Genomic and clinical features in young women with estrogen receptor-positive, HER2-negative breast cancer

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BACKGROUND: Young women (≤40 years at diagnosis) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC) represent a high-risk group with distinct biological features. Conventional biomarkers, such as Ki67 and immunohistochemistry (IHC)-based subtypes, are not validated in this population. This study assessed the prognostic value of clinical and genomic biomarkers and explored age-related clinicopathological and gene expression differences. PATIENTS AND METHODS: A retrospective cohort of 658 patients with ER-positive, HER2-negative EBC who underwent genomic risk testing between 2015 and 2023 at a single institution was analyzed. Patients were stratified by age at diagnosis: ≤40 years (n = 81), 41-50 years (n = 232), and >50 years (n = 345). Clinical data, treatments, and outcomes were assessed. Prediction Analysis of Microarray 50/Prosigna was used to determine intrinsic subtypes and risk of recurrence (ROR); The Cancer Genome Atlas data were used for validation. Survival analyses included Kaplan-Meier, log-rank, and Cox models. RESULTS: Young patients at diagnosis (age ≤40 years) had more locally advanced tumors, higher Ki67, and a greater prevalence of luminal B subtype. Clinical and IHC markers poorly predicted ROR; notably, 50% of Ki67 <10% tumors in young women were ROR high-risk. Five-year disease-free survival (DFS) was lower in young patients (82.8%) compared with older groups (90.5% and 92.8%, respectively; P = 0.042). Among IHC luminal A-like tumors, young age was associated with increased recurrence risk [hazard ratio (HR) 5.75, P < 0.001]. ROR score was independently prognostic in young women (HR 3.12, P = 0.004). Gene expression revealed lower estrogen-related and higher basal-like gene levels in younger patients. CONCLUSION: Young women with ER-positive, HER2-negative EBC have poorer outcomes. Ki67, in particular, is a poor prognostic marker in this group. Genomic profiling improves risk stratification and highlights unique tumor biology, supporting personalized treatment strategies.