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Objective. Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to de-termine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1- methylated tumors.Methods. We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4

We would like to thank ‘the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands’ for their contribution and ongoing support to the EPIC Study., This work was undertaken during the tenure of a doctoral Fellowship supported by INCa (INCa 2016 − 184), by Fondation ARC pour la recherche sur le cancer (ARC 2019-DOC4) and by IARC. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (C864/A 14136 to EPIC- Norfolk (DOI https://doi.org/10.22025/2019.10.105.00004); C8221/A29017 to EPIC-Oxford), Medical Research Council (MR/N003284/1 and MC_UU_00006/1 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford). (United Kingdom)., Data Availability For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php., Background: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. Results: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5-Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. Conclusion: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer., Institut National du Cancer (INCA) France C864/A 14136, Fondation ARC pour la Recherche sur le Cancer ARC 2019-DOC4, IARC, World Health Organization. International Agency for Research on Cancer (IARC), Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Centre (BRC), Danish Cancer Society, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe. German Cancer Aid, Helmholtz Association, German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund International (WCRF), Netherlands Government, Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vaesterbotten (Sweden), Cancer Research UK C8221/A29017 MR/N003284/1, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MC_UU_00006/1 MR/M012190/1 2016 - 184

Introduction Cervical cytology is a well‐stablished cervical cancer screening method. However, due to the anatomical continuity of the genital tract, it can also detect signs of endometrial disease. Our aim was to estimate the sensitivity of cervical cytology in endometrial cancer detection and prognosis in a large population over a 30‐year period in a large academic tertiary hospital in Spain. Methodology We performed a search for women diagnosed with endometrial cancer from 1990 to 2020, who were surgically treated and had a previous cervical cytology result. Information Technologies Department databases from Bellvitge University Hospital and the Screenwide case–control study's database were used. Cervical cytology results were classified as abnormal when squamous lesions, glandular atypia or malignant cells were identified. Results Overall, we evaluated 371 women with endometrial cancer and a documented cervical cytology performed within 3 years previous to surgical treatment. Overall, the sensitivity of cervical cytology for endometrial cancer detection was 25.6%. Several clinico‐pathological characteristics, such as non‐endometrioid histology and a higher stage, were correlated with higher sensitivity. Discussion We observed a low sensitivity of cervical cytology to effectively diagnose endometrial cancer. However, recent technological advances using genomics and epigenomics may offer a promising perspective to detect endometrial cancer with high sensitivity in these cervical specimens., Cervical cytology sensitivity for endometrial cancer was 25.6%. Several clinico‐pathological factors, such as non‐endometrioid histology and a higher stage, were correlated with higher sensitivity.

BackgroundDespite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear.MethodsTo better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+and CD4+EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+and CD4+TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+and CD4+tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival.ResultsWe found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1−and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+and PD-1hiCD39+T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hicompared with PD-1−or PD-1dimT cells, and in fact, it was the CD4+PD-1hisubpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hitumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+TILs and PD-1hiand CXCL13 by CD4+Tconv TILs, correlated with prolonged survival of patients with EC.ConclusionsOur results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hiand CD39 or PD-1hican be used to select and expand CD8+and CD4+tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+and CD4+lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity.

Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case–control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue nationale contre le cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Helmholtz Association, German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund (WCRF-ERC) 232997, Netherlands Government, Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Junta de Andalucia, Principality of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of OncologyICO (Spain), Swedish Cancer Society Swedish Research Council, European Commission, County Council of Skane, County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017 C19335/A21351, UK Research & Innovation (UKRI), Medical Research Council UK (MRC), European Commission 1000143 MR/M012190/1

