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Background: Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations between molecular classification of EC and DTCs. Methods: Patients treated for primary EC at Tuebingen University women's hospital between 2003 and 2016 were identified. A total of 402 patients with a complete set of BM cytology, molecular, and clinical data were evaluable. Results: DTC occurrence was distributed equally among all four molecular groups (p = 0.651). DTC positivity was associated with a less favorable disease-free survival (HR: 1.86, 95% CI: 1.03–3.36, p = 0.036) and progression-free survival (HR: 1.86, 95% CI: 1.01–3.44, p = 0.045). Presence of DTCs was associated with a higher frequency of distant disease recurrence (p = 0.017). Conclusions: In line with our previous findings, tumor cell dissemination is not associated with molecular features in our large cohort of primary EC patients. Since DTCs seem to be associated with survival and location of disease recurrence, further studies are needed to decisively define their role in EC survival. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employ artificial intelligence (AI)-powered histopathology image analysis to differentiate between p53abn and NSMP EC subtypes and consequently identify a sub-group of NSMP EC patients that has markedly inferior progression-free and disease-specific survival (termed 'p53abn-like NSMP'), in a discovery cohort of 368 patients and two independent validation cohorts of 290 and 614 from other centers. Shallow whole genome sequencing reveals a higher burden of copy number abnormalities in the 'p53abn-like NSMP' group compared to NSMP, suggesting that this group is biologically distinct compared to other NSMP ECs. Our work demonstrates the power of AI to detect prognostically different and otherwise unrecognizable subsets of EC where conventional and standard molecular or pathologic criteria fall short, refining image-based tumor classification. This study's findings are applicable exclusively to females. Endometrial cancer (EC) has four molecular subtypes; of these, the No Specific Molecular Profile (NSMP) subtype encompasses patients with heterogeneous outcomes. Here, the authors use artificial intelligence and histopathology images to differentiate p53abn and NSMP subtypes in EC, and identify one distinct subgroup within NSMP with unfavourable outcome. [ABSTRACT FROM AUTHOR]

Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. Most endometrial cancer cases are diagnosed at an early stage and have good prognosis. Unfortunately a subset of patients with early stage and low grade disease experience recurrence for reasons that remain unclear. Recurrence is often accompanied by chemoresistance and high mortality.Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis. DUBs have been shown to be upregulated in a number of human cancers and their aberrant activity has been linked to cancer progression, initiation and onset of chemoresistance. Thus, selective inhibition of DUBs has been proposed as a targeted therapy for cancer treatment.This study suggests the DUB USP14 as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence. Further USP14 is expressed along with the marker of proliferation Ki67 in endometrial cancer cells in situ. Lastly, pharmacological targeting of USP14 with the FDA approved small-molecule inhibitor VLX1570, decreases cell viability in chemotherapy resistant endometrial cancer cells with a mechanism consistent with cell cycle arrest and caspase-3 mediated apoptosis.

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5—HIF-1α—COX2 axis could promote endometrial cancer progression. [ABSTRACT FROM AUTHOR]

Background: Lymph node metastases (LNM) are rare in early-stage endometrial cancer, but a diagnostic systematic lymphadenectomy (LNE) is often performed to achieve reliable N-staging. Therefore, this prospective study aimed to evaluate the benefit of [18F]-Fluorodeoxyglucose (FDG) PET/MRI complementary to SPECT/CT guided sentinel lymphonodectomy (SLNE) for a less invasive N-staging Methods: 79 patients underwent a whole-body FDG-PET/MRI, SLN mapping with 99mTc-Nanocolloid SPECT/CT and indocyanine green (ICG) fluoroscopy followed by LNE which served as ground truth. Results: FDG-PET/MRI was highly specific in N-staging (97.2%) but revealed limited sensitivity (66.7%) due to missed micrometastases. In contrast, bilateral SLN mapping failed more often in patients with macrometastases. The combination of SLN mapping and FDG-PET/MRI increased the sensitivity from 66.7% to 77.8%. Additional SLN labeling with dye (ICG) revealed a complete SLN mapping in 80% (8/10) of patients with failed or incomplete SLN detection in SPECT/CT, reducing the need for diagnostic systematic LNE up to 87%. FDG-PET/MRI detected para-aortic LNM in three out of four cases and a liver metastasis. Conclusions: The combination of FDG-PET/MRI and SLNE can reduce the need for diagnostic systematic LNE by up to 87%. PET/MRI complements the SLN technique particularly in the detection of para-aortic LNM and occasional distant metastases. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. Methods: ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model's overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). Results: A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761–0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595–0.800) as Brier score has been calculated 0.09. Conclusions: We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC. [ABSTRACT FROM AUTHOR]

