---------------------------- 2018 Platform Presentation Winner --------------------------

[1220] Clinicopathological Characterization of Endometrial Carcinomas with More Than One Molecular Classifying Feature

Alicia Leon1, Jessica N McAlpine2, Remi Nout3, Melissa K McConechy4, RAJI GANESAN5, Xavier Matias-Guiu6, Esther Oliva7, Beth T Harrison8, Robert Soslow9, David Church10, C. Blake Gilks11, Tjalling Bosse12.


Background: Molecular stratification of endometrial carcinomas (EC) into DNA polymerase epsilon mutant (POLEmut), mismatch repair deficient (MMRd), p53 mutant (p53abn) and no specific molecular profile has provided a novel classification with prognostic impact: POLEmut EC have an excellent prognosis while p53abn cases have an unfavourable outcome. This approach however leaves unclassifiable cases due to the presence of more than one classifier, referred to as “multiple classifiers”. We aimed to describe the clinicopathological characteristics of these unclassifiable EC.

Design: Multiple classifiers were divided into four groups: POLEmutp53abn, POLEmut-MMRd, MMRd-p53abn and POLEmut-MMRd-P53abn. These were derived from 2312 EC molecularly profiled in multi-institutional collaborative setting by sequencing of exons 9-14 or exons 9 and 13 of POLE and immunohistochemistry of p53 and MMR proteins, completed with TCGA cases. Univariable and multivariable Cox proportional-hazards models were used to evaluate overall survival (OS) and recurrence free survival (RFS) of multiple classifier groups alone and in combination with age, stage and grade. In addition Kaplan Meier curves with log-rank test were performed for RFS and OS.

Results: In total, 82 multiple classifiers were identified (3,5%) with median age 63.6 (range 27-87). FIGO stage (2009) was: 37 IA(45,1%), 32 IB(39%), 13 II-IV(15,9%). 66 (80,5%) cases were endometrioid and 16 (19,5%) non-endometrioid, with 19 cases grade 1 (23,2%), 11 grade 2 (13,4%) and 52 grade 3 (63,4%). There were 20 (24,4%) POLEmutp53abn 17 (20,7%) POLEmut-MMRd, 40 (48,8%) MMRd-p53abn and 5 (6,1%) POLE-MMRd-p53abn. There was no significant difference between multiple classifier groups both for RFS and OS, also when the analysis was limited to stage I patients (table 1). When including age, FIGO stage and grade, multivariable analysis did not reveal a multiple classifier group with distinct impact on RFS or OS (also when limited to stage I). FIGO stage II-IV was the strongest negative independent prognostic factor for RFS and OS. Age was independent prognostic for OS.


Conclusions: This is the first study on ECs with multiple classifying features. These ECs are rare (3,5%) and can be identified in all histotypes and grades. Our data suggests that POLE mutations drive the biological behavior of EC even in the presence of MMRd or p53 mutations. Further characterisation will be required to determine the optimal treatment of these unusual ECs.