Clinicopathological Features And Prognosis Of POLE-mutated Patients In High-grade Endometrial Carcinomas

Background:Endometrial carcinoma is a common gynecologic malignant tumor.In 2013,The Cancer Genome Atlas(TCGA)proposed the molecular classification of endometrial carcinomas,which was classified into four subtypes with unique molecular characteristics and prognostic significance:POLE-mutated subtype,microsatellite instability subtype,copy-number high subtype,and copy-number low subtype.Although the POLE-mutated subtype,which is characterized by POLE exonuclease domain mutation and somatic ultra-mutation,accounts for only 6%?10%it has attracted wide attention because of its perfect prognosis.As a group with poor prognosis,high-grade endometrial carcinomas normally require extra adjuvant therapy,but the exploration of POLE-mutated subtype may help to change the treatment strategy for some patients.However,there is still a lack of relevant studies in Chinese population.Moreover,it is also suggested that patients with POLE exonuclease domain mutation are not homogenous,and a few patients may still relapse and die.The purpose of this study is to investigate the clinicopathological features and prognostic factors of patients with POLE exonuclease domain mutation in high-grade endometrial carcinoma,and to provide help for clinical decisions.Methods:In this study,a total of 323 formalin-fixed and paraffin-embedded(FFPE)specimens from patients with high-grade endometrial carcinoma diagnosed by the pathology department of Peking Union Medical College Hospital(PUMCH)from 2010 to 2018 were collected,which were further screened for POLE exonuclease domain mutation by DNA extraction and Sanger sequencing(exons 9-14).Then,the immunohistochemical staining of MLH1,PMS2,MSH2,MSH6,and P53 was completed.The clinicopathological data of these patients were collected,and the prognosis information was obtained through telephone follow-up.Finally,the clinicopathological and prognostic characteristics of POLE-mutated subtype in high-grade endometrial carcinoma were analyzed.Results:(1)In this study,a total of 44 patients with POLE exonuclease domain mutation were selected,with the prevalence of 14.3%in high-grade endometrial,including 38(86.4%)grade 3 or 2-3 endometrial carcinomas,2(4.5%)serous carcinomas,2(4.5%)clear cell carcinomas,and 2(4.5%)mixed cell adenocarcinomas.The 5-year progression-free and overall survival rates for all patients were 85.5%and 86.8%,respectively.The majority(77.3%)of patients were FIGO stage ?,and multivariate Cox regression analysis showed that FIGO stage ?-? was an independent risk factor for relapse(P=0.044).(2)Of all the POLE exonuclease domain mutations,two hotspot mutations p.P286R(29.5%)and p.V411L(29.5%)were found with the highest frequency.Based on a recent study,the patients were divided into two groups according to the pathogenicity of POLE mutation.Patients with pathogenic POLE mutation accounted for 79.5%and were found with better progression-free survival than patients without the pathogenic POLE mutation by survival analysis(P=0.016).(3)Further study on patients with the pathogenic POLE mutation found that FIGO stage ?-?,lymph-vascular space invasion(LVSI),lymph node metastasis,and abnormal P53 expression still had an adverse effect on the prognosis.However,no relapse occurred in patients with early-stage(FIGO stage ?-?),regardless of postoperative radiotherapy,chemotherapy,both or neither.(4)Among 35 patients with pathogenic POLE mutation,13 cases(37.1%)were found with "multiple-classifier",among which 11 cases were combined with abnormal P53 expression and 4 cases were combined with mismatch repair(MMR)deficiency.Patients with MMR deficiency all had a favorable prognosis,but those with abnormal P53 expression were presented with a higher risk of relapse(P=0.021).Conclusion:In summary,as a study of characteristics of POLE-mutated endometrial carcinomas,which has the largest sample in Chinese population reported so far,it is the first time to verify in a Chinese population that POLE-mutated subtype still has a good prognosis in high-grade endometrial carcinomas.Secondly,it is also found that endometrial carcinomas with POLE exonuclease domain mutations have significant heterogeneity.On the one hand,it can be further distinguished into two different prognostic groups according to the pathogenicity of the POLE mutation.On the other hand,the analysis of patients with multiple classifier also revealed that it is inappropriate to determine the classification and treatment strategy simply by detecting only one molecular feature.Finally,this study also suggests that,although the overall prognosis of high-grade endometrial cancer is unfavorable,current adjuvant therapy may be redundant in early-stage patients with a pathogenic POLE mutation.