title: Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts.
abstract: OBJECTIVE
  Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy.
  
  
  METHODS
  Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, β-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared.
  
  
  RESULTS
  Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant).
  
  
  CONCLUSIONS
  Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215-24. ©2016 AACR.
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Stelloo
authors.affiliation: Department of Medical and Radiation Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Osse
authors.affiliation: Department of Radiation Oncology, University Medical Centre Utrecht, the Netherlands.
authors.forename: Ina J
authors.initials: IJ
authors.lastname: Jürgenliemk-Schulz
authors.affiliation: Department of Radiotherapy, Medisch Spectrum Twente, Enschede, the Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Jobsen
authors.affiliation: MAASTtricht Radiation Oncology Clinic, Maastricht, the Netherlands.
authors.forename: Ludy C
authors.initials: LC
authors.lastname: Lutgens
authors.affiliation: Arnhems Radiotherapeutic Institute, Arnhem, the Netherlands.
authors.forename: Elzbieta M
authors.initials: EM
authors.lastname: van der Steen-Banasik
authors.affiliation: Department of Obstetrics and Gynaecology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.affiliation: Department of Medical and Radiation Oncology, Leiden University Medical Centre, Leiden, the Netherlands. t.bosse@lumc.nl.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Department of Medical and Radiation Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor; D004257:DNA Polymerase II / Q000235:genetics; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D005260:Female; D016158:Genes, p53; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D018570:Risk Assessment; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human