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

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 repai...

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Autores: Bosse, Tjalling, Nout, Remi, McAlpine, Jessica N., McConechy, Melissa, Britton, Heidi, Hussein, Yaser, Gonzalez, Carlene, Ganesan, Raji, Steele, Jane C., Harrison, Beth T., Oliva, Esther, Vidal, August, Matias-Guiu, Xavier, Abu-Rustum, Nadeem R., Levine, Douglas A., Gilks, C. Blake, Soslow, Robert A.
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/71149
Acesso em linha:https://doi.org/10.1097/PAS.0000000000001020
http://hdl.handle.net/10459.1/71149
Access Level:acceso abierto
Palavra-chave:POLE exonuclease domain mutations
Endometrial cancer
Molecular classification
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repository_id_str
spelling Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic SubgroupsBosse, TjallingNout, RemiMcAlpine, Jessica N.McConechy, MelissaBritton, HeidiHussein, YaserGonzalez, CarleneGanesan, RajiSteele, Jane C.Harrison, Beth T.Oliva, EstherVidal, AugustMatias-Guiu, XavierAbu-Rustum, Nadeem R.Levine, Douglas A.Gilks, C. BlakeSoslow, Robert A.POLE exonuclease domain mutationsEndometrial cancerMolecular classificationOur 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.This 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).Wolters Kluwer Health202120212018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionhttps://doi.org/10.1097/PAS.0000000000001020http://hdl.handle.net/10459.1/71149http://hdl.handle.net/10459.1/71149reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1097/PAS.0000000000001020American Journal of Surgical Pathology, 2018, vol. 42, núm. 5, p. 561-568cc-by-nc (c) Wolters Kluwer Health, 2018info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc/4.0/oai:recercat.cat:10459.1/711492026-05-29T05:05:01Z
dc.title.none.fl_str_mv Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
title Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
spellingShingle Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
Bosse, Tjalling
POLE exonuclease domain mutations
Endometrial cancer
Molecular classification
title_short Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
title_full Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
title_fullStr Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
title_full_unstemmed Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
title_sort Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
dc.creator.none.fl_str_mv Bosse, Tjalling
Nout, Remi
McAlpine, Jessica N.
McConechy, Melissa
Britton, Heidi
Hussein, Yaser
Gonzalez, Carlene
Ganesan, Raji
Steele, Jane C.
Harrison, Beth T.
Oliva, Esther
Vidal, August
Matias-Guiu, Xavier
Abu-Rustum, Nadeem R.
Levine, Douglas A.
Gilks, C. Blake
Soslow, Robert A.
author Bosse, Tjalling
author_facet Bosse, Tjalling
Nout, Remi
McAlpine, Jessica N.
McConechy, Melissa
Britton, Heidi
Hussein, Yaser
Gonzalez, Carlene
Ganesan, Raji
Steele, Jane C.
Harrison, Beth T.
Oliva, Esther
Vidal, August
Matias-Guiu, Xavier
Abu-Rustum, Nadeem R.
Levine, Douglas A.
Gilks, C. Blake
Soslow, Robert A.
author_role author
author2 Nout, Remi
McAlpine, Jessica N.
McConechy, Melissa
Britton, Heidi
Hussein, Yaser
Gonzalez, Carlene
Ganesan, Raji
Steele, Jane C.
Harrison, Beth T.
Oliva, Esther
Vidal, August
Matias-Guiu, Xavier
Abu-Rustum, Nadeem R.
Levine, Douglas A.
Gilks, C. Blake
Soslow, Robert A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv POLE exonuclease domain mutations
Endometrial cancer
Molecular classification
topic POLE exonuclease domain mutations
Endometrial cancer
Molecular classification
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1097/PAS.0000000000001020
http://hdl.handle.net/10459.1/71149
http://hdl.handle.net/10459.1/71149
url https://doi.org/10.1097/PAS.0000000000001020
http://hdl.handle.net/10459.1/71149
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1097/PAS.0000000000001020
American Journal of Surgical Pathology, 2018, vol. 42, núm. 5, p. 561-568
dc.rights.none.fl_str_mv cc-by-nc (c) Wolters Kluwer Health, 2018
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc/4.0/
rights_invalid_str_mv cc-by-nc (c) Wolters Kluwer Health, 2018
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Wolters Kluwer Health
publisher.none.fl_str_mv Wolters Kluwer Health
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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