Adjuvant bisphosphonates were shown to reduce bone recurrence and improve survival in postmenopausal patients with early breast cancer. Current guidelines recommend menopausal status as a key factor to select patients who will likely benefit from adjuvant bisphosphonates, though the definition and timing of menopause for some patients may be imprecise and there is no clear biological rationale why benefit is limited to postmenopausal patients.
MAF is a transcription factor that controls the expression of several genes involved in bone metastases in breast cancer, and has been identified as a potential predictor of bone relapse. To determine the link between MAF amplification and outcomes on zoledronic acid treatment, MAF amplification was tested retrospectively in the cohort of patients with available primary tumor samples in the large randomized phase III AZURE trial of standard adjuvant therapy with or without zoledronic acid. Of 1739 patients, 865 (50%) patients had sufficient tumor sample (≥2 cores) for MAF amplification analysis by fluorescence in-situ hybridization (FISH). MAF-positive tumors were detected in 184 patients (21%), including 85 in the control group and 99 in the zoledronic acid group. MAF-positive tumors were more likely high grade, ER negative, and HER2 positive than MAF-negative tumors.
At a median follow-up of 84.6 months, MAF-negative versus MAF-positive status was prognostic for invasive disease-free survival (iDFS) in the zoledronic acid group (HR 0.52), but not in the control group (HR 0.92). Similar impact of MAF status was observed for overall survival (OS).
While use of zoledronic acid was associated with improved iDFS and OS regardless of menopausal status or age in patients with MAF-negative tumors, this was not the case for MAF-amplified tumors. Furthermore, treatment with zoledronic acid in MAF-positive non-postmenopausal patients at the start of study was associated with increased rates of invasive disease, including extraskeletal metastases and a lower iDFS (HR 2.47) and OS (HR 2.27) compared to patients who did not receive zoledronic acid.
In their conclusion, the investigators highlighted that MAF status could become a clinically useful biomarker for selection of patients who will benefit from adjuvant zoledronic acid. However, before MAF testing can be applied in routine practice it needs to be evaluated in another adjuvant bisphosphonate trial. Analysis of the NSABP B-34 tumor bank and dataset is planned. In a commentary accompanying the analysis of the AZURE trial, the authors agreed that if validated, a standard test for MAF amplification could be helpful to guide selection of zoledronic acid and potentially other bisphosphonates in patients with early breast cancer, particularly if they are premenopausal.