by 35%.

According to Ingle, ZO-FAST showed that zoledronic acid improved DFS by about 3.6% over 5 years, but the effect on OS was not significant.

“The findings of an unplanned subgroup analysis are insufficient to recommend zoledronic acid as the standard of care in postmenopausal women. Remaining questions include which is the best type of bisphosphonate to use, schedule and duration of therapy, and the impact of chemotherapy. Other studies will provide more data. That being said, there is mounting evidence that zoledronic acid will become a treatment option for postmenopausal women with early breast cancer,” de Boer stated.

Other Bisphosphonates

Two separate trials showed disappointing results for clodronate and ibandronate, respectively, for patients with breast cancer.


Final results of the NSABP-B34 trial failed to show a benefit of clodronate over placebo in patients with early-stage breast cancer treated with chemotherapy and/or tamoxifen or no therapy. At 2011 SABCS, Alexander H.G. Paterson, MD, director of the Department of Medicine at the Tom Baker Cancer Center in Calgary, Alberta, Canada, presented these findings. The prospective, double-blind, phase III study randomized 3023 patients with stage I-III breast cancer to either 3 years of clodronate therapy (1600 mg/day) or placebo given alone or in addition to adjuvant chemotherapy or hormone therapy. Patients were stratified by age, number of positive nodes, and hormone receptor status.

No significant difference between groups was observed in disease-free survival (DFS), the primary endpoint of the trial. There was a suggestion of benefit for clodronate in women over the age of 50 for distant metastasis-free interval and non-skeletal metastasis-free interval, but little effect was observed in premenopausal women, Paterson said.


The first interim analysis of a separate phase III study called GAIN showed that adjuvant therapy with ibandronate had no effect on DFS or OS in primary node-positive breast cancer in women treated with dose-dense chemotherapy. “This is now considered the final analysis,” stated Volker Möbus, PhD, head of the Department of Obstetrics and Gynecology, Städtische Kliniken Höchst, Frankfurt, Germany.

The study randomized 2015 patients to ibandronate and 1008 to observation. GAIN was designed as a 2 x 2 factorial trial to compare dosedense epirubicin/paclitaxel/cyclophosphamide (ETC) versus EC followed by T and to compare ibandronate versus observation. At SABCS, Möbus reported results only of the ibandronate versus observation comparison. Subgroup analysis failed to show a significant benefit of ibandronate.