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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. Despite often having unfavorable pathological features, women with pathogenic DNA polymerase epsilon (POLE)–mutated endometrial cancers have excellent cancer‐specific clinical outcomes, and this highlights the importance of molecular subtyping for endometrial cancer classification. Adjuvant therapy is not associated with improved outcomes for women with pathogenic POLE‐mutated endometrial cancers, and this supports de‐escalation of therapy for these patients in clinical trials. [ABSTRACT FROM AUTHOR]

Background The impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side effects of this procedure, including lymphedema and lymph cysts, are evident. Primary Objective Evaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence. Study Hypothesis Comprehensive pelvic and paraaortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65. Trial Design Open label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingooophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended. Major Inclusion Criteria Patients with histologically confirmed endometrial cancer stages pT1b--pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible. Exclusion Criteria Patients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease. Primary Endpoint Overall survival calculated from the date of randomization until death. Sample Size 640 patients will be enrolled in the study. Estimated Dates for Completing Accrual and Presenting Results At present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the oncologic and reproductive outcome of a conservative treatment with progestin agents in early-stage grade 1 endometrial cancer (G1EC), grade 2 endometrial cancer (G2EC) or complex atypical hyperplasia (CAH) in young premenopausal women. Methods: Women treated for early-stage endometrial cancer or atypical hyperplasia of the endometrium with a conservative therapy between 2006 and 2018 were enrolled in this retrospective analysis. Progestin agents were orally administered on a daily basis for 3 months for at least one cycle. Endometrial tissue was obtained by hysteroscopy and Dilatation & Curettage (D&C) being performed before and after end of treatment. Therapeutic response was assessed by pathological examination. Results: A total of 14 patients were included. After treatment with progestin agents, 11 of these patients initially showed a complete or partial response. Three patients with early-stage endometrial cancer did not respond. Of the three patients with initially diagnosed atypical hyperplasia, none showed any remaining disease later. Of the eight patients with initially diagnosed endometrial cancer, who had responded to first treatment, three patients were re-diagnosed with endometrial cancer later. One patient with initial endometrial cancer became pregnant but aborted in the 10th week. Conclusion: Due to its good efficacy, progestin agents offer a feasible therapeutic option in the fertility-preserving treatment of early-stage endometrial cancer in young premenopausal women. However, recurrence rate remains high. Therefore, a close follow-up is mandatory, also in responders. Patients should be informed of limitations and risks of conservative treatment. Yet after completion of family planning, hysterectomy should be performed. [ABSTRACT FROM AUTHOR]

