Introduction/Background Genomic instability has been identified in a subgroup of endometrial cancers (EC) that are predominantly TP53 mutated (TP53mut) with high degree of copy-number alterations. Our objective is to report the features associated with Loss-of-Heterozygosity (LOH) in EC.

Methodology We conducted a retrospective analysis of EC patients from France and Singapore. All patients underwent comprehensive molecular profiling using the tumor-based FoundationOneCDX panel. The degree of LOH was correlated with molecular and clinicopathologic findings. LOH-high, intermediate and low were defined as ≥14%, 4–14%, and <4% respectively.

Results 99 patients were identified, including 62% Asian and 38% Caucasian individuals. 58% had FIGO III/IV diseases, 32% low-grade endometrioid histology, 21% high-grade endometrioid, and 17% serous. 63% and 50% of tumors expressed estrogen (ER) and progesterone receptor (PR) in ≥ 10% tumor cells respectively. 1% had a POLE mutation, 17% were MSI-high, 43% TP53mut and 39% exhibited non-specific molecular profiles. The median LOH was 4.5% (Q1-Q3 1.4–10.5) with 18% patients classified LOH-high, 34% LOH-intermediate and 48% LOH-low.

LOH-High was significantly associated with serous and carcinosarcomas whereas LOH-low with low-grade endometrioid (p<0.001). MSI-high status, ARID1A, PIK3CA, CTNNB1, and PTEN mutations were significantly associated with LOH-low whereas TP53, BRCA1 mutations and TERC amplifications were associated with LOH-high (P<0.05). In particular, all BRCA1mut EC and 38% of the TP53mut were LOH-high. There were significantly more ER and PR-negative cases in the LOH-high subgroup. (p<0.05). The median overall survival was 41.5 months, 55.2 and 100.8 months in the LOH-high, intermediate, and low respectively (P=0.034). Among TP53mut EC, LOH-low patients had significantly poorer outcomes (p<0.001).

Conclusion In this large multiethnic cohort, 18% of EC exhibited high LOH exceeding 14%. Higher LOH was correlated with hormone-receptor-negative tumors and poorer survival rates. LOH may serve as a valuable tool for identifying EC cases with high genomic instability that could potentially benefit from PARP inhibitors.

Disclosures None