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Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: A secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial

The Lancet Oncology Oct 19, 2017

Coleman R, et al. - This study was performed to assess whether MAF amplification (a biomarker for bone metastasis) in primary tumours could predict the treatment outcomes of adjuvant zoledronic acid. As per findings, researchers interpreted that likelihood of benefit from adjuvant zoledronic acid could be predicted with MAF status. Thus they advocated its further investigation as a potential companion diagnostic.

Methods

  • Researchers recruited patients enrolled in the international, open-label, randomised, controlled, phase 3 AZURE trial at eligible UK sites who had stage II or III breast cancer and who gave consent for use of their primary tumour samples.
  • They assigned patients randomly (1:1) to receive standard adjuvant systemic therapy alone (control group) or with zoledronic acid every 3–4 weeks for six doses, then every 3–6 months until the end of 5 years.
  • In this study, minimisation considered the number of involved axillary lymph nodes, clinical tumour stage, oestrogen-receptor status, type and timing of systemic therapy, menopausal status, statin use, and treating centre.
  • Disease-free survival was observed as the primary end point.
  • For this study, the secondary endpoint, invasive-disease-free survival, was the primary disease endpoint for the analysis.
  • Using fluorescence in-situ hybridisation of two cores of breast tumour tissue in a microarray, performed in a central laboratory by technicians unaware of treatment assignment, MAF amplification was assessed.
  • Multivariate analyses were used to assess disease outcomes by intention to treat.
  • Interactions between MAF-positive status and menopausal status on efficacy of zoledronic acid were also assessed.

Results

  • Primary tumour samples included 1739 AZURE patients, 865 (50%) of these had two assessable cores (445 in the control groups and 420 in the zoledronic acid group).
  • MAF positivity was observed in 184 (21%) tumours (85 in the control groups and 99 in the zoledronic acid group) and the remaining tumours were MAF negative.
  • Findings revealed that at a median follow-up of 84.6 months (IQR 72.0–95.8), MAF status was not prognostic for invasive-disease-free survival in the control group (MAF-positive vs MAF-negative: hazard ratio [HR] 0.92, 95% CI 0.59–1.41), but was in the zoledronic acid group (0.52, 0.36–0.75).
  • In patients with MAF-negative tumours, there appeared an association of zoledronic acid with higher invasive-disease-free survival in comparison to control treatment (HR 0·74, 95% CI 0.56–0.98), but such an association was not evident in patients who had MAF-positive tumours.
  • In addition, among 121 patients not postmenopausal at randomisation with MAF-positive tumours, zoledronic acid seemed correlated with lower invasive-disease-free survival (HR 2.47, 95% CI 1.23–4.97) and overall survival (2.27, 95% CI 1.04–4.93) than control treatment.

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