El càncer d'endometri és la neoplàsia ginecològica més freqüent a la nostra població. La majoria de pacients són diagnosticades en estadis inicials i tenen pronòstics favorables. Tot i així, un percentatge de pacients situat entre un 10% i un 20%, poden presentar recidives o diagnosticar-se en fases més avançades de la neoplàsia, per tant, la investigació en aquesta patologia ha centrar-se en desenvolupar noves estratègies per precisar el pronòstic i millorar les opcions terapèutiques. Les catecolamines, que intervenen com a neurotransmissors en resposta a l'estrès físic o emocional, s'han perfilat com un dels principals mediadors de la relació entre l'estrès crònic i la progressió del càncer. El treball que es planteja en aquesta tesi doctoral sorgeix de la investigació amb mostres de pacients, amb models in vivo i amb línies cel·lulars de càncer d'endometri per tal de caracteritzar el paper dels receptors catecolaminèrgics en la progressió d'aquest tipus tumoral. L'anàlisi dels nivells d'expressió a nivell de ARNm per als diferents subtipus de receptors catecolaminèrgics, associat a la revisió de resultats de la literatura, ha permès escollir ADRβ2, DRD1 i DRD2 com a principals dianes a ser avaluades mitjançant la tècnica immunohistoquímica. Les nostres dades suggereixen que el receptor adrenèrgic ADRβ2 no determina el pronòstic de les pacients avaluades, a diferència del que s'ha descrit en altres neoplàsies. Per la seva banda DRD1 presenta una expressió reduïda al tumor respecte al teixit endometrial sa. L'anàlisi de l'associació del receptor amb les variables clinico-patològiques suggereix que la seva expressió podria tenir una relació inversa en referència a la mida del tumor i a l'estadi tumoral. Finalment, l'anàlisi de DRD2 s'associa significativament al tipus histològic de càncer d'endometri no endometrioide, a tumors d'alt grau histològic i també a una pitjor supervivència lliure de malaltia i global en la cohort de pacients estudiada. A més, hem establert dos models xenògrafs derivats de mostres de pacient implantats a nivell ortotòpic en ratolí. Aquests models presenten una major rellevància traslacional i clínica. El model generat a partir del tumor END 17 presenta una progressió més ràpida i un pes mitjà tumoral final superior al model END 19, alhora que una supervivència menor; definint-se per tant com un potencial model de CE agressiu. A més, s'ha confirmat en tots dos models la conservació de les característiques del tumor original a partir del perfil immunohistoquímic i del patró d'expressió dels receptors catecolaminèrgics al tumor generat. D'altra banda, l'experimentació in vitro ens ha permès avaluar l'efecte de la neuromodulació de les vies de senyalització adrenèrgica i dopaminèrgica en línies cel·lulars representatives de CE i la seva potencial utilització en teràpia antitumoral. La combinació de l'agonisme de DRD1 i de l'antagonisme de DRD2 ha induït una reducció significativament superior en la capacitat de proliferació cel·lular de la línia AN3CA, comparat amb el seu tractament en monoteràpia, representant una nova estratègia terapèutica. La informació obtinguda en aquest projecte aporta a la comunitat científica nou coneixement sobre el paper dels receptors catecolaminèrgics en càncer d'endometri. La seva aplicació a nivell pronòstic i/o terapèutic podria contribuir a millorar el maneig clínic de les pacients que el pateixen. A partir d'aquest punt, es poden definir dues vies d'actuació. En primer lloc, prosseguir l'experimentació per caracteritzar més detalladament, la contribució nerviosa al microentorn tumoral i els mecanismes implicats en aquesta contribució. En segon lloc, avaluar l'efectivitat terapèutica de la combinació d'agonistes i antagonistes a nivell preclínic, i valorar el reposicionament d'alguns fàrmacs ja aprovats i que podrien tenir noves aplicacions a nivell oncològic. El cáncer de endometrio (CE) es la neoplasia ginecológica más frecuente en nuestra población. La mayoría de pacientes son diagnosticadas en estadios tempranos y tienen pronósticos favorables. Aun así, un porcentaje de pacientes situado entre un 10% y un 20%, pueden presentar recidivas o diagnosticarse en fases más avanzadas de la neoplasia, por lo que la investigación en esta patología debe colaborar en el desarrollo de nuevas estrategias para precisar el pronóstico y las opciones terapéuticas. Las catecolaminas, que intervienen como neurotransmisores en respuesta al estrés físico o emocional, se han perfilado como uno de los principales mediadores de la relación entre el estrés crónico y la progresión del cáncer. El trabajo que se plantea en esta tesis doctoral surge de la investigación con muestras de pacientes, modelos in vivo y líneas celulares de cáncer de endometrio con el objetivo de caracterizar el papel de los receptores catecolaminérgicos en la progresión de este tipo tumoral. El análisis de los niveles de expresión a nivel de ARNm para los distintos subtipos de receptores catecolaminérgicos, asociado a la revisión de resultados de la literatura, ha permitido escoger ADRβ2, DRD1 y DRD2 como principales dianas a evaluar por la técnica inmunohistoquímica. Nuestros datos sugieren el receptor adrenérgico ADRβ2 no determina el pronóstico de las pacientes evaluadas, a diferencia de lo que se ha descrito en otras neoplasias. Por su parte DRD1 presenta una expresión reducida en el tumor con respecto al tejido endometrial sano. El análisis de la asociación del receptor con las variables clínico-patológicas sugiere que su expresión podría tener una relación inversa en referencia al tamaño y al estadio tumoral. Finalmente, el análisis de DRD2, se asocia significativamente al tipo histológico de cáncer de endometrio no endometrioide, a tumores de alto grado histológico y también a una peor supervivencia libre de enfermedad y global en la cohorte de pacientes estudiada. Además, hemos establecido dos modelos xenógrafos