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

dc.contributor.authorBosse, Tjalling
dc.contributor.authorNout, Remi
dc.contributor.authorMcAlpine, Jessica N.
dc.contributor.authorMcConechy, Melissa
dc.contributor.authorBritton, Heidi
dc.contributor.authorHussein, Yaser
dc.contributor.authorGonzalez, Carlene
dc.contributor.authorGanesan, Raji
dc.contributor.authorSteele, Jane C.
dc.contributor.authorHarrison, Beth T.
dc.contributor.authorOliva, Esther
dc.contributor.authorVidal, August
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorAbu-Rustum, Nadeem R.
dc.contributor.authorLevine, Douglas A.
dc.contributor.authorGilks, C. Blake
dc.contributor.authorSoslow, Robert A.
dc.description.abstractOur 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.ca_ES
dc.description.sponsorshipThis study was funded in part by the Dutch Cancer Society (KWF-UL2012-5719) (Dr. Bosse, Dr. Nout). This study was funded in part through the NIH/NCI Support Grant P30 CA008748 (Dr. Abu-Rustum, Dr. Levine, Dr. Soslow).ca_ES
dc.identifier.issn0147-5185 (paper)
dc.identifier.issn1532-0979 (electrònic)
dc.publisherWolters Kluwer Healthca_ES
dc.relation.isformatofVersió postprint del document publicat a:
dc.relation.ispartofAmerican Journal of Surgical Pathology, 2018, vol. 42, núm. 5, p. 561-568ca_ES
dc.rightscc-by-nc (c) Wolters Kluwer Health, 2018ca_ES
dc.subjectPOLE exonuclease domain mutationsca_ES
dc.subjectEndometrial cancerca_ES
dc.subjectMolecular classificationca_ES
dc.titleMolecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroupsca_ES
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