Floor J Backes1, Christopher J Walker2, Paul J Goodfellow2, Erinn M Hade3, Garima Agarwal2, David Mutch4, David E Cohn2, Adrian A Suarez5. 1. Division of Gynecology Oncology, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, The James Comprehensive Cancer Center, Columbus, OH, United States. Electronic address: Floor.Backes@osumc.edu. 2. Division of Gynecology Oncology, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, The James Comprehensive Cancer Center, Columbus, OH, United States. 3. Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States. 4. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, Siteman Cancer Center, St Louis, MO, United States. 5. Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
Abstract
BACKGROUND: We sought to validate the prognostic significance of estrogen receptor alpha (ERα) expression and to investigate the relationship between ESR1 mutation status and outcomes in a large cohort of patients with endometrial cancer. We also investigated the predictive value of ERα for lymph node involvement in a large surgically staged cohort. METHODS: A tumor microarray (TMA) was constructed including only pure endometrioid adenocarcinomas, stained with ER50 monoclonal antibody, and assessed using digital image analysis. For mutation analysis, somatic DNA was extracted and sequenced for ESR1 gene hotspot regions. Differences in patient and tumor characteristics, recurrence and survival between ERα positive and negative, mutated and wild-type tumors were evaluated. RESULTS: Sixty (18.6%) tumors were negative for ERα. Absence of ERα was significantly associated with stage and grade, but not with disease-free or overall survival. ERα was a strong predictor of lymph node involvement (RR: 2.37, 95% CI: 1.12-5.02). Nineteen of 1034 tumors (1.8%) had an ESR1 hotspot mutation; twelve in hotspot 537Y, four in 538D and three in 536L. Patients with an ESR1 mutation had a significantly lower BMI, but were comparable in age, stage and grade, and progression-free survival. CONCLUSION: Patients with ERα negative endometrioid endometrial cancer are more often diagnosed with higher grade and advanced stage disease. Lymph node involvement is more common with lack of ERα expression, and may be able to help triage which patients should undergo lymphadenectomy. Mutations in ESR1 might explain why some low risk women with low BMI develop endometrial cancer.
BACKGROUND: We sought to validate the prognostic significance of estrogen receptor alpha (ERα) expression and to investigate the relationship between ESR1 mutation status and outcomes in a large cohort of patients with endometrial cancer. We also investigated the predictive value of ERα for lymph node involvement in a large surgically staged cohort. METHODS:A tumor microarray (TMA) was constructed including only pure endometrioid adenocarcinomas, stained with ER50 monoclonal antibody, and assessed using digital image analysis. For mutation analysis, somatic DNA was extracted and sequenced for ESR1 gene hotspot regions. Differences in patient and tumor characteristics, recurrence and survival between ERα positive and negative, mutated and wild-type tumors were evaluated. RESULTS: Sixty (18.6%) tumors were negative for ERα. Absence of ERα was significantly associated with stage and grade, but not with disease-free or overall survival. ERα was a strong predictor of lymph node involvement (RR: 2.37, 95% CI: 1.12-5.02). Nineteen of 1034 tumors (1.8%) had an ESR1 hotspot mutation; twelve in hotspot 537Y, four in 538D and three in 536L. Patients with an ESR1 mutation had a significantly lower BMI, but were comparable in age, stage and grade, and progression-free survival. CONCLUSION:Patients with ERα negative endometrioid endometrial cancer are more often diagnosed with higher grade and advanced stage disease. Lymph node involvement is more common with lack of ERα expression, and may be able to help triage which patients should undergo lymphadenectomy. Mutations in ESR1 might explain why some low risk women with low BMI develop endometrial cancer.
Authors: Laura J van 't Veer; Hongyue Dai; Marc J van de Vijver; Yudong D He; Augustinus A M Hart; Mao Mao; Hans L Peterse; Karin van der Kooy; Matthew J Marton; Anke T Witteveen; George J Schreiber; Ron M Kerkhoven; Chris Roberts; Peter S Linsley; René Bernards; Stephen H Friend Journal: Nature Date: 2002-01-31 Impact factor: 49.962
Authors: Robert W Holloway; Ricardo A Molero Bravo; Joseph A Rakowski; Jeffrey A James; Corinne N Jeppson; Susan B Ingersoll; Sarfraz Ahmad Journal: Gynecol Oncol Date: 2012-04-13 Impact factor: 5.482
Authors: Floor J Backes; Marino E Leon; Iouri Ivanov; Adrian Suarez; Wendy L Frankel; Heather Hampel; Jeffrey M Fowler; Larry J Copeland; David M O'Malley; David E Cohn Journal: Gynecol Oncol Date: 2009-06-10 Impact factor: 5.482
Authors: Christopher J Walker; Mario A Miranda; Matthew J O'Hern; Joseph P McElroy; Kevin R Coombes; Ralf Bundschuh; David E Cohn; David G Mutch; Paul J Goodfellow Journal: J Natl Cancer Inst Date: 2015-09-01 Impact factor: 13.506
Authors: Israel Zighelboim; David G Mutch; Amy Knapp; Li Ding; Mingchao Xie; David E Cohn; Paul J Goodfellow Journal: Hum Mutat Date: 2014-01 Impact factor: 4.878
Authors: Weiyi Toy; Yang Shen; Helen Won; Bradley Green; Rita A Sakr; Marie Will; Zhiqiang Li; Kinisha Gala; Sean Fanning; Tari A King; Clifford Hudis; David Chen; Tetiana Taran; Gabriel Hortobagyi; Geoffrey Greene; Michael Berger; José Baselga; Sarat Chandarlapaty Journal: Nat Genet Date: 2013-11-03 Impact factor: 38.330
Authors: Robert Neff; Craig M Rush; Blair Smith; Floor J Backes; David E Cohn; Paul J Goodfellow Journal: Int J Cancer Date: 2018-09-29 Impact factor: 7.396
Authors: Jeffery M Vahrenkamp; Chieh-Hsiang Yang; Adriana C Rodriguez; Aliyah Almomen; Kristofer C Berrett; Alexis N Trujillo; Katrin P Guillen; Bryan E Welm; Elke A Jarboe; Margit M Janat-Amsbury; Jason Gertz Journal: Cell Rep Date: 2018-03-13 Impact factor: 9.423