derivados de muestras de paciente implantados a nivel ortotópico en ratón. Estos modelos presentan una mayor relevancia traslacional y clínica. El modelo generado a partir del tumor END 17 presenta una progresión más rápida y un peso medio tumoral final superior al modelo END 19, a la vez que una supervivencia menor; definiéndose como potencial modelo de CE agresivo. Además, se ha confirmado en ambos modelos la conservación de las características del tumor original a partir del perfil inmunohistoquímico y del patrón de expresión de los receptores catecolaminérgicos en el tumor generado. Por otra parte, la experimentación in vitro, nos ha permitido evaluar el efecto de la neuromodulación de las vías de señalización adrenérgica y dopaminérgica en líneas celulares representativas de CE, y su potencial utilización en terapia antitumoral. La combinación del agonismo de DRD1 y del antagonismo de DRD2 ha inducido una reducción significativamente mayor en la capacidad de proliferación celular de la línea AN3CA, comparado con su tratamiento en monoterapia, representando una novedosa estrategia terapéutica. La información obtenida de este proyecto aporta a la comunidad científica nuevo conocimiento sobre el papel de los receptores catecolaminérgicos en cáncer de endometrio. Su aplicación a nivel pronóstico y/o terapéutico, podría contribuir a mejorar el manejo clínico de las pacientes. A partir de este punto, se pueden definir dos vías de actuación. En primer lugar, proseguir la experimentación para caracterizar más en detalle, la contribución nerviosa al microentorno tumoral y los mecanismos implicados en dicha contribución. En segundo lugar, evaluar la efectividad terapéutica de la combinación de agonistas y antagonistas a nivel preclínico, y valorar el reposicionamiento de algunos fármacos ya aprobados que podrían tener nuevas aplicaciones a nivel oncológico. Endometrial cancer is the most common gynecologic malignancy in our population. Most patients are diagnosed in early stages and have favorable prognoses. However, somewhere between 10% and 20% of those patients may present recurrences or be diagnosed in more advanced stages. Therefore, researchers must make a concerted effort to develop new strategies to optimize the prognosis and offer new therapeutic options for this pathology. Catecholamines, which act as neurotransmitters in response to physical or emotional stress, have emerged as one of the main mediators of the relationship between chronic stress and cancer progression. There are data suggesting that tumor cells use neurotransmitters and their neuroreceptors to activate the mechanisms of tumor growth and metastasis via nerve fibers that are part of the so-called tumor microenvironment. The project proposed in this doctoral thesis arises from research based on patient samples, in vivo models and established cell lines of endometrial cancer to characterize the role of catecholaminergic receptors in the progression of this tumor. The analysis of the mRNA expression levels for the different subtypes of catecholaminergic receptors along with the results seen in a review of the literature, has made it possible to choose ADRβ2, DRD1 and DRD2 as the main targets to be evaluated by means of the immunohistochemical technique. Our data suggest that ADRβ2 does not determine the prognosis of the patients evaluated, unlike what has been described in other tumor types. On the other hand, DRD1 has a reduced expression in the tumor tissue compared to healthy endometrial tissue. The analysis of the association of the receptor with clinicopathological variables suggests that its expression may have an inverse relationship with tumor size and stage. Finally, DRD2 expression analysis is significantly associated with non-endometrioid endometrial cancer, high grade FIGO classification tumors and worse disease-free and overall survival in the cohort of patients studied. In addition, we have established two patient-derived xenograft models from patient samples implanted orthotopically in mice. These models have greater translational and clinical relevance. Initially, its viability as well as its capacity for tumor implantation and dissemination have been verified. The model generated from the END 17 tumor shows a more rapid progression and a greater tumor weight as well as shorter survival than the END 19 model, thereby defining itself as a potential model of aggressive endometrial cancer. In addition, the conservation of the characteristics of the original tumor has been confirmed in both models based on the immunohistochemical profile and the expression pattern of the catecholaminergic receptors in the generated tumor. In the end, in vitro experimentation has made it possible to evaluate the effect of neuromodulation of adrenergic and dopaminergic signaling pathways in cell lines representative of EC and its potential use in antitumor therapy. The combination of DRD1 agonism and DRD2 antagonism induce a significantly greater reduction in the cell proliferation capacity of the AN3CA cell line, compared to its monotherapy treatment, representing a new therapeutic strategy. The information obtained from this project provides new knowledge to the scientific community on the role of catecholaminergic receptors play in endometrial cancer. Its application as a prognostic and/or therapeutic tools may well contribute to improving the clinical management of affected patients. From this point, two courses of action can be defined. First, continued experimentation to further characterize the nervous contribution to the tumor microenvironment and the mechanisms involved in endometrial cancer is called for. Second, there is a need to evaluate the therapeutic effectiveness of the combination of agonists and antagonists at a preclinical level and to assess the repositioning of some drugs already approved that might have new applications for oncological treatment.

