Age-Associated Genetic Variations in Breast Cancer: Somatic Mutations and Co-Mutations

Background/Objectives: Breast cancer (BCa) is a heterogeneous disease with molecular and genetic characteristics that significantly influence prognosis and treatment strategies. Age-related differences in tumor biology may impact therapeutic decisions; however, data on somatic mutation profiles in geriatric patients are limited. Methods: This retrospective study included 371 BCa patients (53 geriatric ≥ 65 years, 318 non-geriatric) whose clinicopathological and next-generation sequencing (NGS) data were analyzed. Immunohistochemical markers and molecular subtypes were assessed according to ASCO/CAP guidelines. Mutational profiles were obtained using the QIAseq Human BCa Panel (93 genes). Results: Among all patients, 1669 somatic mutations were detected, and 93.3% of patients harbored at least one mutation. Mutation prevalence was similar between geriatric (96.2%) and non-geriatric (92.8%) groups (p = 0.526), indicating that age did not significantly affect overall mutational burden. The most frequently mutated genes were ATR, TP53, PIK3CA, PTEN, RAD50, BLM, NF1, AR, BRCA2, and KMT2C. Notably, PIK3CA mutations were significantly more frequent in geriatric patients (28.3% vs. 23.2%, p = 0.0418). TP53 mutations correlated with higher Ki-67 proliferation indices (p = 0.035), while ATR mutations were more common in HER2-enriched subtypes (p = 0.002). Conclusions: Our findings indicate that while the overall somatic mutational load in BCa does not differ significantly with age, specific molecular alterations—particularly the enrichment of PIK3CA mutations in elderly patients—underscore the importance of integrating genomic profiling into personalized treatment planning. This study represents the first comprehensive molecular characterization of geriatric BCa patients in Türkiye, providing valuable insights for age-specific genetic profiling, treatment optimization, and future multicenter translational studies.