Abstract PS1-12-07: Impact of TP53 mutations on Treatment Duration with CDK 4/6 Inhibitors and Immune Checkpoint Inhibitors in ER-positive/HER2-negative Breast Cancer: Insights from Real-World Data

Abstract Background: TP53 mutation is a key driver of breast cancer. However, its clinical impact remains unclear. This study investigates the relationship between TP53 mutations and response to CDK 4/6 inhibitors (CDK4/6i) and immune checkpoint inhibitors (ICI) in breast cancer using real-world data (RWD) from the C-CAT (Center for Cancer Genomics and Advanced Therapeutics) cohort, with particular focus on age-related differences. The duration of treatment was used as a surrogate of unresponsiveness to treatment and progression of disease during treatment. Material and Methods: We used METABRIC data for initial survival analysis and performed Gene Set Enrichment Analysis (GSEA) to identify pathway enriched in TP53-mutated ER-positive/HER2-negative breast cancers. We also investigated the relationship of TP53 mutations and durations of CDK4/6i and ICI treatments in the C-CAT cohort, a database that includes clinical and genomic data of metastatic breast cancer patients from Japan. To evaluate treatment resistance in metastatic breast cancer, we used treatment duration as a clinical endpoint. The CCAT cohort was stratified by age into four groups: Adolescent and Yong Adults (AYA: 15-39 y.o.), perimenopausal (40-54 y.o.), menopausal (55-64 y.o.), and old (over 65 y.o.). Results: TP53 mutations were significantly associated with poor prognosis in ER-positive/HER2-negative breast cancer in the METABRIC cohort. GESA revealed that TP53-mutated tumors were enriched with pro-cancerous gene sets, particularly those related with cell proliferation and immune response, while TP53-wild type tumors enriched estrogen response gene sets. These findings led to investigating the impact of TP53 mutations on durations of CDK4/6i and ICI treatments. In the CCAT cohort. TP53 mutation was not associated with the duration ICI treatment. On the other hand, TP53 mutation was significantly associated with shorter duration of CDK4/6i treatment in entire ER-positive/HER2-negative breast cancer, but not in the patients who received CDK4/6i starting from late treatment phase. This trend was consistent across both Abemaciclib and Palbociclib, suggesting that TP53 mutations similarly affect treatment duration in both drugs. Further, AYA patients had the shortest treatment duration compared to the other age groups, with an earlier initiation of CDK4/6i treatment. The prevalence of TP53 mutation decreased with increasing age. When analyzing the impact of TP53 mutations by age group, TP53 mutation was significantly associated with shorter treatment duration in the perimenopausal, menopausal, and old groups, while no significant difference was found in the AYA group. Conclusion: This study demonstrated that TP53 mutation is associated with shorter duration of CDK4/6i treatment, particularly in the early stages, with similar trends observed for Abemaciclib and Palbociclib. These findings highlight the need for personalized treatment strategies based on TP53 mutation status. While the impact of TP53 mutations on ICI treatment duration was not significant, it suggests that other factors may influence ICI efficacy. Additionally, age-specific therapeutic strategies should be considered, as the impact of TP53 mutations on treatment duration varies by age group. Citation Format: M. Oshi, M. Sugimori, K. Kawashima, A. Yamada, K. Narui, T. Ishikawa, K. Takabe. Impact of TP53 mutations on Treatment Duration with CDK 4/6 Inhibitors and Immune Checkpoint Inhibitors in ER-positive/HER2-negative Breast Cancer: Insights from Real-World Data [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-07.