Clinical outcomes of patients with POLE mutated endometrioid endometrial cancer.

Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.

Stasenko M ，Tunnage I ，Ashley CW ，Rubinstein MM ，Latham AJ ，Da Cruz Paula A ，Mueller JJ ，Leitao MM Jr ，Friedman CF ，Makker V ，Soslow RA ，DeLair DF ，Hyman DM ，Zamarin D ，Alektiar KM ，Aghajanian CA ，Abu-Rustum NR ，Weigelt B ，Cadoo KA ... -  《-》

Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D.

To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects. Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA. FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status. The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers.

Timmerman S ，Van Rompuy AS ，Van Gorp T ，Vanden Bempt I ，Brems H ，Van Nieuwenhuysen E ，Han SN ，Neven P ，Victoor J ，Laenen A ，Vergote I ... -  《-》

Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis.

Billingsley CC ，Cohn DE ，Mutch DG ，Hade EM ，Goodfellow PJ ... -  《-》

Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups.

Bosse T ，Nout RA ，McAlpine JN ，McConechy MK ，Britton H ，Hussein YR ，Gonzalez C ，Ganesan R ，Steele JC ，Harrison BT ，Oliva E ，Vidal A ，Matias-Guiu X ，Abu-Rustum NR ，Levine DA ，Gilks CB ，Soslow RA ... -  《-》

Molecular markers in recurrent stage I, grade 1 endometrioid endometrial cancers.

Stage I, grade 1 endometrial cancers have low recurrence rates and often do not receive adjuvant therapy. We compared recurrent cases to matched non-recurrent controls to evaluate for molecular markers associated with higher risk of recurrence. A case-control study including all cases of recurrent stage I, grade 1 endometrioid endometrial cancer at one institution in a ten-year period. Cases were matched to controls by age, BMI, weight and stage. Molecular testing and immunohistochemistry were performed on archival tumor specimens: microsatellite instability (MSI-H), mismatch repair status, POLE mutational status, and next-generation sequencing. 15 stage I, grade 1 endometrial cancer cases with recurrent disease and available tumor specimens were identified. CTNNB1 and MSI-H were present at significantly higher rates in cases than controls (CTNNB1 60% vs. 28%, OR 3.9, 95%CI 1.1-14.7, p = 0.04 and MSI-H 53% vs. 21%, OR 4.4, 95%CI 1.1-17.0, p = 0.03). POLE mutations were found in 0% of cases vs. 7% of controls (p = 0.54). Among specimens demonstrating microsatellite stability (MSS), 100% of cases vs. 26% of controls had CTNNB1 mutations (p < 0.001). CTNNB1 wild type tumors were MSI-H in 100% of cases vs. 19% of controls (p < 0.001). Compared to controls, CTNNB1 mutation is present at significantly higher rates in recurrent stage I, grade 1 endometrial cancers and is found most commonly in MSS tumors. MSI-H is also present at significantly higher rates in recurrent cases. These markers may be useful for prognostic risk stratification and adjuvant therapy decision-making in this otherwise low-risk population.

Moroney MR ，Davies KD ，Wilberger AC ，Sheeder J ，Post MD ，Berning AA ，Fisher C ，Lefkowits C ，Guntupalli SR ，Behbakht K ，Corr BR ... -  《-》