The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and sensitize tumors to checkpoint blockade immunotherapy. However, many POLE mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we. prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with specific single base substitution signature, high T-cell infiltrates, and high response rate to anti-PD1 monotherapy. This study illustrates how specific DNA repair defects can sensitize to immunotherapy, POLE proofreading deficiency representing a novel tumor agnostic biomarker for response to PD-1 checkpoint blockade therapy.

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.Copyright © 2017 Elsevier Inc. All rights reserved.

The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed.A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS.POLE EDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15-0.73] and 0.35 (95% CI, 0.13-0.92), respectively.POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women. Clin Cancer Res; 22(12); 2865-73. ©2016 AACR.©2016 American Association for Cancer Research.

Inactivating mutations in the exonuclease domain of POLE induce somatic hypermutation resulting in a high tumor mutation burden (TMB) and are associated with immune checkpoint inhibitor (ICI) benefit. POLE mutations outside the exonuclease domain predicted to be deleterious are also observed in cancers, but it is unknown whether they are similarly associated with response to ICIs. We present a patient with hepatocellular carcinoma with a rare POLE mutation (V1368M) outside the exonuclease-domain predicted to be deleterious, a low TMB (1 mut/Mb), and microsatellite stability, who demonstrated an exceptional response to pembrolizumab. To support the generalizability of this finding, an analysis of 1278 patients with advanced cancers harboring low or intermediate TMB treated with ICIs showed that missense non-exonuclease domain POLE mutations were associated with greater overall survival. In contrast, among patients with advanced cancers without ICI exposure, POLE mutations were not associated with overall survival. These results demonstrate that a subset of missense POLE mutations may represent predictive biomarkers independent of TMB. Pathogenic POLE mutations outside the exonuclease domain may result in altered functions beyond DNA replication and proofreading which render cancers sensitive to ICIs.© The Author(s) 2022. Published by Oxford University Press.

Determining the replicative DNA polymerase epsilon (POLE) mutation status in endometrial carcinomas (ECs) has important clinical implications given that the majority of “ultramutated” tumors harboring pathogenic exonuclease domain mutations in POLE (POLEmut) have a favorable prognosis, even among high-grade histotypes. Currently, there are no specific morphologic or immunophenotypic features that allow accurate detection of POLEmut tumors without molecular testing. Consequently, identifying POLEmut tumors has been challenging without employing costly and/or time-consuming DNA sequencing approaches. Here we developed a novel SNaPshot assay to facilitate routine and efficient POLE mutation testing in EC. The SNaPshot assay interrogates 15 nucleotide sites within exons 9, 11, 13, and 14 encoding the POLE exonuclease domain. The variant sites were selected based on recurrence, evidence of functional impact, association with high tumor mutation burden and/or detection in EC clinical outcome studies. Based on the pathogenic somatic variants reported in the literature, the assay is predicted to have a clinical sensitivity of 90% to 95% for ECs. Validation studies showed 100% specificity and sensitivity for the variants covered, with expected genotypic results for both the positive (n=11) and negative (n=20) patient controls on multiple repeat tests and dilution series. Analytic sensitivity was conservatively approximated at a 10% variant allele fraction (VAF), with documented detection as low as 5% VAF. As expected, the SNaPshot assay demonstrated greater sensitivity than Sanger sequencing for VAFs below 20%, an important characteristic for somatic mutation detection. Here we have developed and validated the first SNaPshot assay to detect hotspot POLE mutations. While next-generation sequencing and Sanger sequencing-based approaches have also been used to detect POLE mutations, a SNaPshot approach provides useful balance of analytical sensitivity, cost-effectiveness, and efficiency in a high-volume case load setting.

The author presents a hypothesis that the complex of endocrine and metabolic disturbances arising long before the development of endometrial carcinoma determines the biological peculiarities of the tumor, its clinical course, and the prognosis of the disease. On the basis of a prospective study of 366 patients with endometrial carcinoma, the author postulates that there are two different pathogenetic types of endometrial carcinoma. The first pathogenetic type of the disease arises in women with obesity, hyperlipidemia, and signs of hyperestrogenism: anovulatory uterine bleeding, infertility, late onset of the menopause, and hyperplasia of the stroma of the ovaries and endometrium. The second pathogenetic type of the disease arises in women who have no signs stated above or these signs are not clearly defined. The frequency of the first pathogenetic type in the studied group of women was 65%, whereas the frequency of the second type was 35%. The peculiarities outlined above which are characteristic of the first pathogenetic type of the disease determine the development of highly and moderately differentiated tumors (82.3% G1 and G2), superficial invasion of the myometrium (69.4%), high sensitivity to progestogens (80.2%), and favorable prognosis (85.6% 5-year survival rate). In patients who have the second pathogenetic type of endometrial cancer when endocrine and metabolic disturbances are absent or occult, poorly differentiated tumors arise (62.5% G3), a tendency to deep invasion of tumor into the myometrium is observed (65.7%); high frequency of metastatic spread into the pelvic lymph nodes (27.8%); decrease of sensitivity to progestogens (42.5%); and doubtful prognosis (58.8% 5-year survival rate) are noted.

Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies.The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system.Based on the existing evidence, the substages were defined as follows: Stage I (IA1): non-aggressive histological type of endometrial carcinoma limited to a polyp or confined to the endometrium; (IA2) non-aggressive histological types of endometrium involving less than 50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria; (IA3) low-grade endometrioid carcinomas limited to the uterus with simultaneous low-grade endometrioid ovarian involvement; (IB) non-aggressive histological types involving 50% or more of the myometrium with no LVSI or focal LVSI; (IC) aggressive histological types, i.e. serous, high-grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion. Stage II (IIA): non-aggressive histological types that infiltrate the cervical stroma; (IIB) non-aggressive histological types that have substantial LVSI; or (IIC) aggressive histological types with any myometrial invasion. Stage III (IIIA): differentiating between adnexal versus uterine serosa infiltration; (IIIB) infiltration of vagina/parametria and pelvic peritoneal metastasis; and (IIIC) refinements for lymph node metastasis to pelvic and para-aortic lymph nodes, including micrometastasis and macrometastasis. Stage IV (IVA): locally advanced disease infiltrating the bladder or rectal mucosa; (IVB) extrapelvic peritoneal metastasis; and (IVC) distant metastasis. The performance of complete molecular classification (POLEmut, MMRd, NSMP, p53abn) is encouraged in all endometrial cancers. If the molecular subtype is known, this is recorded in the FIGO stage by the addition of "m" for molecular classification, and a subscript indicating the specific molecular subtype. When molecular classification reveals p53abn or POLEmut status in Stages I and II, this results in upstaging or downstaging of the disease (IICm or IAm ).The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data.© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.

Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment.A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one-stage meta-analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC).Three hundred fifty-nine women with POLE-mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47-7.58; log-rank P <.01). Except for stage (P <.01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease-specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5-14.2 years). Adjuvant treatment was not associated with outcome.Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients.Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE-mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.© 2021 American Cancer Society.

We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application.We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features.Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88.We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

POLE exonuclease domain mutations have recently been described in undifferentiated endometrial carcinoma but, because of the rarity of this aggressive type of endometrial cancer, their prognostic significance is unknown. We have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, β-catenin, and SMARCB1) and mutational status (POLE, PIK3CA, and PTEN) of 21 undifferentiated carcinomas (8 undifferentiated and 13 dedifferentiated carcinomas). Loss of ARID1A expression was observed in 9 of 19 cases (47%), loss of expression of at least 1 DNA mismatch repair protein in 7 (7/21; 33%), and p53 immunoreaction was aberrant (mutated/inactivated) in 11 cases (11/21; 52%). All tumors were negative for β-catenin. Normal nuclear SMARCB1 (INI1) staining was found in all but 1 dedifferentiated case. Two undifferentiated and 7 dedifferentiated carcinomas showed POLE exonuclease domain mutations (9/21; 42%). PIK3CA mutations occurred in six tumors (6/21; 28%) (2 undifferentiated and 4 dedifferentiated carcinomas). PTEN mutations were found in 7 of 15 cases (47%) (4 undifferentiated and 3 dedifferentiated carcinomas). POLE-mutated undifferentiated and dedifferentiated endometrial carcinomas were more frequently stage I tumors than similar carcinomas lacking exonuclease domain mutations (7/9; 78% vs. 3/12; 25%; P=0.023) and patients had significantly better outcome (disease-specific survival) than those without POLE exonuclease domain mutations (P=0.02). Determination of the POLE mutation status is important for the management of these patients.

