Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer
Authors: Vrede Stephanie W. , Kasius Jenneke , Bulten Johan , Teerenstra Steven , Huvila Jutta , Colas Eva , Gil-Moreno Antonio , Boll Dorry , Vos Maria Caroline , van Altena Anne M. , Asberger Jasmin , Sweegers Sanne , van Weelden Willem Jan , van der Putten Louis J. M. , Amant Frédéric , Visser Nicole C. M. , Snijders Marc P. L. M. , Küsters-Vandevelde Heidi V. N. , Kruitwagen Roy , Matias-Guiu Xavier , Weinberger Vit , Reijnen Casper , Pijnenborg Johanna M. A. 
Published: December 2022

ImportancePatients 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.ObjectiveTo determine the association of molecular profiling with outcomes among patients with low-grade EC.Design, Setting, and ParticipantsThis 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.ExposuresMolecular testing of the 4 molecular subgroups.Main Outcomes and MeasuresThe main outcome was disease-specific survival (DSS) within the molecular subgroups.ResultsA 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 &amp;lt; .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 &amp;lt; .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 &amp;lt; .001) disease were independently associated with reduced DSS.Conclusions and RelevanceThis 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.