High Impact Mutation Burden and Integrated Genomic Instability Reveal Subtype-Specific Divergence in Breast Cancer

Genomic instability (GI) is a defining feature of cancer, yet its clinical role in breast cancer remains uncertain. Tumor mutational burden (TMB), high-impact mutation burden (HIMB), and aneuploidy are widely studied, but their relative contributions to prognosis versus therapy prediction have not been systematically compared. We analyzed 1,084 breast cancers from The Cancer Genome Atlas, quantifying TMB, HIMB, and aneuploidy across molecular subtypes. Associations with overall survival were tested using Kaplan–Meier and multivariable Cox models, adjusting for established clinical covariates. Subtype-specific correlations between GI metrics were also examined. Although TMB, HIMB, and aneuploidy were interrelated, their prognostic value was limited once age and stage were included in multivariable models. Importantly, the relationship between TMB and aneuploidy diverged by subtype, positive in basal-like tumors but negative in luminal cancers, revealing context-dependent GI prevalence. HIMB, a measure of functional mutation burden, highlighted subtype-specific enrichment of TP53 and PIK3CA alterations. GI metrics are not robust prognostic markers in breast cancer, but they capture subtype-dependent biological states with potential predictive relevance for targeted and immune therapies. This benchmark analysis clarifies the distinction between prognostic and predictive roles of GI, providing a framework for future precision oncology studies.