TY - JOUR
T1 - Relevance of Molecular Profiling in Patients with Low-Grade Endometrial Cancer
AU - Vrede, Stephanie W.
AU - Kasius, Jenneke
AU - Bulten, Johan
AU - Teerenstra, Steven
AU - Huvila, Jutta
AU - Colas, Eva
AU - Gil-Moreno, Antonio
AU - Boll, Dorry
AU - Vos, Maria Caroline
AU - van Altena, Anne M.
AU - Asberger, Jasmin
AU - Sweegers, Sanne
AU - van Weelden, Willem Jan
AU - van der Putten, Louis J. M.
AU - Amant, Frédéric
AU - Visser, Nicole C. M.
AU - Snijders, Marc P. L. M.
AU - Küsters-Vandevelde, Heidi V. N.
AU - Kruitwagen, Roy
AU - Matias-Guiu, Xavier
AU - Weinberger, Vit
AU - Reijnen, Casper
AU - Pijnenborg, Johanna M. A.
N1 - Publisher Copyright: © 2022 Authors. All rights reserved.
PY - 2022/12/16
Y1 - 2022/12/16
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85144589126&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36525269
U2 - https://doi.org/10.1001/jamanetworkopen.2022.47372
DO - https://doi.org/10.1001/jamanetworkopen.2022.47372
M3 - Article
C2 - 36525269
SN - 2574-3805
VL - 5
JO - JAMA network open
JF - JAMA network open
IS - 12
M1 - e2247372
ER -