IMPORTANCE: Patients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear. OBJECTIVE: To determine the association of molecular profiling with outcomes among patients with low-grade EC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon (POLE)-altered, microsatellite instable (MSI), tumor protein p53 (TP53)-altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022. EXPOSURES: Molecular testing of the 4 molecular subgroups. MAIN OUTCOMES AND MEASURES: The main outcome was disease-specific survival (DSS) within the molecular subgroups. RESULTS: A total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE-altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53-altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% (P < .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P < .001), TP53-altered (HR, 1.76; 95% CI, 1.04-2.95; P = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P < .001) disease were independently associated with reduced DSS. CONCLUSIONS AND RELEVANCE: This cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness.

Biomedical Research Group in Gynecology Vall Hebron Institute of Research Universitat Autònoma de Barcelona Centro de Investigación Biomédica en Red Cáncer Barcelona Spain

Departement of Obstetrics and Gynecology Elisabeth Tweesteden Hospital the Netherlands

Department of Gynaecologic Oncology Netherlands Cancer Institute and Amsterdam Medical Centers Amsterdam the Netherlands

Department of Gynecologic Oncology Amsterdam Medical Centers and Center of Gynecologic Oncology Amsterdam Amsterdam the Netherlands

Department of Health Evidence Radboud University Medial Center Nijmegen the Netherlands

Department of Obstetrics and Gynecology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Department of Obstetrics and Gynecology Catharina Hospital Eindhoven the Netherlands

Department of Obstetrics and Gynecology Medical Center University of Freiburg Freiburg Germany

Department of Obstetrics and Gynecology Radboud University Medical Center Nijmegen the Netherlands

Department of Obstetrics and Gynecology School for Oncology and Reproduction Maastricht University Medical Center Maastricht the Netherlands

Department of Obstetrics and Gynecology University Hospital in Brno and Masaryk University Brno Czechia

Department of Oncology KU Leuven Leuven Belgium

Department of Pathology and Molecular Genetics and Research Laboratory Hospital Universitari Arnau de Vilanova University of Lleida Institut de Recerca Biomèdica de Lleida Centro de Investigación Biomédica en Red Cáncer Lleida Spain

Department of Pathology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Department of Pathology Radboud University Medical Center Nijmegen the Netherlands

Department of Pathology Stichting Laboratory for Pathology and Medical Microbiology Eindhoven the Netherlands

Department of Pathology University of Turku Turku Finland

Department of Radiation Oncology Radboud University Medical Center Nijmegen the Netherlands

Gynecological Department Vall Hebron University Hospital Centro de Investigación Biomédica en Red Cáncer Barcelona Spain

Pathology Department Vall Hebron University Hospital Centro de Investigación Biomédica en Red Cáncer Barcelona Spain

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Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654 PubMed DOI

Concin N, Matias-Guiu X, Vergote I, et al. . ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39. doi:10.1136/ijgc-2020-002230 PubMed DOI

Kandoth C, Schultz N, Cherniack AD, et al. ; Cancer Genome Atlas Research Network . Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. doi:10.1038/nature12113 PubMed DOI PMC

Jamieson A, Thompson EF, Huvila J, Gilks CB, McAlpine JN. p53abn endometrial cancer: understanding the most aggressive endometrial cancers in the era of molecular classification. Int J Gynecol Cancer. 2021;31(6):907-913. doi:10.1136/ijgc-2020-002256 PubMed DOI

Leon-Castillo A, Horeweg N, Peters EEM, et al. . Prognostic relevance of the molecular classification in high-grade endometrial cancer for patients staged by lymphadenectomy and without adjuvant treatment. Gynecol Oncol. 2022;164(3):577-586. doi:10.1016/j.ygyno.2022.01.007 PubMed DOI

Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet. 2016;387(10023):1094-1108. doi:10.1016/S0140-6736(15)00130-0 PubMed DOI

