Linyuan Wang1, Peter F Rambau1,2, Linda E Kelemen3, Michael S Anglesio4, Samuel Leung5, Aline Talhouk5, Martin Köbel1. 1. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada. 2. Department of Pathology, Catholic University of Health and Allied Science, Mwanza, Tanzania. 3. Hollings Cancer Center and Medical University of South Carolina, Charleston, USA. 4. Department of Obstetrics and Gynaecology, Robert HN Ho Research Centre, University of British Columbia, Vancouver, BC, Canada. 5. Department of Pathology, University of British Colombia and British Colombia Cancer Agency, Vancouver, BC, Canada.
Abstract
AIMS: Ovarian endometrioid carcinoma (EC) generally has a good prognosis. Adjuvant chemotherapy can be spared in low-stage disease, but prognostic biomarkers are needed to refine the treatment threshold. Wnt/β-catenin signalling is commonly altered in EC. We examined immunohistochemical expression of nuclear β-catenin and CDX2 as prognostic biomarkers for EC; both are mediators of the Wnt pathway. METHODS AND RESULTS: We evaluated two ovarian EC cohorts, discovery set (n = 183) and validation set (n = 174), with ovarian cancer-specific survival (OCSS) as the primary end-point. In univariable analysis, nuclear β-catenin expression was significantly associated with longer OCSS in the discovery set [hazard ratio (HR) = 0.36, 95% confidence interval (CI) = 0.16-0.74, P = 0.004] and the validation set (HR = 0.35, 95% CI = 0.11-0.89, P = 0.006). Similar significant associations were observed with CDX2 expression in the discovery set (HR = 0.25, 95% CI = 0.11-0.50, P < 0.001) and validation set (HR = 0.27, 95% CI = 0.07-0.75, P = 0.020). In multivariable analysis, combined positivity of both markers was significantly associated with longer OCSS in the discovery set (HR = 0.20, 95% CI = 0.06-0.49, P < 0.001) and in the validation set (HR = 0.33 95% CI = 0.07-0.1.06, P = 0.047). In a stratified analysis for stage IC/II EC, combined positivity identified a subset of patients with a significantly longer OCSS in the discovery cohort but only a non-significant trend in the validation cohort. CONCLUSIONS: Nuclear β-catenin and CDX2 expression individually or in combination are validated prognostic markers for ovarian EC. However, their full potential to stratify low risk patients at adjuvant threshold awaits further multimarker study.
AIMS: Ovarian endometrioid carcinoma (EC) generally has a good prognosis. Adjuvant chemotherapy can be spared in low-stage disease, but prognostic biomarkers are needed to refine the treatment threshold. Wnt/β-catenin signalling is commonly altered in EC. We examined immunohistochemical expression of nuclear β-catenin and CDX2 as prognostic biomarkers for EC; both are mediators of the Wnt pathway. METHODS AND RESULTS: We evaluated two ovarian EC cohorts, discovery set (n = 183) and validation set (n = 174), with ovarian cancer-specific survival (OCSS) as the primary end-point. In univariable analysis, nuclear β-catenin expression was significantly associated with longer OCSS in the discovery set [hazard ratio (HR) = 0.36, 95% confidence interval (CI) = 0.16-0.74, P = 0.004] and the validation set (HR = 0.35, 95% CI = 0.11-0.89, P = 0.006). Similar significant associations were observed with CDX2 expression in the discovery set (HR = 0.25, 95% CI = 0.11-0.50, P < 0.001) and validation set (HR = 0.27, 95% CI = 0.07-0.75, P = 0.020). In multivariable analysis, combined positivity of both markers was significantly associated with longer OCSS in the discovery set (HR = 0.20, 95% CI = 0.06-0.49, P < 0.001) and in the validation set (HR = 0.33 95% CI = 0.07-0.1.06, P = 0.047). In a stratified analysis for stage IC/II EC, combined positivity identified a subset of patients with a significantly longer OCSS in the discovery cohort but only a non-significant trend in the validation cohort. CONCLUSIONS: Nuclear β-catenin and CDX2 expression individually or in combination are validated prognostic markers for ovarian EC. However, their full potential to stratify low risk patients at adjuvant threshold awaits further multimarker study.
Authors: Nicola S Meagher; Linyuan Wang; Peter F Rambau; Maria P Intermaggio; David G Huntsman; Lynne R Wilkens; Mona A El-Bahrawy; Roberta B Ness; Kunle Odunsi; Helen Steed; Esther Herpel; Michael S Anglesio; Bonnie Zhang; Neil Lambie; Anthony J Swerdlow; Jan Lubiński; Robert A Vierkant; Ellen L Goode; Usha Menon; Aleksandra Toloczko-Grabarek; Oleg Oszurek; Sanela Bilic; Aline Talhouk; Montserrat García-Closas; Qin Wang; Adeline Tan; Rhonda Farrell; Catherine J Kennedy; Mercedes Jimenez-Linan; Karin Sundfeldt; John L Etter; Janusz Menkiszak; Marc T Goodman; Paul Klonowski; Yee Leung; Stacey J Winham; Kirsten B Moysich; Sabine Behrens; Tomasz Kluz; Robert P Edwards; Jacek Gronwald; Francesmary Modugno; Brenda Y Hernandez; Christine Chow; Linda E Kelemen; Gary L Keeney; Michael E Carney; Yanina Natanzon; Gregory Robertson; Raghwa Sharma; Simon A Gayther; Jennifer Alsop; Hugh Luk; Chloe Karpinskyj; Ian Campbell; Peter Sinn; Aleksandra Gentry-Maharaj; Penny Coulson; Jenny Chang-Claude; Mitul Shah; Martin Widschwendter; Katrina Tang; Minouk J Schoemaker; Jennifer M Koziak; Linda S Cook; James D Brenton; Frances Daley; Björg Kristjansdottir; Constantina Mateoiu; Melissa C Larson; Paul R Harnett; Audrey Jung; Anna deFazio; Kylie L Gorringe; Paul D P Pharoah; Parham Minoo; Colin Stewart; Oliver F Bathe; Xianyong Gui; Paul Cohen; Susan J Ramus; Martin Köbel Journal: Mod Pathol Date: 2019-06-25 Impact factor: 8.209