SAN ANTONIO — Zoledronic acid prevents the profound loss in bone mineral density that often occurs with combined adjuvant endocrine therapy in premenopausal breast cancer patients, Michael Gnant, M.D., reported at the annual breast cancer symposium sponsored by the Cancer Therapy and Research Center.
Based on new data from the Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG-12), all premenopausal breast cancer patients receiving combination adjuvant therapy with a luteinizing hormone-releasing hormone analog, such as goserelin plus either tamoxifen or an aromatase inhibitor, should undergo annual bone mineral density (BMD) testing. Those showing a treatment-related decline should be considered for intravenous zoledronic acid (Zometa) administered once every 6 months, said Dr. Gnant, professor of surgery at the University of Vienna.
In a separate study presented at the conference, it was reported that zoledronic acid also effectively prevents cancer therapy-induced bone loss in postmenopausal women with early-stage breast cancer on adjuvant aromatase inhibitor therapy.
In clinical practice, the aromatase inhibitors increasingly are replacing tamoxifen, long the standard adjuvant hormonal therapy, because they provide a markedly greater reduction in recurrence along with less risk of endometrial cancer and thromboembolic events.
The price for these advantages has been the greater risk of osteoporosis and fractures associated with aromatase inhibitor therapy.
But prophylactic zoledronic acid appears to erase that downside.
While it is widely appreciated that postmenopausal breast cancer patients face increased risk of accelerated bone loss, the osseus impact of cancer therapies in premenopausal breast cancer patients was much less clear before ABCSG-12. The primary end point in the 1,315-patient Phase-III Austrian study will be relapse-free survival, which awaits longer follow-up. In San Antonio, Dr. Gnant reported on a secondary study end point—change in BMD—in a 401-patient subset.
The ABCSG-12 trial is a 4-part study that randomized patients to 3 years of adjuvant goserelin plus either tamoxifen or anastrozole, with or without 3 years of zoledronic acid given at 4 mg IV every 6 months. After 3 years of goserelin and tamoxifen without zoledronic acid, BMD at the lumbar spine fell an average of 11.6%, compared with baseline. In patients receiving goserelin plus anastrozole but not zoledronic acid, it fell 17.4%. However, patients on either combination who received the potent intravenous bisphosphonate experienced no significant change in BMD, the surgeon said.
Separately, Adam Brufsky, M.D., presented preliminary 6-month results from Z-FAST, a multicenter U.S. trial in which 415 postmenopausal women with early-stage hormone receptor-positive breast cancer receiving adjuvant letrozole (Femara) were randomized to zoledronic acid administered every 6 months either upfront or beginning 1 year after the start of the aromatase inhibitor.
BMD at the lumbar spine and hip increased in patients who got zoledronic acid upfront and decreased in those assigned to delayed bisphosphonate therapy. Biochemical markers of bone turnover decreased from baseline to 6 months in the upfront zoledronic acid group, while increasing or remaining unchanged in the delayed treatment arm.
These early findings suggest administration of zoledronic acid from the onset of adjuvant aromatase inhibitor therapy may prevent cancer therapy-induced bone loss in postmenopausal women. However, longer-term follow-up is needed to fully define the effects of zoledronic acid in this population. The Novartis-sponsored Z-FAST trial is scheduled for 5 years of follow-up, said Dr. Brufsky of the University of Pittsburgh.
Zoledronic acid is more expensive than pamidronate (Aredia), the other intravenous bisphosphonate, but its infusion time is only 15 minutes, compared with 2 hours or more for pamidronate, and there are some data to suggest zoledronic acid is more effective.
Until zoledronic acid receives an indication from the Food and Drug Administration for use in the setting of adjuvant breast cancer therapy, however, many oncologists will continue to follow the American Society for Clinical Oncology's recent guidelines. Those call for increased diligence in screening breast cancer patients for bone loss, advising them on the importance of calcium and vitamin D supplementation and bone-healthy lifestyle measures, and the early use of the clearly less potent oral bisphosphonates in women who show cancer treatment-related decline in BMD.