Background Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with highintermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. Primary objectives To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecularintegrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy Study hypothesis Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. Trial design A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profilebased adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). Major inclusion/exclusion criteria Women aged 18 years and over with a histological diagnosis of highintermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). Endpoints The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. Sample size 500 eligible and evaluable patients. Estimated dates for completing accrual and presenting results Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of secretory cells (MPST) and several markers of ciliated cells (FAM92B, WDR16, and DYDC2) were validated by immunohistochemistry on organoids and tissue sections. We performed single cell sequencing on endometrial and ovarian tumours and found both secretory‐like and ciliated‐like tumour cells. We found that ciliated cell markers (DYDC2, CTH, FOXJ1, and p73) and the secretory cell marker MPST were expressed in endometrial tumours and positively correlated with disease‐specific and overall survival of endometrial cancer patients. These findings suggest that expression of differentiation markers in tumours correlates with less aggressive disease, as would be expected for tumours that retain differentiation capacity, albeit cryptic in the case of ciliated cells. These markers could be used to improve the risk stratification of endometrial cancer patients, thereby improving their management. We further assessed whether consideration of MPST expression could refine the ProMiSE molecular classification system for endometrial tumours. We found that higher expression levels of MPST could be used to refine stratification of three of the four ProMiSE molecular subgroups, and that any level of MPST expression was able to significantly refine risk stratification of the copy number high subgroup which has the worst prognosis. Taken together, this shows that single cell sequencing of putative cells of origin has the potential to uncover novel biomarkers that could be used to guide management of cancers. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations – POLEmut, MMR deficiency – MMRd, p53 abnormal – p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple‐classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple‐classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd–p53abn), 31 with POLEmut (POLEmut–p53abn), and 12 with all three aberrations (MMRd–POLEmut–p53abn). MMRd–p53abn ECs and POLEmut–p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd–p53abn ECs and 7/15 (46.7%) POLEmut–p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd–p53abn tumours mostly clustered with single‐classifier MMRd tumours (20/23) rather than single‐classifier p53abn tumours (3/23), while POLEmut–p53abn tumours mostly clustered with single‐classifier POLEmut tumours (12/13) and seldom with single‐classifier p53abn tumours (1/13) (both p ≤ 0.001, chi‐squared test). Finally, the clinical outcome of patients with MMRd–p53abn and POLEmut–p53abn ECs [stage I 5‐year recurrence‐free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single‐classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd–p53abn EC as MMRd and POLEmut–p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE‐ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE‐score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co‐existent with MSI‐H showed genomic alterations characteristic of POLE‐ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI‐H and a pathogenic POLE EDM had a 5‐year recurrence‐free survival (RFS) of 92.3%, comparable to previously reported POLE‐ultramutated ECs. Additionally, 14 cases with non‐pathogenic POLE EDM and MMRd/MSI‐H had a 5‐year RFS of 76.2%, similar to MMRd/MSI‐H, POLE wild‐type ECs, suggesting that these should be categorised as MMRd, rather than POLE‐ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Objective: In cancer patients, the pathology report serves as an important basis for treatment. Therefore, a correct cancer diagnosis is crucial, and diagnostic discrepancies may be of clinical relevance. It was the aim of this study to perform a specialized histopathology review and to investigate potential clinical implications of expert second opinion pathology in endometrial cancer. Methods: Patients treated for endometrial carcinoma at the Tübingen University Women's hospital between 2003 and 2013 were identified. Original pathology reports were reviewed, and contributing pathologists were asked to submit original slides and paraffin blocks. Case review was subsequently performed by 3 pathologists specialized in gynecological pathology who were blinded for clinical information. For histological typing, the World Health Organization 2014 classification was used, grading and staging were performed according to International Federation of Gynecology and Obstetrics 2009. Risk assignment was performed based on the 2013 European Society for Medical Oncology clinical practice guidelines. Results: In 565 of 745 cases, which had originally been diagnosed as endometrial carcinoma, archival histological slides and blocks were available. In 55 (9.7%) of 565 cases, a major diagnostic discrepancy of potential clinical relevance was found after expert review. In 38 of these 55 cases, the diagnostic discrepancy was related to tumor type (n = 24), grade (n = 10) or myoinvasion (n = 4). In 17 cases, the diagnosis of endometrial carcinoma could not be confirmed (atypical hyperplasia, n = 10; endometrial carcinosarcoma, n = 4; neuroendocrine carcinoma, n = 1; leiomyosarcoma, n = 1; atypical polypoid adenomyoma, n = 1). Minor discrepancies not changing risk classification were also noted in 214 (37.9%) of 565, most frequently for grade within the low-grade (G1/G2) category (n = 184). Conclusions: A retrospective gynecopathological case review was shown to reveal limited but significant discrepancies in histological diagnoses as well as typing and grading of endometrial carcinomas, some directly impacting clinical management. Second opinion pathology therefore not only helps to improve the quality of translational research study cohorts but might also help to optimize patient care in difficult cases. [ABSTRACT FROM AUTHOR]

