Introduction Endometrial cancer (EC) can be classified into four molecular subgroups: POLE mutant, MSI/dMMR, non-specific profiles and P53 mutant (P53mut). P53mut EC comprise ~20% of cases and have the worst prognosis. There is an urgent medical need to better understand P53mut EC in order to propose effective new therapeutic strategies.

Methods We conducted a retrospective analysis of P53abn EC patients from PORTEC3 (NCT00411138) with available DNA for a large-scale panel sequencing (Discovery Cohort). Results were confirmed on an independent cohort of EC patients (Gustave Roussy, France and National University Cancer Institute, Singapore) identified by their molecular profile using FoundationOneCDX or FoundationOne Liquid CDX panel (Validation Cohort). Molecular findings were correlated with clinicopathologic features from medical record review.

Results 39 P53abn cases were included in the discovery cohort. Molecular profiling was able to distinguish 4 mutually exclusive subgroups: CCNE1 amplified (15%), ERBB2 amplified (21%), PTEN alteration (21%) and a non-specific group. In the Validation Cohort, 71 P53mut EC patients were included. Median age was 66 years, 40% were serous, 30% endometrioid and 20% carcinosarcoma. 38% presented with primary metastatic diseases. We detected the same four molecular subgroups defined by CCNE1amp (13%), ERBB2amp (16%), and PTEN mutation or loss (34%). Only two patients (3%) harbored co-alterations. We did not observe any overall survival difference between these subgroups.

Conclusion/Implications Among P53mut EC, we detected 3 nearly mutually-exclusive molecular subgroups: CCNE1 amplified, ERBB2 amplified and PTEN loss, accounting together for 60% of cases. Whether these subgroups might benefit from personalized therapeutic strategies is currently being explored.