Implementation of the 2021 molecular ESGO/ESTRO/ESP risk groups in endometrial cancer

Abstract

Introduction In 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system. Materials and methods We classified molecularly a cohort of 604 women diagnosed with endometrial cancer using immunohistochemistry for TP53 and MMR proteins on a tissue microarray, as well as Sanger sequencing for POLE mutations. These results, combined with clinicopathologic data, allowed the patients to be risk grouped using both the new 2021 molecular/clinicopathologic parameters and the prior 2016 clinicopathologic system. In addition, clinical treatment and outcome data were collected from medical records. Results The application of the 2021 molecular markers shows Kaplan-Meier curves with a significant difference between the groups for all survival. Molecular classification under the 2021 guidelines revealed a total of 39 patients (39/594, 7%) with a change in risk group in relation to the 2016 classification system: the shift was alone due to either P53abn or POLEmut molecular marker. In order to ensure correct 2021 molecular risk classification, not all patients with endometrial cancer need a molecular diagnostic: 386 (65.0%) cases would need to be analyzed by TP53 IHC, only 44 (7.4%) by MMR IHC and 109 (18.4%) POLE sequencing reactions. Conclusion Application of the 2021 molecular risk groups is feasible and shows significant differences in survival. IHC for TP53 and MMR and applying POLE sequencing is only needed in selected

Selection of endometrial carcinomas for p53 immunohistochemistry based on nuclear features

“…p53 status changes ESGO risk group assignment in a small number of patients (7/292, 2.4%), which is similar to another recent study (17/594, 2.9%) [28]. Of note, in our study, only one additional patient would have been offered adjuvant chemotherapy.…”

“…However, Based on our experience that prototypical non-endometrioid carcinomas do not harbor POLE mutations [13,33], testing of non-endometrioid carcinomas in the IR (9 cases) and HR (22 cases) groups could be further restricted to cases with ambiguous/mixed histology, POLE phenotype [34], and cases with multiple subclonal p53 patterns. Taken together, in our study, about 5% (15/292, 8 POLEmut + 7 p53abn) potentially change ESGO risk categories based on molecular information, which is slightly lower than the 7% reported by Imboden et al [28]. Yet, when it comes to changes in adding or withdrawing chemotherapy, only 2-3 patients (1-2 POLEmut + 1 p53abn) would be affected.…”

“…Imboden et al . recommend testing all stage I and II tumors (largely EEC1/2), requiring 72.0% of cases to be tested [28]. In contrast, we propose a morphology/nuclear feature driven approach in which roughly half of the EEC1/2 cases with bland nuclear features would not require p53 IHC testing.…”

“…The second p53abn case represents the danger of underdiagnosing a p53abn case as EEC2 despite severe nuclear atypia: on histotype study review, this case was labelled as high‐grade endometrioid carcinoma by the observers. Overall, our recent rate of p53abn EEC1/2 is much lower compared to the historical cohorts [27,28]. This shows the impact of pathologists as rational decision‐makers when adapting p53 IHC in their diagnostic approach [29].…”

“…Taken together, in our study, about 5% (15/292, 8 POLE mut + 7 p53abn) potentially change ESGO risk categories based on molecular information, which is slightly lower than the 7% reported by Imboden et al . [28]. Yet, when it comes to changes in adding or withdrawing chemotherapy, only 2–3 patients (1–2 POLE mut + 1 p53abn) would be affected.…”