TP53 mutations predict poor breast cancer–specific survival in ER-positive breast cancer patients

BACKGROUND: TP53 mutations are among the most frequent genetic alterations in breast cancer and are strongly associated with aggressive tumor features and poor outcome. Although TP53 mutations occur across all major breast cancer subtypes, their prognostic significance appears to vary according to estrogen receptor (ER) status and remains incompletely defined. METHODS: Breast cancer-specific survival (BCSS) was analyzed in a population-based Icelandic cohort of 1201 patients diagnosed between 1970 and 2003. TP53 mutation status was determined using Sanger sequencing or next-generation sequencing and clinical data were collected from medical records. BCSS was analyzed using Kaplan-Meier methods and multivariable Cox regression models with follow-up through 2021. RESULTS: TP53 mutations were associated with significantly poorer BCSS, with the adverse prognostic effect confined to ER-positive disease. In multivariable analyses, ER-positive tumors harboring TP53 mutations showed a markedly increased risk of breast cancer-specific death (HR 2.68, 95% CI 1.77-4.06), whereas no independent association was observed in ER-negative tumors, with a corresponding estimate of 1.00 (95% CI 0.59 - 1.71). Among ER-positive tumors, TP53 mutation was independently associated with poorer BCSS in Luminal A disease (HR 4.99, 95% CI 1.64-15.17), while no significant association was observed in Luminal B tumors. CONCLUSION: TP53 mutation is a strong and independent predictor of poor BCSS in ER-positive cases especially in Luminal A tumors. These findings identify ER-positive tumors with TP53 mutations as a unique high-risk subgroup, highlighting the importance of TP53 status for prognostic stratification in breast cancer.