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

<b>Background/Objectives:</b> 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. <b>Methods:</b> 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). <b>Results:</b> 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 (<i>p</i> = 0.526), indicating that age did not significantly affect overall mutational burden. The most frequently mutated genes were <i>ATR</i>, <i>TP53</i>, <i>PIK3CA</i>, <i>PTEN</i>, <i>RAD50</i>, <i>BLM</i>, <i>NF1</i>, <i>AR</i>, <i>BRCA2</i>, and <i>KMT2C</i>. Notably, <i>PIK3CA</i> mutations were significantly more frequent in geriatric patients (28.3% vs. 23.2%, <i>p</i> = 0.0418). <i>TP53</i> mutations correlated with higher Ki-67 proliferation indices (<i>p</i> = 0.035), while <i>ATR</i> mutations were more common in HER2-enriched subtypes (<i>p</i> = 0.002). <b>Conclusions:</b> 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 <i>PIK3CA</i> 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.