Abstract A017: Prevalence and significance of common molecular alterations in Tp53-mutated uterine serous carcinoma

Abstract Background: Uterine Serous Carcinoma (USC) is an aggressive subtype of endometrial cancer characterized by ubiquitous TP53 mutations and high replication stress. The resulting dependency on DNA damage repair and cell cycle checkpoints triggers sensitivity to the abrogation of the G2 checkpoint using Wee1 inhibitors (Wee1i) such as Azenosertib. Wee1i sensitivity has been associated with high levels of Cyclin E1, which may result from gene amplification of CCNE1 or the alteration of its ubiquitin ligase FBXW7 1. In addition, signaling activity of Wee1 is controlled by the PP2A protein phosphatase2, the regulatory subunit of which, PPP2R1A, is frequently mutated in USC. Comprehensive molecular profiling has only been performed in a limited number of cohorts and the distribution and relationship of these candidate biomarkers to one another and other molecular alterations is unclear. Methods: Genomic and phenotypic data from TP53-mutated USC were collected from TCGA-pancancer (N=95), AACR-GENIE v13 (N=796) or Azenosertib studies (N=46). The mutational status of 6 mutated genes and 1 gene set (HRR; N=14 genes) was determined from pathogenic alterations. The prevalence of altered genes was measured accounting for variable gene inclusion for each assay. Cross-cohort prevalence or gene-pair mutual exclusivity and co-occurrence were measured using Fisher exact test. Results: The prevalence of alterations in TCGA, AACR-GENIE and Azenosertib cohorts were similar for PIK3CA (37%, 34%, 28%), FBXW7 (21%, 17%, 8%), PPP2R1A (37%, 30%, 29%), PIK3R1 (13%, 12%, 8%), HRR genes (7%, 7%, 15%), or amplification of ERBB2 (19%, 14%, 9%). In contrast, prevalence of CCNE1 amplification in TCGA was significantly higher (27% vs 16% and 7%), which could reflect differences in patient population or methodology. Of all 28 combinations, no gene pairs were significantly co-mutated and only FBXW7 and PPP2R1A were mutually exclusive in both TCGA and AACR-GENIE. The prevalence of the corresponding co-alterations was similar between cohorts: mutated in both (3% in both), neither (45% and 57%), FBXW7 only (18% and 13%) or PPP2R1A only (34% and 27%). Furthermore, alterations in genes encoding components of the PI3K enzyme (PIK3CA or PIK3R1) affected 45% of the patients in either cohort. None of the mutational status or derived subtypes had prognostic value (TCGA). Similarly, apart from CCNE1 amplification, none of the subtypes evaluated were associated with Cyclin E1 expression as measured by reverse phase protein array (TCGA) or immunohistochemistry (Azenosertib studies). Conclusion: Important processes related to CCNE1, FBXW7 and PPP2R1A function have been associated with high replication stress and Wee1i sensitivity. Our analyses suggest that alterations in these genes are common and sometimes mutually exclusive, leading to broad genomic instability across USC and suggesting an explanation for the clinical efficacy that has been seen with Azenosertib and other Wee1i. Citation Format: Olivier Harismendy, Jianhui Ma, Adrian M. Jubb, Carrie Brownstein, Mark R. Lackner, Ramez N. Eskander, Joyce Liu, Shannon N. Westin. Prevalence and significance of common molecular alterations in Tp53-mutated uterine serous carcinoma abstract. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30 (5Suppl): Abstract nr A017.