1072 Large-scale Validation Confirms Lack of Prognostic Impact of Aberrant p53 Status in POLEmut and MMRd Endometrial Carcinoma

Abstract

Background: A small but clinically relevant subset of endometrial carcinomas (EC) have more than one molecular classifying feature; e.g. a pathogenic POLE mutation as well as mismatch repair deficiency, and/or abnormal p53-expression. Prior studies suggest these patients with POLE-mutated (POLEmut) or mismatch repair deficient (MMRd) tumors that also have aberrant p53 expression, so-called "double classifiers", have clinical outcomes and genomic profiles more aligned with single-classifier POLEmut or MMRd tumors respectively. Using the largest collection of molecularly classified EC-cohorts to date, we evaluated whether aberrant p53 status affects outcome in such cases. Design(s): We analyzed tumor material from 12 international molecularly classified EC cohorts (retrospective, prospective, and randomized clinical trials; n=5958). Cases harboring a pathogenic TP53 mutation and/or aberrant p53 immunohistochemistry together with a pathogenic POLE mutation and/or MMR deficiency were included. Recurrence-free survival (RFS) was compared among patients with POLEmut-p53abn, MMRd-p53abn and POLEmut-MMRd-p53abn EC versus their respective single-classifier counterparts using Kaplan-Meier and log-rank tests. Result(s): We identified 164 (2.8%) double classifier EC, including 51 (31.1 %) POLEmut-p53abn EC, and 113 (68.9 %) MMRd-p53abn EC. The stage distribution was as follows; 120 stage I (73.2%), 17 stage II (10.4%), 22 stage III (13.4%), and 5 stage IV (3.0%). Five-year RFS (Figure 1A) did not differ between POLEmut-p53abn and POLEmut tumors (93.4% vs 96.8%; p = 0.48) or between MMRd-p53abn and MMRd tumors (78.1% vs 80.0%; p = 0.63). In contrast, single-classifier p53abn EC showed markedly worse 5-year RFS (52.6%). Subanalyses including only stage I cases (Figure 1B), for which molecular classification has a great impact on clinical management, also revealed no significant differences in five-year RFS between POLEmut-p53abn and POLEmut tumors (96.8% vs 97.3%; p = 0.78) or between MMRd-p53abn and MMRd tumors (87.2% vs 86.3%; p = 0.94). [Formula presented] [Formula presented] Conclusion(s): Aberrant p53 status does not impact prognosis in EC with pathogenic POLE mutations or MMR deficiency. These findings further support classifying POLEmut-p53abn as POLEmut EC, and MMRd-p53abn as MMRd EC. Copyright © 2025