Despite endocrine therapy (ET), approximately 20-40% of Stage I-III estrogen receptor-positive breast cancer (ER + BC) patients experience recurrence. Recurrence while on ET is indicative of ET resistance. This study aimed to identify differentially expressed genes (DEGs) associated with recurrence during ET (ET resistance) and to explore gene expression differences across PAM50 molecular subtypes. Eighty tumor specimens from 79 patients treated at the City of Hope Comprehensive Cancer Center (2012-2016) were analyzed using NanoString technology. Fourteen patients (17.7%) experienced recurrence over a median follow-up of 68 months (range 35-104 months). Key upregulated DEGs in the recurrence group included EZH2 (log2 fold change[log2FC]: 0.67, p = 0.0017), WNT11 (log2FC: 1.08, p = 0.0088), ITGB6 (log2FC: 0.80, p = 0.0312), and TOP2A (log2FC: 0.79, p = 0.0381). Downregulated DEGs included SNAI2 (log2FC: - 0.63, p = 0.0055), ITPR1 (log2FC: - 0.75, p = 0.0083), CD10 (log2FC: - 0.70, p = 0.0092), PTEN (log2FC: - 0.29, p = 0.0163), VRD (log2FC: - 0.46, p = 0.0184), and WNT5A (log2FC: - 0.76, p = 0.0272). EZH2 and TOP2A were positively correlated with proliferation scores, while WNT11 and ITGB6 emerged as potential biomarkers independently associated with recurrence. These findings suggest novel biomarker candidates that could help overcome ET resistance, reduce recurrence, and improve outcomes in ER + BC.