Abstract 3397: Survival stratification for <i>TP53</i>-mutated endometrial cancers under platinum-based chemotherapy

Background: Endometrial cancers (EC) with mutated TP53 or abnormal p53 show unfavorable clinical outcomes, with high recurrence rates, and additional chemotherapy has been considered within these patients. Genomic biomarkers may be critical to increasing the precision in developing treatment strategy for TP53-mutated EC. Methods: We applied an in-house developed targeted sequencing homologous recombination deficiency (HRD) assessment bioinformatic algorithm (GeneseeqPrime® HRD) on 529 the Cancer Genome Atlas (TCGA) EC samples, covering all exons and translocation-related introns of 437 cancer-relevant genes. The HRD score threshold to determine HRD status as well as to stratify survival outcomes under platinum-based chemotherapy, and associations of HRD status with signaling pathways and protein expression were investigated. Results: Of 529 EC samples, 18.0% was determined as HRD-positive (HRD score threshold: 38), including 85 patients carrying mutated TP53, which was associated with increased HRD scores (p&amp;lt;0.001). However, pathogenic BRCA1/2 mutations appeared to be less common in TP53-mutated EC (p=0.08). HRD-negative EC had higher tumor mutation burden (p=0.03), with more prevalent homologous recombination-related ATM, and RAD50 mutations, whereas positive HRD status was associated with higher aneuploidy score (p&amp;lt;0.001) and fraction of genome altered (p&amp;lt;0.001). Serous and endometrioid carcinomas were enriched in HRD-positive (p&amp;lt;0.001) and HRD-negative EC (p&amp;lt;0.001), respectively. HRD-positive EC exhibited higher patient age (p&amp;lt;0.001), disease stage (p=0.03), and histologic grade (p=0.04) than HRD-negative EC. Under platinum-based chemotherapy, HRD-positive TP53-mutated EC had improved progression-free survival [adjusted hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.29-1.10; p=0.09] and superior overall survival (adjusted HR, 0.49; 95% confidence interval (CI), 0.24-1.00; p=0.05) compared to HRD-negative patients, when adjusting for clinical characteristics and molecular subtypes. Suppressed p53, Hedgehog, and hippo signaling pathways were observed in HRD-positive EC with TP53 mutations (p.adjust &amp;lt;0.05). Additionally, MAPK14 (p&amp;lt;0.001) and PIK3CA (p&amp;lt;0.001) expression were significantly associated with higher HRD score. Conclusions: HRD status may identify patients with TP53-mutated EC who could get survival benefits from platinum-based chemotherapy. Further research is required to determine the utilization of HRD assessment in EC receiving PARP inhibitors. Citation Format: Xiaotian Zhao, Haimeng Tang, Xue Wu, Qiuxiang Ou. Survival stratification for TP53-mutated endometrial cancers under platinum-based chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3397.