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

Abstract

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 = 0.02).

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.

Keywords: HER2 negative; HER2 positive; Immunotherapy; MSI-H; Molecular classification; Molecular profiling; POLE; Precision oncology; TP53 mutated; TP53 wildtype; Tiered survival; Uterine carcinosarcoma.