Bosse T, Powell M, Crosbie E, et al. . 595 Implementation of collaborative translational research (TransPORTEC) findings in an international endometrial cancer clinical trials program (RAINBO). Int J Gynecol Cancer. 2021;31(suppl 3):A108-A109. doi:10.1136/ijgc-2021-ESGO.171 DOI

Bosse T, Nout RA, McAlpine JN, et al. . Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups. Am J Surg Pathol. 2018;42(5):561-568. doi:10.1097/PAS.0000000000001020 PubMed DOI PMC

Reijnen C, Küsters-Vandevelde HVN, Prinsen CF, et al. . Mismatch repair deficiency as a predictive marker for response to adjuvant radiotherapy in endometrial cancer. Gynecol Oncol. 2019;154(1):124-130. doi:10.1016/j.ygyno.2019.03.097 PubMed DOI

Reijnen C, Küsters-Vandevelde HVN, Ligtenberg MJL, et al. . Molecular profiling identifies synchronous endometrial and ovarian cancers as metastatic endometrial cancer with favorable clinical outcome. Int J Cancer. 2020;147(2):478-489. doi:10.1002/ijc.32907 PubMed DOI PMC

van Weelden WJ, van der Putten LJM, Inda MA, et al. . Oestrogen receptor pathway activity is associated with outcome in endometrial cancer. Br J Cancer. 2020;123(5):785-792. doi:10.1038/s41416-020-0925-4 PubMed DOI PMC

van der Putten LJ, Visser NC, van de Vijver K, et al. . L1CAM expression in endometrial carcinomas: an ENITEC collaboration study. Br J Cancer. 2016;115(6):716-724. doi:10.1038/bjc.2016.235 PubMed DOI PMC

Kommoss S, McConechy MK, Kommoss F, et al. . Final validation of the PROMISE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol. 2018;29(5):1180-1188. doi:10.1093/annonc/mdy058 PubMed DOI

León-Castillo A, Gilvazquez E, Nout R, et al. . Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas. J Pathol. 2020;250(3):312-322. doi:10.1002/path.5373 PubMed DOI PMC

Eijkelenboom A, Kamping EJ, Kastner-van Raaij AW, et al. . Reliable next-generation sequencing of formalin-fixed, paraffin-embedded tissue using single molecule tags. J Mol Diagn. 2016;18(6):851-863. doi:10.1016/j.jmoldx.2016.06.010 PubMed DOI

WHO Classification of Tumours Editorial Board . WHO Classification of Tumours. 5th ed. International Agency for Research on Cancer; 2020.

McAlpine J, Leon-Castillo A, Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol. 2018;244(5):538-549. doi:10.1002/path.5034 PubMed DOI

Köbel M, Nelson GS. Letter in response to: McAlpine J, Leon-Castillo A, Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol 2018; 244: 538-549. J Pathol. 2018;245(2):249-250. doi:10.1002/path.5068 PubMed DOI

Vrede SW, van Weelden WJ, Visser NCM, et al. ; ENITEC Consortium . Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer. Gynecol Oncol. 2021;161(3):787-794. doi:10.1016/j.ygyno.2021.03.031 PubMed DOI

Visser NCM, van der Wurff AAM, IntHout J, et al. . Improving preoperative diagnosis in endometrial cancer using systematic morphological assessment and a small immunohistochemical panel. Hum Pathol. 2021;117:68-78. doi:10.1016/j.humpath.2021.08.006 PubMed DOI

Hamilton CA, Pothuri B, Arend RC, et al. . Endometrial cancer: a Society of Gynecologic Oncology evidence-based review and recommendations. Gynecol Oncol. 2021;160(3):817-826. doi:10.1016/j.ygyno.2020.12.021 PubMed DOI

Sheikh A, Netuveli G, Kai J, Panesar SS. Comparison of reporting of ethnicity in US and European randomised controlled trials. BMJ. 2004;329(7457):87-88. doi:10.1136/bmj.38061.593935.F7 PubMed DOI PMC

Lu KH, Broaddus RR. Endometrial cancer. N Engl J Med. 2020;383(21):2053-2064. doi:10.1056/NEJMra1514010 PubMed DOI