Reporting complete results of the AZURE trial online in the New England Journal of Medicine on September 25, researchers concluded that the bisphosphonate zoledronic acid (Zometa [ZA]) should not be used routinely in adjuvant management of breast cancer. In what they described as an "intriguing" finding, however, small improvements in disease-free and overall survival (DFS, OS) were seen with the addition of ZA to adjuvant therapy in a subgroup of early-stage breast cancer patients who had been postmenopausal for more than 5 years.
AZURE lead investigator Robert E. Coleman, MB, BS, MD, from the Weston Park Hospital, Sheffield, United Kingdom, presented the findings at the European Multidisciplinary Cancer Congress (EMCC; abstract 5019) in Stockholm, on September 26.
In AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence), an open-label phase III study of patients from 174 cancer centers, 3,360 women with stage II or III breast cancer were randomly assigned to receive standard chemotherapy and/or endocrine therapy, with or without ZA. The ZA was given every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. DFS was the primary end point of the study. A second interim analysis showed that a prespecified boundary for lack of benefit had been crossed.
At a median follow-up of 59 months, each group had a DFS rate of 77% (adjusted hazard ratio [HR] in the ZA group, 0.98; 95% confidence interval [CI], 0.85–1.13; P = .79). Disease recurrence or death occurred in 377 patients in the ZA group, vs 375 women in the control group. OS rates of 85.4% and 83.1% were seen in the ZA and control groups, respectively (adjusted HR, 0.85; 95% CI, 0.72–1.01; P = .07).
Yet among women who had gone through menopause more than 5 years earlier (a subgroup representing about one-third of the total study population), the 5-year OS rate in the ZA group (n = 519) was 84.6% vs 78.7% in the control group (n = 522) (adjusted HR, 0.74; 95% CI, 0.55–0.98; P = .04). Among the other patients, OS rates were 85.7% in the ZA group and 85.1% in the control group (adjusted HR, 0.97; 95% CI, 0.78–1.21; P = .81). The differences were independent of estrogen-receptor status, tumor stage, and lymph-node involvement.
In their article in NEJM, the authors wrote, "In a prespecified analysis, our finding of a possible benefit of [ZA] in patients who had undergone menopause more than 5 years before study entry is intriguing…and showed a small but significant survival advantage for patients who received [ZA]. Furthermore, the use of [ZA] appeared to have divergent effects on metastasis to visceral and locoregional sites according to menopausal status." Analyses of the findings "suggest a systemic effect of [ZA] that operates differently according to menopausal status and that is distinct from any effect in bone," they said, hypothesizing that "perhaps bone provides a sanctuary for cancer cells, and after treatment with [ZA], the ability of cancer cells to disseminate to other body sites is dependent on the presence of reproductive hormones."