Zoledronic Acid Benefit in Early Breast Cancer Varies by MAF Status

Women with early breast cancer have varying outcomes with zoledronic acid treatment depending on MAF positivity, according to the AZURE trial.

Women with early breast cancer have varying outcomes with zoledronic acid treatment depending on MAF positivity, according to the AZURE trial. MAF-negative patients appear to derive benefit from the bisphosphonate therapy, while MAF-positive patients have poorer outcomes with this treatment.

MAF is a biomarker of bone relapse in early breast cancer, and it regulates expression of genes that support breast cancer cell metastasis. “These observations suggest that MAF amplification in tumors could be a way to identify patients at high risk of metastasis,” wrote study authors led by Robert Coleman, MD, MBBS, of Weston Park Hospital in Sheffield, United Kingdom.

The AZURE trial included 865 women; all had stage II or III breast cancer and were randomized to either a control group receiving standard adjuvant systemic therapy alone (445 patients), or to a group receiving that therapy along with zoledronic acid (420 patients) every 3 to 4 weeks for 6 doses and then every 3 to 6 months until the end of 5 years. MAF amplification was assessed by fluorescence in situ hybridization. Results of the study were published in Lancet Oncology.

A total of 184 patients (21%) had MAF-positive tumors, with 85 in the control group and 99 in the zoledronic acid group. The median follow-up was 84.6 months, after which 147 control patients and 135 zoledronic acid patients had an invasive disease–free survival (iDFS) event; the 5-year rate was 74.1% with zoledronic acid and 73.7% without it.

In the control group, MAF status was not significantly associated with iDFS, with a hazard ratio (HR) favoring MAF-negative patients of 0.92 (95% CI, 0.59–1.41). However, only among postmenopausal women in the control group did MAF-negative patients fare better in terms of iDFS, with an HR of 0.47 (95% CI, 0.25–0.88).

The effect of MAF status was more pronounced in the zoledronic acid group, where all patients had an HR for iDFS of 0.52 (95% CI, 0.36–0.75). This was similar for both postmenopausal women and non-postmenopausal women receiving zoledronic acid.

In MAF-positive patients, there was no association between zoledronic acid use and iDFS. In MAF-negative patients, however, there was a significant benefit with the bisphosphonate, with an HR of 0.74 (95% CI, 0.56–0.98).

Specifically among the 121 patients who were not postmenopausal at randomization and who had MAF-positive tumors, zoledronic acid was actually associated with poorer iDFS, with an HR of 2.47 (95% CI, 1.23–4.97), as well as with poorer overall survival, with an HR of 2.27 (95% CI, 1.04–4.93).

“Our findings suggest that MAF status could become a clinically useful biomarker for selection of patients who will benefit from adjuvant zoledronic acid,” the authors wrote. “Women with MAF-negative tumors are likely to represent almost 80% of those with breast cancers who could benefit from the use of adjuvant zoledronic acid.”

In an accompanying editorial, Luís Costa, MD, PhD, and Arlindo R. Ferreira, MD, both of the University of Lisbon in Portugal, wrote that validation in an independent cohort and further research in this field are needed. Still, they added that “creation of a standard test for MAF amplification status could be clinically helpful to exclude patients with early breast cancer receiving zoledronic acid and potentially other bisphosphonates.”