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Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups

Bosse, Tjalling, MD*; Nout, Remi, A., MD*; McAlpine, Jessica, N., MD; McConechy, Melissa, K., MD; Britton, Heidi, MD; Hussein, Yaser, R., MD§; Gonzalez, Carlene, BA§; Ganesan, Raji, MD; Steele, Jane, C., MD; Harrison, Beth, T., MD; Oliva, Esther, MD; Vidal, August, MD#; Matias-Guiu, Xavier, MD#; Abu-Rustum, Nadeem, R., MD**; Levine, Douglas, A., MD**; Gilks, C., Blake, MD; Soslow, Robert, A., MD§

The American Journal of Surgical Pathology: May 2018 - Volume 42 - Issue 5 - p 561–568
doi: 10.1097/PAS.0000000000001020
Original Articles

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.

*Department of Pathology and Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands

Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia

Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada

Departments of §Pathology

**Surgery, Memorial Sloan Kettering Cancer Center, New York, NY

Department of Pathology, Massachusetts General Hospital, Boston, MA

Birmingham Women’s HS Foundation Trust, Birmingham, UK

#Department of Pathology, University Hospital Arnau de Vilanova and Bellvitge University Hospital, Universities of Lleida and Barcelona, Idibell, Irblleida, Ciberonc, Spain

Present address: Douglas A. Levine, MD, New York University Langone Medical Center, New York, NY.

Conflicts of Interest and Source of Funding: Supported in part by the Dutch Cancer Society (KWF-UL2012-5719) (Dr Bosse, Dr Nout) and in part through the NIH/NCI Support Grant P30 CA008748 (Dr Abu-Rustum, Dr Levine, Dr Soslow). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Robert A. Soslow, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail:

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