TP53 mutation is associated with resistance to CDK4/6 Inhibitors, but not to Immune Checkpoint Inhibitors, in ER-positive/HER2-negative Breast Cancer: Real-World perspective

Background TP53 mutation is a critical driver of breast cancer, yet its relationship with resistance to therapy for breast cancer remains unclear. This study investigates the association between TP53 mutation and response to CDK4/6 inhibitors (CDK4/6i) and immune checkpoint inhibitors (ICI) in breast cancer using real-world data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) cohort, focusing on age-related differences. Methods METABRIC (n = 1,355) was used for initial survival analysis, and Gene Set Enrichment Analysis (GSEA) was performed to identify pathways enriched in TP53-mutated ER-positive/HER2-negative breast cancers. Clinical and genomic data of metastatic breast cancer (mBC) patients in Japan were analyzed in the C-CAT (n = 1,668) cohort. Duration of treatments were used as a surrogate for treatment resistance and disease progression. Patients were stratified by age into four groups: Adolescents and Young Adults (AYA; 15–39 years), perimenopausal (40–54 years), menopausal (55–64 years), and old (65 + years). Results TP53 mutations were associated with poor prognosis in the METABRIC cohort. GSEA showed TP53-mutated tumors were enriched with gene sets related to cell proliferation and immune response, while TP53-wild type tumors enriched estrogen response pathways. In the C-CAT cohort, TP53 mutations were linked to shorter CDK4/6i treatment duration with similar trends observed for both abemaciclib and palbociclib. However, TP53 mutations were not associated with ICI treatment duration. Patients in the AYA group had the shortest treatment duration, with TP53 mutation prevalence decreasing with age. TP53 mutations were significantly associated with shorter treatment duration in perimenopausal, menopausal, and old groups but not in the AYA group, likely because various factors, not just TP53 mutations, contribute to the aggressive nature of the disease in this population. Conclusion TP53 mutation is associated with resistance to CDK4/6i, highlighting the need for personalized treatment strategies. Although TP53 mutation was not significantly associated with resistance to ICI, age-specific strategies should be considered in treatment planning.