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BackgroundThe molecular classification of endometrial cancer revolutionized our knowledge of its biology but so far has not affected our surgical approach. The exact risk of extra-uterine metastasis and hence the type of surgical staging for each of the four molecular subgroups are currently unknown.Primary ObjectiveTo determine the association between molecular classification and disease stage.Study HypothesisEach endometrial cancer molecular subgroup has a specific pattern of spread and this pattern of spread could guide the extent of surgical staging.Trial DesignProspective, multicenter studyMajor Inclusion/Exclusion CriteriaParticipants eligible for inclusion in this study must meet all the following criteria: women ≥18 years with primary endometrial cancer, any histology and stage.Primary EndpointNumber and site of metastasis in each endometrial cancer molecular subgroup.Sample Size1000 patients will be enrolled.Estimated Dates for Completing Accrual and Presenting ResultsThe trial will last 6 years: 4 years of accrual, and 2 years of follow-up of all patients. Results on staging and oncological outcomes are expected in 2027 and 2029, respectively.Trial RegistrationThe study has been accepted by UZ Leuven Ethical Committee. Belg. Reg. nr: B3222022000997

Introduction: Immunohistochemical expression (IHC) of estrogen receptor (ER) and progesterone receptor (PR) are biomarkers for prognosis and response to hormonal therapy in endometrial cancer (EC). However, the presence of ER/PR is not inherently reflective of estrogen driven tumor growth. Previously, ER pathway activity score (ERPAS), a test to asses ER pathway, was shown to reflect estrogen driven tumor growth and to have additional prognostic and predictive value over ER and PR-IHC. Within the four molecular subgroups of EC, ER and PR-IHC are present in all subgroups. Yet, the relation of ERPAS with molecular subgroups is unclear. In this study we aim to identify estrogen driven tumor growth by application of ERPAS in the molecular subgroups. Methods: ER and PR-IHC expression, ERPAS testing and molecular analysis was available in 72 endometrial cancer cases. ER and PR-IHC expression was analyzed from formalin-fixed paraffin-embedded (FFPE) tumor sections using standard procedures. A cut-off value of 10% was defined as positive. ERPAS was performed using RT-qPCR analysis of the most relevant ER-related genes (www.philips.com/oncosignal). A Bayesian computational model was used to infer ERPAS that were normalized on a scale from 0 to 100. The cut-off value for an active ER pathway was 29.7, as previously defined. Molecular analysis was performed using Next Generation Sequencing with single-molecule Molecular Inversion Probes (smMIPs). Accordingly patients were grouped in the POLE-mutant, MSI high, TP53-mutant or no specific molecular profile, NSMP group. Results: The TP53-mutant-group had a worse outcome compared to other groups. ER pathway was active in 75% of POLE-mutant, 83.3% of MSI-high, 87.5% of NSMP and 38.9% of TP53-mutant cases. Similarly, PR-IHC expression was present in 100% of POLE-mutant, 72.2% of MSI-high, 81.3% of NSMP and 27.8% of TP53-mutant cases. The mean ERPAS was significantly higher in MSI-high and NSMP groups compared to the TP53-mutant group. Within the NSMP subgroup, an active ER pathway was significantly associated with improved disease-free survival and disease-specific survival in Kaplan-Meier analysis. Analysis in other subgroups was not possible due to limited number of cases. Conclusions: The majority of POLE-mutant, MSI-high and NSMP tumors showed an active ER pathway, indicating relevance of estrogen driven tumor growth in these groups. In the NSMP subgroup, ERPAS can be used to stratify patients for prognosis. Whether ER pathway is prognostic in the MSI-high and TP53-mutant subgroups needs to be evaluated in larger cohorts. If hormonal therapy is applied, we suggest to tailor it to patient with an active ER pathway. Citation Format: Willem Jan van Weelden, Stephanie Vrede, Louis van der Putten, Hans Bulten, Marc Snijders, Sanne Sweegers, Andrea Romano, Astrid Eijkelenboom, Anja van de Stolpe, Johanna Pijnenborg. The relevance of estrogen driven tumor growth within the molecular subgroups of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1962.

Three primigravidae were admitted during the first trimester of pregnancy with nausea, vomiting, ketonuria and liver enzyme elevation of varying severity. A 29-year-old woman had elevated aminotransferase values, at levels described in the literature (ASAT 112 U/l, ALAT 214 U/l). The second patient, a woman aged 26 years, had undergone in vitro fertilisation and showed higher liver enzyme elevation, including the total bilirubin level (ASAT 250 U/l, ALAT 474 U/l, total bilirubin 59.8 micromol/l). A 30-year-old woman had extremely high aminotransferase values (ASAT 705 U/l, ALAT 1674 U/l) and she is the first reported patient with ALAT values exceeding 1,000 U/l in connection with hyperemesis gravidarum. Gallstone disease, viral and drug-induced hepatitis were excluded in all of these patients. Treatment was symptomatic and the abnormal liver tests returned to normal promptly when the vomiting resolved, independent of the severity of liver enzyme elevation. The pregnancies proceeded normally and all three patients delivered healthy babies.

There is no consensus on the management of Stage I endometrioid endometrial cancer (EEC) with grade 3 histology. This study evaluates the opinion of gynecologists in The Netherlands on the management of Stage I, grade 3 EEC.Members of the Dutch Gynecologic Oncology Working Group were requested to complete a digital questionnaire on the management of Stage I, grade 3 EEC. Actual treatment of patients with Stage I, grade 3 EEC was assessed by analysis of PALGA, the Dutch Pathology Registry.Most gynecologists prefer routine lymphadenectomy or complete staging (62.3%), while these were actually performed in 27.3% of the cases. Gynecologic oncologists are more likely to perform a lymphadenectomy than general gynecologists. There was a wide variation of clinical practice.The results of this study underline the need for additional research into management of Stage I, grade 3 EEC as well as the need for conclusive guidelines.