Background/Objectives: Breast cancer remains the leading malignancy affecting women worldwide, with significant mortality rates. This study aimed to evaluate the prognostic significance of FOXM1 expression specifically in hormone receptor-positive, HER2-negative (HR+HER2-) breast cancer patients with high KPNA2 expression, and to identify potential FOXM1-targeted therapeutic strategies for this patient subgroup. Methods: We analyzed RNA sequencing and microarray data from three independent cohorts: Mackay Memorial Hospital patient samples, The Cancer Genome Atlas, and Gene Expression Omnibus databases. The expression levels of KPNA2, FOXM1, CCNB1, and CCNB2 were evaluated, with particular emphasis on stratifying patients based on KPNA2 expression levels. Their associations with clinical outcomes were assessed using Gene Set Enrichment Analysis and survival analyses. Results: While KPNA2 expression showed strong positive correlations with FOXM1, CCNB1, and CCNB2 across all datasets, our analysis revealed a distinct prognostic pattern in HR+HER2- breast cancer patients with high KPNA2 expressions. In this specific subgroup, low FOXM1 expression emerged as a favorable prognostic indicator, despite the generally poor prognosis associated with high KPNA2 levels. Gene Set Enrichment Analysis demonstrated significant enrichment of the G2/M checkpoint pathway in high KPNA2-expressing patients, suggesting potential therapeutic vulnerability to FOXM1 inhibition in this subgroup. Conclusions: This study establishes FOXM1 expression as a critical prognostic marker, specifically in KPNA2-high HR+HER2- breast cancer patients, where low FOXM1 levels correlate with improved survival outcomes. These findings suggest that FOXM1 inhibition could be particularly effective in patients with high KPNA2 expression, offering a novel therapeutic strategy for this specific molecular subtype. Several FOXM1 inhibitors, including thiostrepton and FDI-6, warrant investigation as potential targeted treatments for KPNA2-high HR+HER2- breast cancer patients.

Introduction: The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor‐positive, human epidermal growth factor receptor‐2‐negative early‐stage invasive breast cancer (EBC) in a real‐world setting is uncertain. Therefore, we aimed to determine the correlation between a 22‐gene mutational profile and long‐term survival outcomes in patients with ER+/ERBB2‐ EBC.Patients and Methods: A total of 73 women diagnosed with ER+/ERBB2‐ EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse‐free survival (RFS) and overall survival (OS). The log‐rank test derived p‐value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset.Results: At follow‐up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty‐three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85‐fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60–5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6‐fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31–18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32–27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes.Conclusions: Our single‐institution tissue bank study of Taiwanese women with ER+/ERBB2‐ EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.