The majority of breast cancer patients have tumors expressing estrogen receptor α (ER) and are treated with adjuvant endocrine therapy. However, nearly one-third relapse, most with retained ER expression.

This study investigated patients with ER-positive and human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer. Patients with ER-positive relapses within five years of ongoing endocrine therapy were defined as endocrine-resistant (N = 69). Patients with no disease progression after 10 years were defined as endocrine-sensitive (N = 77). RNA was extracted from archived tumor blocks, followed by gene expression analysis.

Significant differences were observed with higher tumor grades, intrinsic subtype risk scores, and upregulated cell-cycle gene sets in resistant compared to sensitive patients’ primary tumors. Metabolism-associated gene sets were upregulated, and estrogen-response gene sets downregulated in resistant patients' relapse compared to primary tumors.

This study highlights gene sets associated with endocrine resistance and identifies transcriptomic and clinicopathological profiles that may serve as potential prognostic markers for therapy response.