MAF Amplification and Outcomes With Adjuvant Zoledronic Acid in Early Breast Cancer

Key Points

  • In patients with early breast cancer, MAF-negative status was associated with a better outcome in the zoledronic acid group.
  • Outcome was poorer among patients with MAF-positive status in the zoledronic acid group, particularly among nonpostmenopausal women. 

An analysis from the phase III AZURE trial has shown that MAF-negative status was associated with a benefit and MAF-positive status, with a detriment of adjuvant zoledronic acid in early breast cancer. The analysis was reported by Coleman et al in The Lancet Oncology.

Study Details

The current study included patients from UK sites who had stage II or III breast cancer who gave consent for use of their primary tumor samples. In the trial, patients were randomized to receive standard adjuvant systemic therapy alone or with zoledronic acid every 3 to 4 weeks for six doses and then every 3 to 6 months for up to 5 years. The primary endpoint for the current analysis was invasive disease–free survival. MAF amplification was assessed by fluorescence in situ hybridization of two cores of breast tumor tissue in a microarray in a blinded central laboratory.

Among the 1,739 AZURE patients contributing primary tumor samples, 865 (50%) had 2 assessable cores, including 445 in the control group (328 nonpostmenopausal at randomization, 137 postmenopausal) and 420 (282 nonpostmenopausal at randomization, 138 postmenopausal) in the zoledronic acid group. Among these patients, 184 tumors (21%) were MAF-positive, including 85 in the control group and 99 in the zoledronic acid group.

Impact of MAF Status

At a median follow-up of 84.6 months, MAF-negative vs MAF-positive status was prognostic for invasive disease–free survival in the zoledronic acid group (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.36–0.75) but not in the control group (HR = 0.92, 95% CI = 0.59–1.41) among all patients. However, in the control group, nonpostmenopausal patients with MAF-positive tumors had longer invasive disease–free survival than nonpostmenopausal patients with MAF-negative tumors (HR = 1.58, 95% CI = 0.82–3.03), whereas postmenopausal women with MAF-negative tumors had a better outcome than those with MAF-positive tumors (HR = 0.47, 95% CI = 0.25–0.88). In the zoledronic acid group, hazard ratios were similar for benefit in patients with MAF-negative tumors both among nonpostmenopausal patients (HR = 0.54, 95% CI = 0.34–0.84) and postmenopausal patients (HR = 0.47, 95% CI = 0.23–0.94).

Overall, invasive disease–free survival was greater in the zoledronic acid than in the control group among patients with MAF-negative tumors (HR = 0.74, 95% CI = 0.56–0.98) but was nonsignificantly better in the control group vs zoledronic acid group among those with MAF-positive tumors (HR = 1.34, 95% CI = 0.83–2.14). Among 121 nonpostmenopausal patients with MAF-positive tumors, zoledronic acid was associated with poorer invasive disease–free survival (HR = 2.47, 95% CI = 1.23–4.97) and overall survival (HR = 2.27, 95% CI = 1.04–4.93) vs control treatment.

The investigators concluded: “Our findings suggest that MAF status could become a clinically useful biomarker for selection of patients who will benefit from adjuvant zoledronic acid. Women with MAF-negative tumours are likely to represent almost 80% of those with breast cancers who could benefit from the use of adjuvant zoledronic acid. MAF positivity seemed to be associated with adverse disease outcomes when women were treated with zoledronic acid, especially if treatment was started in women not definitely postmenopausal, and we recommend that exposure to bisphosphonates should be avoided in such women in the adjuvant setting.”

The study was funded by Novartis Global and Inbiomotion.

Robert Coleman, FRCP, of the Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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