788P Molecular Profiling of P53 Mutant Endometrial Cancer Reveals Distinct Subgroups with Opportunities for Personalized Therapeutic Approaches

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. 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. 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. 40 patients were molecularly characterized on tumor tissue and 31 on circulating tumor DNA. Median age was 66 years, 38% presented with primary metastatic diseases, 40% were serous, 30% endometrioid and 20% carcinosarcoma. We detected the same four molecular subgroups defined by CCNE1amp (13%), ERBB2amp (16%), and PTEN mutation or loss (34%). These subgroups were also almost exclusive to one another. Only two patients (3%) harbored co-alterations. In terms of outcomes, we did not observe any overall survival difference between these subgroups. 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.