Simple Summary PTEN is a protein highly altered in endometrial cancer. PTEN mutation or deficiency leads to the activation of other downstream proteins that are important to the development of cancers. In this study, we have identified the SMAD2/3 proteins as targets of PTEN deficiency. We have found that loss of PTEN in endometrial cells leads to SMAD2/3 activation. To investigate the role of SMAD2/3 activation downstream of PTEN deficiency, we have used endometrial cells lacking both PTEN and SMAD2/3 proteins. These cells display even more tumorigenic potential than cells lacking only PTEN. These results suggest that SMAD2/3 acts as an obstacle for cancer development triggered by PTEN loss. Abstract TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal transduction pathways have an important role in the regulation of epithelial cell homeostasis and perturbations in either of these two pathways’ contributions to endometrial carcinogenesis. We have previously demonstrated that both PTEN and SMAD2/3 display tumor-suppressive functions in the endometrium, and genetic ablation of either gene results in sustained activation of PI3K/AKT signaling that suppresses TGF-β-induced apoptosis and enhances cell proliferation of mouse endometrial cells. However, the molecular and cellular effects of PTEN deficiency on TGF-β/SMAD2/3 signaling remain controversial. Here, using an in vitro and in vivo model of endometrial carcinogenesis, we have demonstrated that loss of PTEN leads to a constitutive SMAD2/3 nuclear translocation. To ascertain the function of nuclear SMAD2/3 downstream of PTEN deficiency, we analyzed the effects of double deletion PTEN and SMAD2/3 in mouse endometrial organoids. Double PTEN/SMAD2/3 ablation results in a further increase of cell proliferation and enlarged endometrial organoids compared to those harboring single PTEN, suggesting that nuclear translocation of SMAD2/3 constrains tumorigenesis induced by PTEN deficiency.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary 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 & 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. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway. However, whether MRE11A is a true predisposition gene for HBOC is still questionable. We determined to investigate this notion by dissecting the molecular genetics of the c.1516G > T;p.E506* truncating MRE11A variant, that we pinpointed in two unrelated French-Canadian (FC) HBOC patients. We performed a case–control study for the variant in ~ 2500 breast, ovarian, and endometrial cancer patients from the founder FC population of Quebec. Furthermore, we looked for the presence of second somatic alterations in the MRE11A gene in the tumors of the carriers. In summary, these investigations suggested that the identified variant is not associated with an increased risk of developing breast or ovarian cancer. We finally performed a systematic review for all the previously reported MRE11A variants in breast and ovarian cancer. We found that MRE11A germline variants annotated as pathogenic on ClinVar often lacked evidence for such classification, hence misleading the clinical management for affected patients. In summary, our report suggests the lack of clinical utility of MRE11A testing in HBOC, at least in the White/Caucasian populations.

Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals.Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals; EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort.Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.

Purpose To evaluate the preliminary results of the use of 68 Gy EQD2(α/β=3 Gy) as a dose limit to the lowest dose in the most exposed 2 cm3 of the vagina in order to reduce G2 late vaginal problems in postoperative endometrial carcinoma (EC). Methods From November 2016 to October 2019, 69 postoperative EC patients receiving vaginal brachytherapy (VBT) ± external beam radiotherapy (EBRT) were prospectively analyzed. The median EBRT dose was 45 Gy (range: 44–50.4 Gy), 1.8−2 Gy/day, 5 fractions(Fr)/week. VBT was administered with the following schedule: 1Fr of 7 Gy after EBRT and 2 daily Fr × 7.5 Gy in exclusive VBT. The dose was prescribed at 0.5 cm from the applicator surface with an active length of 2.5 cm; 56 patients were treated with vaginal cylinders (49–3.5 cm, 6–3 cm, and 1–2.5 cm) and 13 with the colpostat technique. The overall VBT dose was adjusted to meet the vaginal restriction of (α/β=3 Gy) at 2 cm3. Late toxicity was prospectively assessed using RTOG scores for bladder and rectum, and the objective LENT-SOMA criteria for vagina. Results With a median follow-up of 31.0 months, no vaginal-cuff recurrences were found. Late toxicity: only 1G1(1.4%) rectal toxicity; 21G1(30.4%) and 3G2(4.3%) vaginal complications. Only one (1.4%) of 3 G2 manifested as vaginal shortening. Conclusions In postoperative EC patients treated with VBT, only one developed G2 vaginal stenosis with the use of 68 Gy EQD2(α/β=3 Gy) as a dose constraint. These preliminary results seem to indicate the value of this dose limit for reducing G2 vaginal stenosis. Nonetheless, these findings should be confirmed in a larger number of patients with longer follow-up.

Objective. Endometrial cancers have historically been classified by histomorphologic appearance, which is subject to interobserver disagreement. As molecular and biomarker testing has become increasingly available, the prognostic significance and accuracy of histomorphologic diagnoses have been questioned. To address these issues for a large, prospective cohort study, we provide the results of a centralized pathology review and biomarker analysis of all incidental endometrial carcinomas occurring between 1976 and 2012 in the Nurses’ Health Study. Methods. Routine histology of all ( n = 360 ) cases was reviewed for histomorphologic diagnosis. Cases were subsequently planted in a tissue microarray to explore expression of a variety of biomarkers (e.g., ER, PR, p53, PTEN, PAX2, AMACR, HNF1β, Napsin A, p16, PAX8, and GATA3). Results. Histologic subtypes included endometrioid (87.2%), serous (5.6%), carcinosarcoma (3.9%), clear cell (1.7%), and mixed type (1.7%). Biomarker results within histologic subtypes were consistent with existing literature: abnormal p53 was frequent in serous cases (74%), and HNF1β (67%), Napsin A (67%), and AMACR (83%) expression was frequent in clear cell carcinomas. Our dataset also allowed for examination of biomarker expression across non-preselected histologies. The results demonstrated that (1) HNF1β was not specific for clear cell carcinoma, (2) TP53 mutations occurred across many histologies, and (3) GATA3 was expressed across multiple histotypes, with 75% of positive cases demonstrating high-grade features. Conclusions. Our findings establish the subtypes of endometrial cancer occurring in the Nurses’ Health Study, corroborate the sensitivity of certain well-established biomarkers, and call into question previously identified associations between certain biomarkers (e.g., HNF1B) and particular histotypes.

