Abstract P1-17-01: Long term survival benefits of adjuvant zoledronic acid associated with maf status of primary tumor
Authors: Coleman R , Gregory W , Jean-Mairet J , Tercero JC , Torres-Martin J , Gomis R 
Published: May 2019

Background: Meta-analysis of clinical trials has shown that adjuvant bisphosphonates reduce bone metastases and improve survival in postmenopausal (PM) breast cancer and are now recommended for routine clinical use by international guidelines1. However, evaluation of menopause is imprecise and the biological rationale for lack of benefit in premenopausal women unclear. To address this, the biomarker, transcription factor MAF on 16q23 was tested retrospectively in the prospective randomized AZURE trial of standard adjuvant therapy +/- zoledronic acid (ZOL). Initial evaluation indicated that women with MAF negative tumors treated with ZOL had a lower rate of disease relapse irrespective of menopausal status.2 Here we present the long-term findings of this predictive biomarker on 10 year overall survival.

Materials and methods: The biomarker analysis was completed on TMAs from primary tumors. Quadruplicate cores of breast tumor tissue were arrayed across replicate TMAs. MAF+ was detected using a validated (MAF/D16Z3) FISH test (Inbiomotion SL, Spain). A central laboratory (Targos, Germany) validated the assay for analytic and diagnostic performance, established acceptance criteria, included appropriate quality controls for each assay, and performed the analyses in a blinded fashion. A copy number cut-off ≥2.5 was preset for MAF+ for both prognostic and predictive testing. Interactions between MAF+ and effects of ZOL on Invasive disease free (IDFS), overall (OS) survival and time to bone metastases by menopausal status were evaluated using a Cox proportional hazards model.

Results: 1769 of the 3360 AZURE pts donated primary tumor samples. Median follow-up was 117 (interquartile range 70.4-120) months. 865 pts (49%) had 2 FISH evaluable cores and were included in the analysis. These pts had similar disease and treatment characteristics to the overall study population as well as similar IDFS and OS at 10 years. 184 (21%) had MAF+ tumors and these tumors were more likely to be of higher grade, ER-ve and HER2+. In 680 pts with MAF- tumors, ZOL was associated with improved IDFS (HR=0.75; 95%CI:0.58-0.97, [P=0.02]), reduced relapse in bone (HR=0.65; 95%CI:0.45-0.94, [P=0.022] and, most importantly, better OS (HR=0.69; 95%CI:0.50-0.94, [P=0.019]). In the 185 patients with MAF+ tumors, there was a suggestion of worse outcome (IDFS HR=1.54; 95%CI:0.96-2.47 and OS HR 1.40; 95%CI:0.83-2.33), with a strong interaction between treatment effects and menopausal status. Outcomes in ZOL treated MAF+ pts who were non-PM appeared to be much worse (IDFS HR=2.31; 95%CI:1.18-4.42] and OS HR=2.28; 95%CI:1.07-4.82) due predominantly to an excess of extra-skeletal metastases in ZOL treated patients (HR=4.47; 95%CI:1.66-12.57).

Conclusions: Adjuvant ZOL significantly improved disease outcomes in 79% of patients with MAF negative tumors, irrespective of menopausal status and other clinico-pathologic features. Conversely, more extra-skeletal metastases and breast cancer deaths were seen in women with MAF+ tumors who were not PM at the start of treatment. If validated in ongoing studies, the MAF FISH test could provide a clinically useful biomarker for selection of patients for adjuvant bisphosphonate treatment.

1EBCTCG, Lancet 2015; 2Coleman RE et al, Lancet Oncol 2017

Citation Format: Coleman R, Gregory W, Jean-Mairet J, Tercero JC, Torres-Martin J, Gomis R. Long term survival benefits of adjuvant zoledronic acid associated with maf status of primary tumor [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-01.