PMID- 29505428 OWN - NLM STAT- MEDLINE DCOM- 20190318 LR - 20231112 IS - 1532-0979 (Electronic) IS - 0147-5185 (Print) IS - 0147-5185 (Linking) VI - 42 IP - 5 DP - 2018 May TI - Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. PG - 561-568 LID - 10.1097/PAS.0000000000001020 [doi] AB - Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications. FAU - Bosse, Tjalling AU - Bosse T AD - Department of Pathology and Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Nout, Remi A AU - Nout RA AD - Department of Pathology and Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands. FAU - McAlpine, Jessica N AU - McAlpine JN AD - Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia. FAU - McConechy, Melissa K AU - McConechy MK AD - Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada. FAU - Britton, Heidi AU - Britton H AD - Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada. FAU - Hussein, Yaser R AU - Hussein YR AD - Departments of Pathology. FAU - Gonzalez, Carlene AU - Gonzalez C AD - Departments of Pathology. FAU - Ganesan, Raji AU - Ganesan R AD - Birmingham Women's HS Foundation Trust, Birmingham, UK. FAU - Steele, Jane C AU - Steele JC AD - Birmingham Women's HS Foundation Trust, Birmingham, UK. FAU - Harrison, Beth T AU - Harrison BT AD - Department of Pathology, Massachusetts General Hospital, Boston, MA. FAU - Oliva, Esther AU - Oliva E AD - Department of Pathology, Massachusetts General Hospital, Boston, MA. FAU - Vidal, August AU - Vidal A AD - Department of Pathology, University Hospital Arnau de Vilanova and Bellvitge University Hospital, Universities of Lleida and Barcelona, Idibell, Irblleida, Ciberonc, Spain. FAU - Matias-Guiu, Xavier AU - Matias-Guiu X AD - Department of Pathology, University Hospital Arnau de Vilanova and Bellvitge University Hospital, Universities of Lleida and Barcelona, Idibell, Irblleida, Ciberonc, Spain. FAU - Abu-Rustum, Nadeem R AU - Abu-Rustum NR AD - Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. FAU - Levine, Douglas A AU - Levine DA AD - Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. FAU - Gilks, C Blake AU - Gilks CB AD - Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada. FAU - Soslow, Robert A AU - Soslow RA AD - Departments of Pathology. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Surg Pathol JT - The American journal of surgical pathology JID - 7707904 RN - 0 (Biomarkers, Tumor) RN - 0 (Poly-ADP-Ribose Binding Proteins) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.7.7.7 (DNA Polymerase II) RN - EC 2.7.7.7 (POLE protein, human) RN - EC 6.5.1.- (DNA Repair Enzymes) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers, Tumor/*genetics MH - Carcinoma, Endometrioid/classification/*genetics/pathology/therapy MH - DNA Mismatch Repair MH - DNA Mutational Analysis MH - DNA Polymerase II/*genetics MH - DNA Repair Enzymes/*genetics MH - Endometrial Neoplasms/classification/*genetics/pathology/therapy MH - Europe MH - Female MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - Mutation MH - Neoplasm Grading MH - North America MH - Poly-ADP-Ribose Binding Proteins/*genetics MH - Predictive Value of Tests MH - Progression-Free Survival MH - Retrospective Studies MH - Risk Factors MH - Time Factors MH - Treatment Outcome MH - Tumor Suppressor Protein p53/*genetics PMC - PMC5893364 MID - NIHMS927632 COIS- Conflicts of Interest: The authors have no conflicts of interest to disclose. EDAT- 2018/03/06 06:00 MHDA- 2019/03/19 06:00 PMCR- 2019/05/01 CRDT- 2018/03/06 06:00 PHST- 2018/03/06 06:00 [pubmed] PHST- 2019/03/19 06:00 [medline] PHST- 2018/03/06 06:00 [entrez] PHST- 2019/05/01 00:00 [pmc-release] AID - 10.1097/PAS.0000000000001020 [doi] PST - ppublish SO - Am J Surg Pathol. 2018 May;42(5):561-568. doi: 10.1097/PAS.0000000000001020.