This study sought to characterize the distinctive features of breast cancer in young adults and adolescents (AYA; <40 years) relative to other age groups within estrogen receptor–positive/human epidermal growth factor receptor 2–negative disease, taking into account the influence of age-related hormonal status. Patients were stratified into four age-defined groups: adolescents and young adults (AYA; 15–39 years), perimenopausal (40–54 years), menopausal (55–64 years), and older adults (≥65 years). Clinicopathological characteristics and tumor biology were interrogated through gene set variation analysis and the xCell algorithm, leveraging transcriptomic data from large publicly available cohorts of estrogen receptor–positive/HER2-negative breast cancer, including SCAN-B (n = 2,381) and METABRIC (n = 1,353). Analysis restricted to estrogen receptor–positive/HER2-negative disease demonstrated that tumors arising in adolescents and young adults were characterized by more aggressive pathological features, including increased lymph node involvement and a higher prevalence of high-grade histology (Nottingham grade 3; P < 0.001). Outcome analyses suggested poorer prognosis in this age group, with disease-specific and overall survival appearing less favorable, particularly when contrasted with patients in the perimenopausal age range. Across both METABRIC and SCAN-B cohorts, transcriptional activity related to late estrogen responsiveness showed a consistent inverse relationship with age (P ≤ 0.001). At the molecular level, tumors from younger patients displayed elevated signatures of homologous recombination deficiency, reflected by increased BRCAness and DNA repair activity relative to older counterparts (P < 0.05). Pathway-level interrogation further revealed that AYA tumors preferentially activated gene programs associated with cell cycle progression and oncogenic signaling, including mTORC1, unfolded protein response, and PI3K–AKT–mTOR cascades (P < 0.03). Interestingly, these biological patterns were also evident in small tumors (<2 cm), suggesting that tumor size alone does not account for the observed molecular aggressiveness. Immune microenvironment profiling indicated that breast cancers in adolescents and young adults harbored a distinct immune landscape, with increased infiltration of cytotoxic T lymphocytes, regulatory T cells, Th2 cells, and classically activated (M1) macrophages, alongside a relative depletion of alternatively activated (M2) macrophages (P < 0.03). In addition, somatic mutation analysis revealed age-associated differences in genomic alterations, with higher mutation frequencies in AHNAK2, GATA3, HERC2, and TG, and reduced prevalence of KMT2C mutations in AYA tumors compared with those from older patients. Among estrogen receptor–positive/HER2-negative tumors, those occurring in adolescents and young adults displayed heightened proliferative activity and a more immune-enriched microenvironment than tumors from older patients.
