Abstract
OBJECTIVE: The molecular underpinnings of primary treatment-naïve endometrial carcinoma (EC) are well described. Here we sought to characterize the genomic landscape of distant metastatic EC. METHODS: Distant metastatic ECs from a total of 1888 cases subjected to a clinical panel sequencing between 4/2015 and 6/2020 were identified, and their genomic profiles, affected pathways and actionable alterations were compared to those of 711 primary ECs. Wilcoxon and Fisher's exact tests were used for continuous and categorical variables, respectively, and p-values adjusted for multiple hypothesis-testing. RESULTS: Distant EC metastases (n = 137) of 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 %) were included. Distant EC metastases were most commonly of copy number (CN)-high/TP53 abnormal (42 %) or CN-low/no specific molecular profile (NSMP) (39 %) molecular subtype; 18 % were microsatellite instability (MSI)-high/mismatch repair (MMR)-deficient and 1 % were of POLE molecular subtype. Distant EC metastases were significantly more chromosomally unstable compared to primary ECs across molecular subtypes (p < 0.0001). CTNNB1 mutations were more prevalent in distant CN-low/NSMP and MSI-high/MMR-deficient metastases compared to primary ECs (q < 0.1). Clinically actionable alterations were significantly less common in metastatic ECs (27 % vs 37 % primary; p = 0.025). PI3K, p53 and epigenetic pathways were the most altered pathways among all anatomic sites. CONCLUSIONS: Distant metastatic ECs are more frequently chromosomally unstable but less commonly exhibit hypermutator phenotypes. Exploitation of genetic differences of metastatic EC is warranted for targeted treatment strategy development.