Purpose: Low- and intermediate-risk endometrial carcinomas have an excellent prognosis. Nonetheless, a small subgroup of such patients will experience unexpected relapse. Recently L1CAM was suggested to be a strong prognosticator in endometrial carcinoma. The focus of our study was on low- and intermediate-risk disease, where no or only limited adjuvant treatment is recommended according to current guidelines. Methods: Endometrial carcinomas of low, intermediate and high-intermediate risk according to published 2016 consensus guidelines were identified. The study was limited to cases with previous central pathology review focusing on histotype, depth of myometrial invasion, presence of lymphovascular space invasion (LVSI) and MELF pattern of invasion. Standard L1CAM immunohistochemistry was performed. Disease-specific uni- and multivariate survival analyses were calculated. Results: A total of 344 cases were available for immunohistochemistry (low-risk: n = 250; intermediate-risk: n = 67; high-intermediate-risk: n = 27). L1CAM positivity rates were: 29/344 (8.4 %; all cases), 18/250 (7.2 %; low-risk), 6/67 (9.0 %; intermediate-risk) and 5/27 (18.5 %; high-intermediate-risk). Expression of L1CAM was independent of LVSI and MELF. L1CAM was a significant independent prognosticator for disease-specific survival with a hazard ratio of 5.98 [CI 1.50-22.14, p = 0.012]. Adverse prognostic significance of L1CAM positivity was maintained after low-risk subgroup analysis (5-year disease-specific survival rates 71.8 vs. 100 %, p < 0.0001). All four tumour-related deaths in the subgroup of low-risk disease occurred in patients with L1CAM-positive tumours. Conclusion: The current definition of 'low-risk' in endometrial carcinoma should be amended. 'Low-risk carcinomas' should be limited to L1CAM-negative tumours. L1CAM status will play a key role in future algorithms to tailor adjuvant treatment and patient follow-up strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: The scientific community widely agrees that molecular classification will be key to endometrial carcinoma therapeutic strategies in the future. Retrospective analyses of large endometrial carcinoma patient cohorts gave rise to a new understanding of one of the most relevant gynecologic malignancies. Potentially replacing the current type I and type II terminology, four molecular subtypes have been established, each of them reflecting underlying molecular aberrations and distinct clinical behavior. Future research will have to focus on how to integrate these new findings into clinical practice with the ultimate goal to drive personalized endometrial carcinoma patient care forward. Endometrial cancer has been histologically classified as either an estrogen-dependent cancer with a favorable outcome or an estrogen-independent cancer with a worse prognosis. These parameters, along with the clinical attributions, have been the basis for risk stratification. Recent molecular and histopathological findings have suggested a more complex approach to risk stratification. Findings from the Cancer Genome Atlas Research Network established four distinctive genomic groups: ultramutated, hypermutated, copy-number low and copy-number high prognostic subtypes. Subsequently, more molecular and histopathologic classifiers were evaluated for their prognostic and predictive value. The impact of molecular classification is evident and will be recognized by the upcoming WHO classification. Further research is needed to give rise to a new era of molecular-based endometrial carcinoma patient care. [ABSTRACT FROM AUTHOR]

Mismatch repair (MMR) deficiency is found in 20 to 40% of endometrial cancers (ECs) and was recently identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas. There is accumulating evidence that MMR proteins are involved in the DNA repair processes following radiotherapy. We investigated the predictive value of MMR status for response to adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between adjuvant treatment and outcome. A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p = 0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n = 55], vaginal brachytherapy [n = 27]). In multivariable analysis, adjuvant radiotherapy was associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05–0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37–2.31). Adjuvant radiotherapy improved survival in patients with MMR-deficient EECs. MMR status could be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy. • MMR-deficiency is a common feature of grade 3 endometrioid endometrial cancer (EEC). • Radiotherapy improved survival in patients with MMR-deficient EECs. • Patients with MMR-proficient ECs did not experience improved survival after radiotherapy. • MMR status could be used to select patients that benefit most from adjuvant radiotherapy. [ABSTRACT FROM AUTHOR]

