Introduction While the genomic landscape of untreated primary endometrial carcinoma (EC) is well characterized, the molecular underpinnings of distant metastatic EC are poorly understood. We sought to define genomic alterations associated with distant metastatic EC.

Methods We obtained sequencing data from distant metastatic ECs from a total of 1888 ECs subjected to a clinical tumor-normal sequencing panel between 8/2013 and 6/2020; these metastatic ECs were compared against 711 primary ECs using appropriate statistical analyses.

Results One hundred thirty-seven ECs met the study inclusion criteria, with distant metastases in the lung (n=66, 48%), liver (n=21, 15%), soft tissue (n=15, 11%), distant lymph nodes (n=15, 11%), gastrointestinal tract (n=10, 7%), central nervous system (n=5, 4%), bone (n=4, 3%), and renal system (n=1, 1%). The majority of distant metastases were of copy number (CN)-high (42%) or CN-low (39%) molecular subtype; 18% were microsatellite instability (MSI)-high and 1% were of POLE molecular subtype. Distant EC metastases were significantly more chromosomally unstable compared with primary ECs (p<0.0001) and were enriched in AKT1, CTNNB1, ANKRD11, and ZFHX3 mutations. Clinically actionable alterations, particularly tumor mutational burden (TMB) ≥10 mut/Mb and MSI-high status, were significantly less common in metastatic compared with primary ECs (4% vs 29%; p=0.017). Epigenetic, PI3K, and TP53 pathways were the most commonly altered pathways among all anatomic sites.

Conclusion/Implications Compared with primary tumors, distant metastatic ECs exhibited increased chromosomal instability but decreased hypermutator phenotypes. Exploitation of genetic differences to understand the pathogenesis of metastatic EC is necessary to develop biomarkers for targeted therapy.