Background: The causal link between elevated systemic inflammation biomarkers and poor survival has been demonstrated in cancer patients. However, the evidence for this correlation in endometrial cancer (EC) is too weak to influence current criteria of risk assessment. Here, we examined the role of inflammatory indicators as a tool to identify EC patients at higher risk of death in a retrospective observational study. Methods: A total of 155 patients surgically diagnosed with EC stage I-III FIGO 2009 and treated with postoperative External Beam Radiotherapy (EBRT) &plusmn, brachytherapy and chemotherapy according to ESMO-ESTRO-ESGO recommendation for patients at high risk of recurrence at the Gustave Roussy Institut, France, and Hospital Cl&iacute, nic, Spain, between 2008 and 2017 were evaluated. The impact of pre-treatment Neutrophil-to-Lymphocyte Ratio (NLR &ge, 2.2), Monocyte-to-Lymphocyte Ratio (MLR &ge, 0.18), Systemic Immune-Inflammatory Index (SII &ge, 1100) and lymphopenia (&lt, 1.0&times, 109/L) on overall survival (OS), cancer-specific survival and progression-free survival was evaluated. Subsequently, a cohort of 142 patients within high-advanced risk groups according to ESMO-ESGO-ESTRO classification was evaluated. Results: On univariate analysis, NLR (HR = 2.2, IC 95% 1.1&ndash, 4.7), SII (HR = 2.2, IC 95% 1.1&ndash, 4.6), MLR (HR = 5.0, IC 95% 1.1&ndash, 20.8) and lymphopenia (HR = 3.8, IC 95% 1.6&ndash, 9.0) were associated with decreased OS. On multivariate analysis, NLR, MLR, SII and lymphopenia proved to be independent unfavorable prognostic factors. Conclusions: lymphopenia and lymphocytes-related ratio are associated with poorer outcome in surgically staged I-III FIGO EC patients classified as high risk and treated with adjuvant EBRT and could be considered at cancer diagnosis. External validation in an independent cohort is required before implementation for patients&rsquo, stratification.

Endometrial cancer (EC) incidence rates vary ~10‐fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low‐risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow‐up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2) and HT use (to all non‐HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks., What's new? Endometrial cancer rates vary considerably around the world, with incidence rates higher in Europe and North America than in parts of Asia and Africa. Here, the authors investigated how much of the risk disparity arises from modifiable factors, and how much modifying these factors could reduce cancer incidence. The 10% of European women with lowest risk had similar incidence to women in low‐risk countries, they found. Their model predicted that in European women, maintaining BMI below 23 kg/m2 and avoiding postmenopausal hormone use could reduce risk by 30%. Long‐term use of oral contraceptives could reduce risk by 42.5%.

Background: To evaluate whether EQD2(&alpha, /&beta, = 3Gy) at 2 cm3 of the most exposed area of the vagina is related to late vaginal toxicity in postoperative endometrial cancer (PEC) patients (p) treated with exclusive brachytherapy (BT). Methods: From 2014 to 2017, 43p were included in this study. BT was administered: 3-fractions of 6Gy in 37p and 2-fractions of 7.5Gy in 6p. The dose was prescribed at a depth of 5 mm from the applicator surface with dose-point optimization based on distance. The active treatment length was 2.5 cm. CTV-D90 and the dose to the most exposed 2 cm3 of the vagina was calculated for each patient. Late toxicity of the bladder and rectum was assessed using Radiation Therapy Oncology Group (RTOG) criteria, and vaginal toxicity by objective Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) (LENT-SOMA) criteria. Statistics: frequency tables, mean, median, range, standard deviation, and box plot. Results: The median follow-up was 51 months (12&ndash, 68). 20 p (46.5%) and 2 p (4.7%) developed G1 and G2 vaginal complications, respectively. Only 1/2 p-G2 receiving EQD2(&alpha, = 3Gy) at 2 cm3 &gt, 68Gy presented vaginal shortening and 18/20 p-G1 received doses &lt, 68Gy. Conclusions: PECp receiving exclusive brachytherapy with doses &lt, 68Gy EQD2(&alpha, = 3Gy) at 2 cm2 of the vagina presented only G0&ndash, G1 vaginal toxicity, except for one with bleeding telangiectasias. Larger prospective studies are necessary to confirm the present results.