Our aim was to characterize the pathological, molecular and clinical outcomes of clear cell carcinoma of the endometrium (CCC).CCC underwent ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification identifying four molecular subtypes: i) 'POLEmut' for ECs with pathogenic POLE mutations, ii) 'MMRd', if there is loss of mismatch repair proteins by immunohistochemistry (IHC), iii) 'p53wt' or iv) 'p53abn' based on p53 IHC staining. Clinicopathologic parameters, immune markers (CD3, CD8, CD79a, CD138, PD-1), ER, L1CAM, and outcomes were assessed.52 CCCs were classified, including 1 (2%) POLEmut, 5 (10%) MMRd, 28 (54%) p53wt and 18 (35%) p53abn. Women with p53abn and p53wt CCCs were older than women with MMRd and POLEmut subtypes. p53wt CCC were distinct from typical p53wt endometrioid carcinomas; more likely to arise in older, thinner women, with advanced stage disease, LVSI and lymph node involvement, and a higher proportion ER negative, L1CAM overexpressing tumors with markedly worse outcomes. High levels of immune infiltrates (TIL) were observed in 75% of the CCC cohort. L1CAM overexpression was highest within p53abn and p53wt subtypes of CCC.CCC is a heterogeneous disease encompassing all four molecular subtypes and a wide range of clinical outcomes. Outcomes of patients with POLEmut, MMRd and p53abn CCC are not distinguishable from those of other patients with these respective subtypes of EC; p53wt CCC, however, differ from endometrioid p53wt EC in clinical, pathological, molecular features and outcomes. Thus, p53wt CCC of endometrium appear to be a distinct clinicopathological entity within the larger group of p53wt ECs.Copyright © 2020 Elsevier Inc. All rights reserved.

The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications.© 2012 AACR.

Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs.Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]).ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society.© 2017 American Cancer Society.

Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided.POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P <.001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P =.15; HR = 0.19, 95% CI = 0.03 to 1.44, P =.11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P =.03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P =.03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P =.06).POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.© The Author 2014. Published by Oxford University Press.

Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.

The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC).

Multiple studies have proven the prognostic value of molecular classification for stage I-III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients are lacking. Hypothetically, poor prognostic molecular subtypes are more common in higher stages of endometrial cancer. Considering the poor prognosis of stage IV endometrial cancer patients, it is questionable whether molecular classification has additional prognostic value. Therefore, we determined which molecular subclasses are found in stage IV endometrial cancer and if there is a correlation with progression-free and overall survival.A retrospective multicenter cohort study was conducted using data from five Dutch hospitals. Patients with stage IV endometrial cancer at diagnosis who were treated with primary cytoreductive surgery or cytoreductive surgery after induction chemotherapy between January 2000 and December 2018 were included. Exclusion criteria were age <18 years or recurrent disease. The molecular classification was performed centrally on all tumor samples according to the World Health Organization 2020 classification (including and estrogen receptor status). The Kaplan-Meier method was used to calculate progression free and overall survival in the molecular subclasses, for the different histological subtypes and for estrogen receptor positive versus estrogen receptor negative tumors. Groups were compared using the log-rank test.164 stage IV endometrial cancer patients were molecularly classified. Median age of the patients was 67 years (range 33-86). Most patients presented with a non-endometrioid histological subtype (58%). Intra-abdominal complete cytoreductive surgery was achieved in 60.4% of the patients. 101 tumors (61.6%) were classified as p53 abnormal, 35 (21.3%) as no specific molecular profile, 21 (12.8%) as mismatch repair deficient, and 6 (3%) as mutated. Molecular classification had no significant impact on progression free (p=0.056) or overall survival (p=0.12) after cytoreductive surgery. Overall survival was affected by histologic subtype (p<0.0001) and estrogen receptor status (p=0.013).The distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I-III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers.

To investigate the association of molecular subtype with progesterone response in patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH).Premenopausal patients aged ≤48 years with tumor-normal sequencing data who received progesterone for EC/AEH from 1/1/2010-6/30/2021 were identified. Tumors were classified as POLE-ultramutated, microsatellite instability-high (MSI-H), copy number-high (CN-H), or copy number-low (CN-L) molecular subtype. Best response to progesterone was compared by subtype. Appropriate statistical tests were performed.Of 20 patients, 7 (35%) had AEH and 13 (65%) had EC. Sixteen tumors (80%) were CN-L, 3 (15%) were MSI-H, and 1 (5%) was POLE-ultramutated. Median time on progesterone was 22 months (range, 3-115). Ten patients (50%) had complete response (CR); median time to CR was 9 months (range, 3-32). Four patients (20%) had stable disease (SD) and 6 (30%) had progressive disease (PD). For CN-L tumors, 10 patients (62%) had CR, 3 (19%) had SD, and 3 (19%) had PD. For MSI-H tumors, 1 patient (33%) had SD and 2 (66%) had PD. For POLE-ultramutated tumors, 1 patient had PD. Median follow-up was 48 months (range, 12-123). Four of 10 patients (40%) with CR recurred; median time from CR to recurrence was 16 months (range, 5-102).Molecular subtype may be associated with progesterone response in patients with EC/AEH. CN-L tumors had the best response, and MSI-H tumors had the poorest. Recurrence after CR is common, and close surveillance is warranted. Larger studies investigating the role of molecular classification in medical management of EC/AEH are needed.Copyright © 2023 Elsevier Inc. All rights reserved.