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

Abstract

Novartis Global and Inbiomotion.

Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer

“…Although zoledronate is advantageous in terms of preventing skeletal metastasis in DOCK4 high patients, it may also remove a potentially advantageous effect for non-skeletal metastases. Although our data do not point to any particular mechanistic explanation for this effect, it is possible that zoledronate may have effects other than on the skeleton and, in this respect, we note the negative impact of zoledronate on overall survival in premenopausal women recently reported, where in non-postmenopausal patients with MAF-positive tumours, zoledronate was associated with worse invasive DFS and overall survival [28]. Clearly, these factors need to be borne in mind in the consideration of DOCK4 as a predictive biomarker for zoledronate response in bone metastasis prevention.…”

Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial

“…Using primary tumor tissue from patients in the AZURE study, we showed that a novel composite biomarker comprising the proteins CAPG and GIPC1 was prognostic for developing bone metastasis (HR = 4.5, 95% CI = 2.1 to 9.8, P < .001) and predicted response to zoledronate ( P = .008) ( 21 ). In another study, amplification of the 16q23 chromosomal region, including amplification of the MAF gene ( 22 ), was predictive of breast cancer metastasis to bone ( 23 ). However, there remains a need for a simple blood-based test in early breast cancer that can identify patients with a high risk for development of bone metastasis.…”

Application of “omics” sciences to the prediction of bone metastases from breast cancer: State of the art

“…Interestingly, this CNV was also tested in an independent validation set of 334 primary BC patient samples, and the presence of at least 1.5 copies of the region, normalized to the CEP16 centromeric probe, significantly correlated with BM occurrence at any time (hazard ratio, HR = 14.5, 95% CI = 6.4 to 32.9, p < 0.001) [55] . Moreover, MAF over-expression was associated with high-risk primary tumour features and worse prognosis in pre-menopausal BC patients enrolled in the zoledronate arm of AZURE clinical trial, further confirming the potential utility of this molecular alteration in the management of BC [56] ( Table 1 ).…”

“… PUTATIVE BIOMARKERS TECHNIQUE OF BIOMARKER INVESTIGATION VALIDATION ON CELL LINES OR CLINICAL SAMPLES MAJOR MECHANISMS OF BM REGULATION REFERENCES ND NGS mutational analysis of 50 commonly mutated cancer-related genes 389 BC patients ND [54] MAF Oligonucleotide Array Assays and FISH Bone-homing human BC cell lines 334 primary BC Control of tumour cell/bone stroma interaction; regulation of cell adhesion, migration and osteoclast differentiation; regulation of PTH-rP expression. [55] FISH 1739 BC patients enrolled in AZURE clinical trial [56] 102-gene signature, including CXCR4, FGF5, CTGF, IL11, MMP1, FST, ADAMTS1, PRG1 (fold change > 4) Microarray analysis MDA-MB-231 human BC cell subclones divided in weakly and highly metastatic to bone Modulation of tumour cell invasion, angiogenesis, bone-homing, osteoclastogenesis and osteoclast activation [57] 31-gene signature Microarray analysis Human B02 BC cells derived from BM caused by MDA-MB-231 cells Osteoblast differentiation [58] APOPEC3B, ATL2, C6orf61, C6orf167, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PGD5, SFT2D2, STEAP, NAT1, BBS1, PH-4. Microarray analysis 157 metastatic BC patients + a dataset of 376 BC used as validation cohort EMT, invasion/migration, bone-homing [47] IL-1B RT-PCR IHC Bone-homing sub-clone of MDA-MB-231 cells; 150 primary BC Bone homing [59] RT-PCR MDA-MB-231 human BC cell line; 1300 patients included in AZURE clinical trial promotion of EMT, invasion, migration, and bone homing [60] IL-6 gene signature Microarray analysis RT-PCR Co-culture of MDA-MB231 BC cell line with osteoblast; 295 early stage BC from Netherlands Cancer Institute osteoclast activation, BC stem cell biology [62] ZNF217 gene signature RT-PCR 113 wome...…”