Work

Primary Tumor Epigenetic and Transcriptomic Alterations Associated with Nodal Burden and Metastatic Risk in ER+/HER2− Breast Cancer

Year: 2026

Type: article

Abstract: De-escalation of axillary surgery in breast cancer (BC) reduces surgical morbidity but limits pathological assessment of nodal burden, a key determinant of prognosis and adjuvant therapy in estrogen receptor-positive (ER+)/HER2- BC. Tumor-intrinsic biomarkers that reflect the extent of lymph node disease may help bridge this gap. We performed genome-wide DNA methylation profiling of primary tumors from patients with ER+/HER2- BC stratified by pathological nodal stage (1-3 positive nodes, pN1; 4 or more positive nodes, >pN1). Findings were validated across multiple independent cohorts (TCGA-BRCA, SCAN-B, AURORA US), integrating molecular and clinical data. Forty-seven tumors passed EPIC quality control (pN1: n=29; >pN1: n=18). Tumors with >pN1 disease showed epigenetic reprogramming, including promoter hypermethylation and suppression of genes in pathways related to development and cell adhesion. Across datasets, five genes (TTC23, ARL10, RIC3, CXCL14, KCNH2) were consistently associated with nodal involvement and outcomes. Based on these genes, we developed the LION (Lymph-node Involvement Outcome Numerator) score, which distinguishes tumors with >pN1 disease and is associated with worse distant metastasis-free survival across cohorts. The LION score represents a biologically informed molecular metric associated with nodal involvement in ER+/HER2- BC. These findings provide insight into tumor-intrinsic epigenetic programs linked to dissemination.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27177901