For premenopausal women with early hormone-responsive breast cancer, bisphosphonates during adjuvant endocrine treatment may improve disease-free survival, researchers found.
* Explain to interested patients that zoledronic acid is given to breast cancer patients on endocrine therapy to protect bone health.
Note that zoledronic acid has been shown to have potential antitumor activity in preclinical and early phase studies.
The addition of zoledronic acid (Zometa) reduced the risk of disease progression by 36% compared with adjuvant endocrine therapy alone (absolute difference -3.2 percentage points, P=0.01), found Michael Gnant, M.D., of the Medical University of Vienna, and colleagues.
While the randomized trial showed no mortality benefit, toxicity was minimal, they reported in the Feb. 12 issue of the New England Journal of Medicine.
The results confirm the initial report of the data at last year's American Society of Clinical Oncology meeting.
This effect was comparable to the absolute advantage in disease-free survival seen in prior trials for aromatase inhibitors versus tamoxifen among postmenopausal women with early breast cancer, the researchers noted.
Given the similar advantage of aromatase inhibitors in one prior study of premenopausal women, their Austrian Breast and Colorectal Cancer Study Group trial was also designed to compare endocrine treatments.
The study included 1,803 premenopausal women with endocrine-responsive stage I or II breast cancer who were given the gonadotropin-releasing hormone analog goserelin (Zoladex, 3.6 mg subcutaneously every 28 days) after primary surgery.
They were randomized to adjuvant treatment with tamoxifen (20 mg per day given orally) or anastrozole (Arimidex) at 1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every six months) for three years.
However, unexpectedly, anastrozole did not improve outcomes among premenopausal women in the study at a median follow-up of 47.8 months. The findings compared with tamoxifen included:
* No effect on disease-free survival (hazard ratio 1.10, P=0.59)
* No impact on recurrence-free survival (HR 1.11, P=0.53)
* No advantage for overall mortality (HR 1.80, P=0.70)
The difference compared with postmenopausal women might have been "because of the dominant effect of ovarian suppression on estrogen levels in premenopausal women," the researchers suggested. "Moreover, long-term administration of goserelin can reduce androgen levels, thereby limiting the available substrate for aromatase activity."
Other findings for the addition of zoledronic acid compared with endocrine therapy alone included:
* Improved disease-free survival rates (94.0% versus 90.8%, P=0.01)
* A 36% relative reduction in risk of disease progression (P=0.01)
* Improved recurrence-free survival at 47.8 months (94.0% versus 90.9%, P=0.01)
* A 35% reduction in risk of recurrence (P=0.02)
* No difference in risk of death (HR 0.60, P=0.11).
* No significant effect on survival free of bone metastasis despite a 32% risk reduction (HR 0.68, P=0.22), which the researchers attributed to a small number of events
The number needed to treat with zoledronic acid to prevent disease progression in one patient was 31 in the study, "consistent with the number needed to treat for cancer therapies that in the past have caused a shift in treatment standards," such as docetaxel (Taxotere) and paclitaxel (Taxol), Dr. Gnant's group noted.
The researchers noted no excess toxicity aside from "known drug-safety profiles." Zoledronic acid-treated patients had slightly higher incidences of bone pain (35% versus 25%), arthralgia (24% versus 18%), and fever (9% versus 2%), with apparently additive effects for the bone-related adverse events.
Three suspected cases of osteonecrosis of the jaw among zoledronic acid-treated patients were all ruled out after review of dental records. There were also no signs of renal toxicity.
The effect on breast cancer may be explained by preclinical and early phase studies that showed zoledronic acid inhibited tumor-cell adhesion, invasion, and proliferation and induced tumor cell apoptosis, acted synergistically with chemotherapy agents, and exerted antiangiogenic effects, Dr. Gnant's group said.