This work was supported by Cancer Research UK (CRUK) (grant number C19335/A21351, to MJG and HK) . The metabolomics infrastructure in the Division of Cancer, Imperial College London is supported by the Imperial College Experimental Can-cer Medicine Centre, the This work was supported by Cancer Research UK (CRUK) (grant number C19335/A21351, to MJG and HK) . The metabolomics infrastructure in the Division of Cancer, Imperial College London is supported by the Imperial College Experimental Can-cer Medicine Centre, the Imperial College Cancer Research UK Centre and the NIHR Imperial Biomedical Research Centre (APS & HK) . The co-ordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Im-perial Biomedical Research Centre (BRC) . The national cohorts are sup-ported by: Danish Cancer Society (Denmark) ; Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France) ; German Cancer Aid, German Cancer Research Center (DKFZ) , German Institute of Human Nutrition PotsdamRehbruecke (DIfE) , Federal Ministry of Education and Research (BMBF) (Germany) ; Associazione Italiana per la Ricerca sul CancroAIRCItaly, Compagnia di SanPaolo and National Research Council (Italy) ; Dutch Ministry of Public Health, Welfare and Sports (VWS) , Netherlands Can-cer Registry (NKR) , LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland) , World Cancer Research Fund (WCRF) , Statistics Netherlands (The Netherlands) ; Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII) , Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain) ; Swedish Cancer Society, Swedish Research Council and County Councils of Skkne and Vasterbotten (Sweden) ; Cancer Research UK (14136 to EPICNorfolk; C8221/A29017 to EPICOxford) , Medical Research Council (1000143 to EPICNorfolk; MR/M012190/1 to EPICOxford) . (United Kingdom) ., Background. Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from853 case-control pairs fromthe European Prospective Investigation into Cancer and Nutrition (EPIC). Methods. A total of 129metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. Results. After adjustment for body mass index, sphingomyelin [SM] C18:0was positively (OR1SD: 1.18,95%CI: 1.05–1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80–0.99; OR1SD: 0.89, 95% CI: 0.79–1.00 and OR1SD: 0.91, 95% CI: 0.81–1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02–1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00–1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. Conclusion. These findings suggest that variation in levels of glycine, serine, SMC18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention., Cancer Research UK C19335/A21351, Imperial College Experimental Cancer Medicine Centre Imperial College Cancer Research UK Centre, NIHR Imperial Biomedical Research Centre, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France) Institut Gustave Roussy (France) Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany) German Institute of Human Nutrition PotsdamRehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro Compagnia di San Paolo Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skkne (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/M012190/1

Ascitic fluid; Biomarkers; Endometrial cancer Líquido ascítico; Biomarcadores; Cáncer de endometrio Ascites; Biomarcadors; Càncer d'endometri Endometrial cancer (EC) is the sixth most common cancer in women worldwide and is responsible for more than 89,000 deaths every year. Mortality is associated with presence of poor prognostic factors at diagnosis, i.e., diagnosis at an advanced stage, with a high grade and/or an aggressive histology. Development of novel approaches that would permit us to improve the clinical management of EC patients is an unmet need. In this study, we investigate a novel approach to identify highly sensitive and specific biomarkers of EC using extracellular vesicles (EVs) isolated from the peritoneal lavage of EC patients. EVs of peritoneal lavages of 25 EC patients were isolated and their miRNA content was compared with miRNAs of EVs isolated from the ascitic fluid of 25 control patients. Expression of the EV-associated miRNAs was measured using the Taqman OpenArray technology that allowed us to detect 371 miRNAs. The analysis showed that 114 miRNAs were significantly dysregulated in EC patients, among which eight miRNAs, miRNA-383-5p, miRNA-10b-5p, miRNA-34c-3p, miRNA-449b-5p, miRNA-34c-5p, miRNA-200b-3p, miRNA-2110, and miRNA-34b-3p, demonstrated a classification performance at area under the receiver operating characteristic curve (AUC) values above 0.9. This finding opens an avenue for the use of EV-associated miRNAs of peritoneal lavages as an untapped source of biomarkers for EC. Funded by Generalitat de Catalunya, grant numbers SLT002/16/00274, 2017SGR1661, and 2017SGR1368; by CIBERONC, grant numbers CB16/12/00328 and CB16/12/00231; by Instituto Salud Carlos III, grant number PIE15/00029 and by Asociación Española Contra el Cáncer (AECC), grant number GCTRA1804MATI

