Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer—Combined Analysis of the PORTEC Cohorts

By E. Stelloo, Remi A. Nout, E. M. Osse, I. Jürgenliemk-Schulz, J. Jobsen, L. Lutgens, E. M. van der Steen-Banasik, H. Nijman, Hein Putter, T. Bosse and 2 more. Clinical Cancer Research, 2016

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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, β-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. ©2016 AACR.

Subfields: Epidemiology, Obstetrics and Gynecology

View Paper: https://www.semanticscholar.org/paper/49b780a0f4472970bb79ce5a42e721aaea4a109b

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Citations in the corpus

Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series (2018, methodology): “Women with ECs harboring POLE EDMs were younger than those with other subtypes, and thinner than women with MMR-D and p53wt ECs.”
ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma (2020, methodology): “The reintroduction of carboplatin may be considered after a prolonged interval from the last platinum treatment, based on the results of a single-centre retrospective series in patients treated with a median platinum-free interval of 25 (8-79) months.”