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SABCS: Mixed Findings Fail to Clarify Role of Bisphosphonates

SABCS: Mixed Findings Fail to Clarify Role of Bisphosphonates

SAN ANTONIO—Results of 4 trials involving bisphosphonates in a range of protocols and patient cohorts suggest that the role of these agents in preventing recurrence of breast cancer remains to be defined. In 2 of the 4 studies reported, favorable outcomes were obtained following intravenous administration of zoledronic acid. Neither of two trials in which a bisphosphonate was administered orally, however, achieved its primary endpoint.

3D representation of zoledronic acid

ABCSG-12—Data from the Austrian Breast & Colorectal Cancer Study Group (ABCSG-12) confirmed and extended data reported at 48 months and 62 months of follow-up, reported Michael Gnant, MD, professor of surgery at the Medical University of Vienna. Now at 84 months of follow-up, patients are experiencing fewer recurrences of breast cancer and improved rates of survival with few toxic side effects (SABCS 2011 abstract S1-2).

"We have confirmed what this trial showed initially, which was both exciting and surprising," said Dr. Gnant. "The continued success of this treatment means we can intervene early and still observe persistence of the benefit of treatment."

In the 4-arm trial, researchers randomly assigned 1,803 premenopausal patients with early-stage, estrogen receptor (ER)-positive breast cancer to receive tamoxifen or anastrozole or each of these two treatments with zoledronic acid for three years. In the initial report, presented in 2008, Gnant and his colleagues reported significantly improved disease-free survival.

Long-term data at 84 months after treatment shows a 28% reduced risk for recurrence and a 36% reduction in risk for death among patients treated with zoledronic acid. There have been no reports of osteonecrosis of the jaw or renal failure. 

Patients aged > 40 years with presumed complete ovarian blockade had a 34% reduced risk for recurrence and a 44% percent reduced risk for death. No significant survival benefits were observed among patients aged < 40 years. 

These data, considered with previously demonstrated bone-protective effects of zoledronic acid, suggest that adding zoledronic acid to adjuvant endocrine therapy including ovarian function suppression should be considered for premenopausal women with ER-positive early breast cancer, said D. Gnant.

ZO-FAST: Long-term Outcomes—Post-hoc data from the ZO-FAST (Zometa-Femara Adjuvant Synergy Trial) show that immediate initiation of zoledronic acid with letrozole led to a 34% improvement in disease-free survival (DFS) at 5 years among postmenopausal women with hormone receptor–positive early breast cancer compared to delayed initiation of zoledronic acid. Findings were reported by Richard H. de Boer, MD, of Royal Melbourne Hospital, Victoria, Australia (SABCS 2011 abstract S1-3). ZO-FAST assessed the impact of zoledronic acid (Zometa) on aromatase inhibitor-associated bone loss after surgery for early breast cancer (SABCS 2010).

The new, long-term data confirm the beneficial effects on bone mineral density (BMD). An exploratory subgroup analysis based on menopausal status indicates that zoledronic acid confers the most benefit to women who are truly menopausal at diagnosis, Dr. de Boer reported.

The study involved 1,065 postmenopausal women with hormone receptor–positive early breast cancer with a bone mineral density T score of –2. In addition to receiving adjuvant endocrine therapy with 2.5 mg of letrozole (Femara) four times daily for 5 years, the women were randomized to receive 4 mg of zoledronic acid injected intravenously every 6 months either immediately or when their post-baseline T score dipped below –2 or they suffered a nontraumatic/asymptomatic fracture.

Exploratory analyses of the 670 women who were postmenopausal for more than 5 years or older than 60 years at study entry showed that immediate zoledronic acid treatment significantly improved DFS, with a hazard ratio of 0.63, and significantly prolonged overall survival, with a hazard ratio of 0.50, compared with the delayed treatment group.

The benefits observed in BMD continued over 5 years, with a net difference of 10% favoring the immediate zoledronic acid group, Dr. de Boer said. Findings of this study, together with those of other recent studies "support the hypothesis that the anticancer benefits of zoledronic acid may best be realized in a low-estrogen environment," Dr. de Boer concluded.

Three confirmed cases of osteonecrosis of the jaw occurred during the trial, all in the immediate group.

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