Background: Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals. Methods: Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals, EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort. Results: Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (p = 0.04) and all-cause mortality cumulative incidence was 38.6% vs. 55.3% (p = 0.31), for ES and SS, respectively. Cumulative, incidence at 75 years was 11.2% vs. 46.3% for EC (p = 0.001) and 0% vs. 12.7% for OC (p N/A) and all-cause mortality cumulative incidence was 0% vs. 52.7% (p N/A), for RRGS vs. surveillance, respectively. Conclusions: RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.

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. This study was funded in part by the Dutch Cancer Society (KWF-UL2012-5719) (Dr. Bosse, Dr. Nout). This study was funded in part through the NIH/NCI Support Grant P30 CA008748 (Dr. Abu-Rustum, Dr. Levine, Dr. Soslow).

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Most patients are diagnosed at an early stage with a low risk of relapse. However, there is a group of patients with a high risk of relapse and poor prognosis. Despite the recent publication of randomized trials, the adjuvant treatment of high-risk EC is still to be defined and there are many open questions about the best approach and the right timing. Unfortunately, the survival of metastatic or recurrent EC is short, due to the poor results of chemotherapy and the lack of a second line of treatment. Advances in the knowledge of the molecular abnormalities in EC have permitted the development of promising targeted therapies.

Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC. However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response., This review was funded by grants from the Instituto de Salud Carlos III (ISCIII) (PIE15/00050 and PI16/00887) and CIBERONC (CB16/12/00316 and CB16/12/00231, CB16/12/00361), co-financed by the European Development Regional Fund. ‘A way to achieve Europe’ (FEDER), and by the Spanish Association Against Cancer Scientific Foundation (grants: AIO-aecc 2016 and Grupos Coordinados Traslacionales aecc 2018).

Endometrial cancer (EC) is the most common gynecologic malignancy of the female genital tract and the fourth most common neoplasia in women. In EC, myometrial invasion is considered one of the most important prognostic factors. For this process to occur, epithelial tumor cells need to undergo an epithelial to mesenchymal transition (EMT), either transiently or stably, and to differing degrees. This process has been extensively described in other types of cancer but has been poorly studied in EC. In this review, several features of EMT and the main molecular pathways responsible for triggering this process are investigated in relation to EC. The most common hallmarks of EMT have been found in EC, either at the level of E-cadherin loss or at the induction of its repressors, as well as other molecular alterations consistent with the mesenchymal phenotype-like L1CAM and BMI-1 up-regulation. Pathways including progesterone receptor, TGF beta, ETV5 and microRNAs are deeply related to the EMT process in EC.

Although endometrial carcinoma (EC) is generally considered to have a good prognosis, over 20% of women with EC die of their disease, with a projected increase in both incidence and mortality over the next few decades. The aim of accurate prognostication is to ensure that patients receive optimal treatment and are neither overtreated nor undertreated, thereby improving patient outcomes overall. Patients with EC can be categorized into prognostic risk groups based on clinicopathologic findings. Other than tumor type and grade, groupings and recommended management algorithms may take into account age, body mass index, stage, and presence of lymphovascular space invasion. The molecular classification of EC that has emerged from the Cancer Genome Atlas (TCGA) study provides additional, potentially superior, prognostic information to traditional histologic typing and grading. This classifier does not, however, replace clinicopathologic risk assessment based on parameters other than histotype and grade. It is envisaged that molecular and clinicopathologic prognostic grouping systems will work better together than either alone. Thus, while tumor typing and grading may be superseded by a classification based on underlying genomic abnormalities, accurate assessment of other pathologic parameters will continue to be key to patient management. These include those factors related to staging, such as depth of myometrial invasion, cervical, vaginal, serosal surface, adnexal and parametrial invasion, and those independent of stage such as lymphovascular space invasion. Other prognostic parameters will also be discussed. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.