Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early stage Endometrial Cancer Combined Analysis of the PORTEC Cohorts
Purpose: Recommendations for adjuvant treatment for women with early stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53 mutant, microsatellite instability (MSI) POLE mutant, and no specific molecular profile (NSMP) We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy. Experimental Design: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, b catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early stage endometrioid endometrial carcinomas from the PORTEC 1 and 2 trials, mostly high intermediate risk (n 614) Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared. Results: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53 mutant (9% MSI (26% POLE mutant (6% and NSMP (59% Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53 mutant, and/or >10% L1CAM) 50% favorable features (POLE mutant, NSMP being microsatellite stable, and CTNNB1 wild type) and 35% intermediate features (MSI or CTNNB1 mutant) Conclusions: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16) 4215 24. (c)2016 AACR.
Clinical Cancer Research