Breast cancer (BC) exhibits age-related alterations in its biological characteristics. This study aimed to investigate the natural progression of these changes. A total of 2,383 women with clinically T0-2N0-1M0 BC, treated with primary surgery and appropriate adjuvant therapy at a specialized BC center, were included. Tissue microarrays were prepared from surgical specimens, and indirect immunohistochemistry was performed to assess a comprehensive panel of 16 relevant biomarkers. Significant decade-wise changes were observed in the expression patterns of biomarkers associated with luminal phenotypes (estrogen receptor [ER], progesterone receptor [PgR], human epidermal growth factor receptor 2 [HER2], E-cadherin, MUC1, Bcl2, CK7/8, CK18) and basal phenotypes (CK5/6, CK14, p53, Ki67), as well as in lymph node involvement, histological grade, and tumor size (p < 0.05). Ages 40 and 70 years emerged as key milestones marking shifts in these biological patterns. Older women with ER-positive tumors demonstrated significantly higher metastasis-free and breast cancer-specific survival rates, whereas no age-related differences were observed in ER-negative tumors. Overall, BC biology evolves with advancing age, with <40 years representing a phase of aggressive phenotypes, >70 years corresponding to less aggressive characteristics, and the 40–70-year range constituting a transitional phase.
