Clinical and biological characteristics associated with of loss-of-heterozygosity in endometrial cancer.

Objective: Genomic instability has been identified in a subgroup of endometrial cancers (ECs) that are predominantly TP53 mutated (TP53mut). We report the features associated with loss-of-heterozygosity (LOH) in EC.

Methods: We conducted a retrospective analysis of EC patients from France and Singapore. All patients underwent comprehensive molecular profiling using the tumor based FoundationOne CDX 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: One hundred twelve patients were identified, including 66% Asian and 34% Caucasian. Fifty nine percent had International Federation of Gynecology and Obstetrics III/IV diseases, 34% low-grade endometrioid, 19% high-grade endometrioid, and 15% serous. The 63% and 50% of tumors expressed estrogen receptor (ER) and progesterone receptor (PR). One percent had a POLE mutation, 18% were microsatellite instability (MSI)-, 40% TP53mut and 41% non-specific molecular profiles. The 17% of patients were classified LOH-high, 37% LOH-intermediate and 46% LOH-low. LOH-high was significantly associated with serous and carcinosarcomas, ER/PR negative tumors, TP53 mutations, BRCA1 mutations and TERC amplification whereas LOH-low with low-grade endometrioid, MSI, ARID1A, PIK3CA, CTNNB1, and PTEN mutations. The median overall survival was 42.2, 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, 17% of EC exhibited high LOH and correlated with hormone-receptor-negative tumors and poorer survival rates. LOH may serve as a tool for identifying EC cases with high genomic instability that could potentially benefit from PARP inhibitors.