Abstract
BackgroundThe glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer. We previously found that methylation of the GR promoter CpG island represses gene expression and occurs in ER+ breast tumors. In this study, the prognostic and predictive value of GR methylation was examined in ER+ patients from the CCTG MA.12 clinical trial of tamoxifen versus placebo in women with early breast cancer.MethodsWe developed a targeted multiplex bisulfite next-generation sequencing assay to detect methylation at multiple GR promoter regions in DNA from formalin-fixed paraffin-embedded (FFPE) samples. Following validation in a small cohort of breast tumors, ER+ FFPE tumor samples from MA.12 (n = 208) were tested. Survival analyses evaluated the impact of GR promoter methylation on patient overall survival (OS) and disease-free survival (DFS).ResultsAn analysis of TCGA data found that GR methylation is prevalent in ER+ tumors and is associated with decreased gene expression and analysis of public microarray data (KM Plotter) linked decreased GR expression to a poor outcome. In MA.12, two GR promoter regions (U and C) each had prognostic value, but with opposite effects on the outcome. U methylation was associated with poor OS (HR = 1.79, P = 0.041) whereas C methylation was associated with better OS (HR = 0.40, P = 0.040) and DFS (HR = 0.49, P = 0.037). The classification of patients based on the methylation status of the two regions was prognostic for OS (P = 0.006) and DFS (P = 0.041) and revealed a group of patients (U methylated, C unmethylated) with very poor outcomes. Placebo-treated patients in this high-risk group had worse OS (HR = 2.86, P = 0.002) and DFS (HR = 2.09, P = 0.014) compared to the rest of the cohort.ConclusionRegion-specific GR promoter methylation was an independent prognostic marker for patient survival and identified a subset of patients with poor prognosis, particularly without tamoxifen treatment. These findings provide a foundation for future studies into GR methylation as a promising prognostic biomarker in ER+ breast cancer.
Highlights
The glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer
Given that methylation influences GR expression and that low GR-expressing tumors have been associated with poor relapse-free survival in ER+ tamoxifen-treated patients [13, 18], we propose that GR methylation may act as a biomarker for increased relapse risk and/or poor survival
We developed a multiplex bisulfite sequencing assay for detecting GR promoter methylation and used it to investigate the prognostic and predictive significance of GR methylation in a cohort of ER+ patients from a placebo-controlled trial of adjuvant tamoxifen in premenopausal women with early breast cancer (CCTG MA.12)
Summary
The glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer. Several multigene expression profiling assays have been developed as prognostic tools for the ER+ patient population including OncotypeDX, Prosigna (PAM50-based), and Mammaprint, all of which are in clinical use [2, 7, 8]. These tests further stratify ER+ patients by recurrence risk, their primary utility is to identify individuals who can safely be spared chemotherapy and they do not usually influence endocrine therapy treatment decisions [2, 7, 8]. Due to the limitations of current prognostic and predictive tools, there is an urgent need for the development of robust markers that can predict patient response to therapy prior to them undergoing treatment, allowing for timely interventions to minimize their risk of relapse and maximize survival
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
