Multi-dimensional assessment of tumor hypoxia, survival outcomes, and molecular stratification in breast cancer using computational skills

Tumor hypoxia plays a critical role in cancer progression and treatment resistance, and gene expression-based scoring systems such as Buffa, Ragnum, and Winter have been developed to quantify hypoxia levels. Under-standing the relationship between hypoxia, survival outcomes, and clinical stratifiers like molecular subtype and race is essential for advancing personalizedcare in breast cancer. Hypoxia scores were analyzed across tumor stages using Buffa, Ragnum, and Winter models. Kaplan-Meier survival analysis evaluated the prognostic impact of high versus low Buffa scores on progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS). Stratified analyses were conducted by molecular subtype, AJCC stage, and race. Pearson correlation measured concordance among hypoxia scores. Microsatellite instability (MSI) was assessed using MANTIS and MSI Sensor scores, and their association with genomic instability (Fraction Genome Altered) was explored. Buffa and Winter scores revealed higher hypoxia in inter- mediate stages (IIA, IIB), whereas Ragnum showed more uniform levels. Elevated Buffa scores were significantly associated with worse PFS, DFS, and DSS. Lumi- nal A subtype had better prognosis than Basal-like and Luminal B; advanced stages an Black or African American patients showed poorer outcomes. Strong correlations were found among hypoxia scores (r = 0.65–0.88). Most tumors were microsatellitestable, but a subset with high MSI Sensor scores also showed increased genomic alterations. Hypoxia levels vary by stage and scoring system and are strongly linked to survival outcomes. Molecular subtype, tumor stage, and race significantly affect prognosis, emphasizing the need for multidimensional stratification. Hypoxia scores are concordant and useful, and MSI may contribute to genomic instability in specific subgroups of breast cancer. Received: 10th August 2025Accepted: 11th September 2025.