BackgroundMost patients present with low-grade (grade 1-2) early-stage (FIGO I-II) endometrioid EC (EEC), it is questioned whether these patients benefit from molecular profiling. We aim to investigate the prognostic relevance of molecular profiling within low-grade EEC.MethodsA retrospective multicenter study within the European Network for Individualized Treatment (ENITEC) network. Patients with early-stage EC were excluded if lymph node status was unknown. Molecular profiling was conducted using single-molecule Molecular Inversion Probes based on Next Generation Sequencing. Subsequently, cases were classified as: polymerase epsilon (POLE) mutant, microsatellite instable (MSI), tumor protein (TP53) mutation and no-specific molecular profile (NSMP).ResultsTotal of 393 EC patients were included, 75% had early-stage EC, and 54% low-grade EEC. Of all patients, 8.1% was classified as POLEmut, 16.8% as MSI, 21.4% as TP53-mutated and 53.7% as NSMP. Median follow-up was 5.3-years. Across all molecular subgroups, patients with low-grade EEC had superior disease-specific survival (DSS) compared to high-grade (grade 3) EC, respectively >89% vs. >43%. Equally, patients with low-grade EEC had improved recurrence-free survival (RFS) compared to high-grade EC within POLEmut, MSI and NSMP. Within TP53-mutated, only grade 1 EEC showed an excellent RFS (92%) when compared to grade 2 (54%) and grade 3 EC (44%). In multivariate analysis that included age, lymphovascular space invasion, grade, FIGO stage and the four molecular subgroups, TP53-mutated, high-grade and advanced-stage (FIGO III-IV) remained independent prognostic factors for reduced DSS and RFS (respectively, hazard ratio (HR) 9.20 (95%-CI 1.23-68.90) p=0.031, HR 5.91 (95%-CI 2.63-13.28) p<0.001, HR 3.02 (95%-CI 1.61-5.62) p<0.001 and respectively, HR 12.27 (95%-CI 1.66-90.78) p=0.014, HR 2.66 (95%-CI 1.54-4.57) p<0.001, HR 2.58 (95%-CI 1.56-4.24) p<0.001).ConclusionsPatients with grade 1 EEC have an excellent prognostic outcome across all molecular subgroups. In patients with grade 2 EEC, TP53-mutated seems to be prognostic relevant. Based on current data, routine molecular profiling in patients with low-grade EEC has shown limited contributive value to prognostic outcome.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest. BackgroundMost patients present with low-grade (grade 1-2) early-stage (FIGO I-II) endometrioid EC (EEC), it is questioned whether these patients benefit from molecular profiling. We aim to investigate the prognostic relevance of molecular profiling within low-grade EEC. Most patients present with low-grade (grade 1-2) early-stage (FIGO I-II) endometrioid EC (EEC), it is questioned whether these patients benefit from molecular profiling. We aim to investigate the prognostic relevance of molecular profiling within low-grade EEC. MethodsA retrospective multicenter study within the European Network for Individualized Treatment (ENITEC) network. Patients with early-stage EC were excluded if lymph node status was unknown. Molecular profiling was conducted using single-molecule Molecular Inversion Probes based on Next Generation Sequencing. Subsequently, cases were classified as: polymerase epsilon (POLE) mutant, microsatellite instable (MSI), tumor protein (TP53) mutation and no-specific molecular profile (NSMP). A retrospective multicenter study within the European Network for Individualized Treatment (ENITEC) network. Patients with early-stage EC were excluded if lymph node status was unknown. Molecular profiling was conducted using single-molecule Molecular Inversion Probes based on Next Generation Sequencing. Subsequently, cases were classified as: polymerase epsilon (POLE) mutant, microsatellite instable (MSI), tumor protein (TP53) mutation and no-specific molecular profile (NSMP). ResultsTotal of 393 EC patients were included, 75% had early-stage EC, and 54% low-grade EEC. Of all patients, 8.1% was classified as POLEmut, 16.8% as MSI, 21.4% as TP53-mutated and 53.7% as NSMP. Median follow-up was 5.3-years. Across all molecular subgroups, patients with low-grade EEC had superior disease-specific survival (DSS) compared to high-grade (grade 3) EC, respectively >89% vs. >43%. Equally, patients with low-grade EEC had improved recurrence-free survival (RFS) compared to high-grade EC within POLEmut, MSI and NSMP. Within TP53-mutated, only grade 1 EEC showed an excellent RFS (92%) when compared to grade 2 (54%) and grade 3 EC (44%). In multivariate analysis that included age, lymphovascular space invasion, grade, FIGO stage and the four molecular subgroups, TP53-mutated, high-grade and advanced-stage (FIGO III-IV) remained independent prognostic factors for reduced DSS and RFS (respectively, hazard ratio (HR) 9.20 (95%-CI 1.23-68.90) p=0.031, HR 5.91 (95%-CI 2.63-13.28) p<0.001, HR 3.02 (95%-CI 1.61-5.62) p<0.001 and respectively, HR 12.27 (95%-CI 1.66-90.78) p=0.014, HR 2.66 (95%-CI 1.54-4.57) p<0.001, HR 2.58 (95%-CI 1.56-4.24) p<0.001). Total of 393 EC patients were included, 75% had early-stage EC, and 54% low-grade EEC. Of all patients, 8.1% was classified as POLEmut, 16.8% as MSI, 21.4% as TP53-mutated and 53.7% as NSMP. Median follow-up was 5.3-years. Across all molecular subgroups, patients with low-grade EEC had superior disease-specific survival (DSS) compared to high-grade (grade 3) EC, respectively >89% vs. >43%. Equally, patients with low-grade EEC had improved recurrence-free survival (RFS) compared to high-grade EC within POLEmut, MSI and NSMP. Within TP53-mutated, only grade 1 EEC showed an excellent RFS (92%) when compared to grade 2 (54%) and grade 3 EC (44%). In multivariate analysis that included age, lymphovascular space invasion, grade, FIGO stage and the four molecular subgroups, TP53-mutated, high-grade and advanced-stage (FIGO III-IV) remained independent prognostic factors for reduced DSS and RFS (respectively, hazard ratio (HR) 9.20 (95%-CI 1.23-68.90) p=0.031, HR 5.91 (95%-CI 2.63-13.28) p<0.001, HR 3.02 (95%-CI 1.61-5.62) p<0.001 and respectively, HR 12.27 (95%-CI 1.66-90.78) p=0.014, HR 2.66 (95%-CI 1.54-4.57) p<0.001, HR 2.58 (95%-CI 1.56-4.24) p<0.001). ConclusionsPatients with grade 1 EEC have an excellent prognostic outcome across all molecular subgroups. In patients with grade 2 EEC, TP53-mutated seems to be prognostic relevant. Based on current data, routine molecular profiling in patients with low-grade EEC has shown limited contributive value to prognostic outcome. Patients with grade 1 EEC have an excellent prognostic outcome across all molecular subgroups. In patients with grade 2 EEC, TP53-mutated seems to be prognostic relevant. Based on current data, routine molecular profiling in patients with low-grade EEC has shown limited contributive value to prognostic outcome.

21MO Limited Benefit of Molecular Profiling in Patients with Low-Grade Endometrial Cancer