Tumor hypoxia is associated with global copy-number alteration burden and subtype-dependent overall survival in breast cancer: Evidence from TCGA and METABRIC.

Tumor hypoxia is biologically important in breast cancer, but its prognostic value may be distorted by intrinsic molecular subtype composition. This study evaluated whether hypoxia-related prognosis was subtype-dependent and whether hypoxia was associated with genome-wide copy-number alteration (CNA) burden. Transcriptome-derived hypoxia scores, CNA burden, and overall survival data were analyzed from TCGA and METABRIC. Survival differences between hypoxia groups were assessed using Kaplan-Meier analysis and log-rank tests. Multivariable Cox models were used to evaluate hypoxia-related prognosis after adjustment for subtype and eligible clinical covariates. Proportional hazards diagnostics and Weibull accelerated failure time models were further applied to address potential model-assumption violations. In TCGA, the cohort-wide survival association was no longer evident after adjustment for subtype and clinical covariates. The clearest subtype-specific signal was observed in Luminal B tumors. Within this subtype, low hypoxia was associated with better survival after adjustment for age, stage, and CNA burden. In METABRIC, high hypoxia remained associated with poorer survival in Weibull accelerated failure time models. Higher hypoxia was also consistently associated with greater CNA burden across both cohorts. These findings support subtype-aware interpretation of hypoxia biomarkers and suggest a reproducible link between hypoxia and genomic instability in breast cancer.