Zoledronic Acid Prolongs Survival Only in Postmenopausal Breast Cancer Patients

Web Exclusives - Breast Cancer, In the News

SAN ANTONIO—In a trial involving women with stage II/III breast cancer (N = 3360), adding zoledronic acid (ZA) to standard adjuvant chemotherapy did not prolong overall survival (OS) or disease-free survival (DFS) after a median follow-up of 59 months, contrary to some previous reports. However, older, postmenopausal women did see a benefit when ZA was added, according to results from the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial reported at the 33rd annual San Antonio Breast Cancer Symposium. 

Participants, who had complete resection of their primary tumors and no evidence of metastases or any dental problems, were randomized to adjuvant chemotherapy with or without ZA. The ZA group received six doses of 4 mg every 3 to 4 weeks, then eight doses every 3 months, followed by five doses every 6 months, for a total of 5 years. 

Lead investigator Robert Coleman, MD, professor of medical oncology at the University of Sheffield, United Kingdom, explained that the AZURE trial tested ZA because earlier trials suggested a direct antitumor effect when combined with adjuvant chemotherapy. In addition to the drug’s effect of building bone, the investigators hypothesized that a bone-targeted drug could prevent cancer recurrence by “interrupting the vicious cycle between cancer cells and bone cells,” a biological effect now under intensive investigation. ZA was chosen because it is the most powerful of the available bisphosphonates and the most promising in preclinical studies. 

Overall, there was no significant difference between the groups in DFS or invasive DFS (hazard ratio [HR], 0.98 for each; P = .79, P = .73, respectively). Similarly, OS did not differ (HR, 0.85; P = .07). 

However, in a prespecified subgroup analysis, menopausal status was important. ZA did not benefit younger women, “but for older women who have gone through menopause, [who] will have low estrogen levels, then this treatment appears to significantly reduce recurrences and actually significantly improve survival by nearly 30%,” Coleman reported. Women more than 5 years postmenopause or older than 60 years of age receiving ZA had a 29% greater OS compared with similar controls (HR, 0.71; P = .017). 

The ZA group experienced 17 (1.16%) confirmed (P <.0001) and nine possible cases of osteonecrosis of the jaws compared with none for controls. Neutropenic sepsis affected 9.5% of each cohort.


Coleman compared the AZURE trial with the large Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12) involving younger, premenopausal women, which showed a positive benefit from ZA. On first sight, he said the results therefore look completely different from AZURE, but all women in ABCSG-12 received goserelin, “which made them menopausal, and so biologically and endocrinologically they’re actually more like our postmenopausal women.” He said the benefit seen in AZURE was almost identical to that in ABCSG-12. 

The implication is that if ZA is administered to a young woman, it should be done with ovarian suppression with goserelin or oophorectomy, Coleman advised. He said a next step is to understand the biology regarding the effects of estrogen in this treatment setting.

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Last modified: July 22, 2021