TP53 mutation is associated with shorter treatment duration with CDK4/6 inhibitors, but not with 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 treatment outcomes 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 = 1355) 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 = 1668) cohort. Treatment duration was used as a real-world surrogate endpoint reflecting treatment exposure and potential clinical benefit. 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 older (≥ 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 for 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. In age-stratified analyses, TP53 mutation was associated with shorter treatment duration in perimenopausal, menopausal, and older groups but not in the AYA group. However, formal interaction testing did not detect a significant interaction between TP53 mutation and age group. CONCLUSION: TP53 mutation is associated with shorter CDK4/6i treatment duration, highlighting the importance of considering both genomic and age-related clinical context when interpreting treatment duration in ER-positive/HER2-negative breast cancer.