Approximately 15% of endometrial carcinomas (ECs) arise in young women who may wish to avoid surgical menopause and/or preserve fertility. Our aim was to evaluate the prognostic significance of Proactive Molecular risk classifier for Endometrial Carcinoma (ProMisE) in young (<50 yo) women with EC. ProMisE was applied to a retrospective cohort of women with ECs <50 yo at diagnosis, and associations between the four ProMisE molecular subtypes (MMR deficient (MMRd), POLE mutated (POLE), p53 wild type (p53wt), and p53 abnormal (p53abn)) and clinicopathological parameters, including outcomes, were assessed. Of 257 ECs, there were 48 (19%) MMRd, 34 (13%) POLE, 164 (64%) p53wt and 11 (4%) p53abn. ProMisE subtypes were associated with differences in all measured clinicopathological parameters except for presence of synchronous ovarian tumours and fertility. Age at diagnosis was youngest and BMI highest in women with p53wt ECs. MMRd and p53abn tumours were more likely to be advanced stage (III/IV), high-risk (ESMO), and receive chemotherapy. ProMisE subtypes were strongly associated with outcomes (overall, disease-specific, and progression-free survival (p < 0.0001 for all)). Advanced stage, grade, LVSI, myometrial invasion and ESMO risk groups showed associations with some but not all survival parameters. ProMisE maintained a strong association with OS and DSS on multivariable analysis. ProMisE molecular classification is prognostic in young women with EC, enabling early stratification and risk assignment to direct care. Further studies can assess response to therapy, fertility, and cancer-related outcomes within the framework of molecular subtype. • Management of young women with endometrial carcinoma (EC) presents unique challenges, impacting fertility and menopause. • Better tools are needed to help direct management, identifying patients for whom conservative management is safe. • Molecular classification enables consistent categorization of ECs and biologically relevant information to guide care. • Molecular subtype is prognostic in young women with EC and achievable on biopsies enabling risk stratification from first diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: Molecular classification of endometrial cancer (EC) has been shown to have a strong prognostic value. Recent data support the predictive implications of molecular subtype assignment. Using combined EC cohorts that have undergone molecular classification, our objective was to assess the response to adjuvant therapy based on ESMO 2016 risk group criteria within the four molecular subtypes (MMRd, POLE mut, NSMP, and p53abn). Methods: Historical institutional (29%) and population-based cohorts of EC from 2016 (53%) and prior to 2016 (18%) that had undergone molecular classification were identified. We assessed outcomes (overall, disease-specific, or progression-free survival [OS, DSS, PFS]) based on the adjuvant treatment given, including none, vault brachytherapy (VB) only, external beam radiation (EBRT) ± VB, or chemotherapy (± any RT including EBRT or VB) across ESMO risk groups (low, intermediate, high-intermediate, high and advanced/metastatic) within the four molecular subtypes. Results: A total of 2495 ECs were included; 1997 were endometrioid carcinomas (69.9% grade 1-2), 277 serous carcinomas, 73 clear cell carcinomas, 45 carcinosarcomas, 75 mixed tumors, ten undifferentiated, six dedifferentiated, and 12 were unknown. Among the cases, 58.7% were stage IA, 18.3% stage IB, and 23% stage II-IV. The molecular subtypes were 641 (25.6%) MMRd, 184 (7.4%) POLE mut, 1233 (49.5%) NSMP and 437 (17.5%) p53abn. ESMO 2016 risk groups for the total cohort were 41.7% low, 8.3% intermediate, 10.1% high-intermediate, 37.3% high, 0.3% advanced, and 2.3% metastatic. No adjuvant treatment was given in 53.9% of the total cohort, with 14.1% receiving VB only, 9.6% receiving EBRT ± VB, and 22.4% receiving chemotherapy ± RT. In patients with MMRd and NSMP ECs, there was no observed benefit in OS, DSS, or PFS from chemotherapy used either alone or in combination with radiation compared to radiation only across any of the ESMO risk groups or when ESMO high, advanced, and metastatic risk groups were combined. In patients with p53abn EC, there was a trend (0.054) towards improved OS, DSS, and PFS with the use of chemotherapy compared to radiation alone in the ESMO high, advanced and metastatic risk groups combined (Figure 1). Adjuvant treatment was not associated with outcomes in POLE mut EC. [Display omitted] Conclusions: Although retrospective data regarding where the treatment was given was not confined to clinical trial parameters and need to be interpreted with caution, these results are consistent with the PORTEC3 trial subgroup analysis showing chemotherapy does not appear to add benefit within MMRd EC but may improve outcomes for patients with p53abn EC. These findings support molecular subtype-directed trials, such as radiation alone ± investigational agent for MMRd, chemotherapy ± investigational agent for p53abn, and de-escalation of adjuvant therapy for POLE mut EC. [ABSTRACT FROM AUTHOR]