Not all uterine carcinosarcomas are created equal: Survival outcomes according to molecular characterization of uterine carcinosarcoma

Objectives. To assess if ProMisE classifier molecular subtypes are associated with differing survival outcomes in uterine carcinosarcoma (UCS) and compare these outcomes to endometrioid endometrial cancer (EEC) tumors. Methods. There were 2235 UCS and 6469 EEC tumors using next-generation sequencing of DNA, whole exome sequencing, and RNA. Microsatellite instability (MSI) was tested by IHC and NGS. Real-world overall survival (OS) was obtained from Caris Life Sciences database and paired with insurance claims data. Hazard ratios (HR) were calculated using the Cox proportional hazards model, and p-values were calculated using the log-rank test. Results. Of the 2235 UCS samples, 2.7 % (n = 48) were POLE mutant (MT), 7.4 % (n = 132) MSI-H, 78.2 % (n = 1402), TP53 MT, and 11.7 % (n = 210), TP53 wild type (WT). In UCS POLE MT tumors, median OS (74.8 mos; 95 % CI: 30.5-not reached [NR]; p < 0.01) was significantly longer than all other subtypes. There was no difference in median post-chemo OS between POLE MT UCS and POLE MT EEC (p = 0.75) or MSI-H UCS and MSI-H EEC (p = 0.14). TP53 MT UCS and TP53 WT UCS tumors had worse median OS compared their respective ECC subtypes (27.9 vs 35.3 mos; HR: 1.3 95 % CI (1.1-1.5); p = 0.01, 29.4 vs 70.7 mos; HR: 2.0 95 % CI (1.5-2.7); p < 0.01). HER2 negative UCS had worse post-chemo OS compared to HER2 negative EEC (32.9 vs 77 mos; HR 1.60 95 % CI (1.092-2.348); p = 0.0 2). Conclusion. TP53 MT is the most common molecular UCS sub-type. Overall, UCS has tiered survival according to molecular classification, which mirrors EEC survival patterns. Despite UCS being considered a more aggressive histology, POLE MT and MSI-H outcomes when comparing UCS and EEC were not statistically different.