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Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Aug 15; Vol. 22 (16), pp. 4215-24. Date of Electronic Publication: 2016 Mar 22. - Publication Year :
- 2016
-
Abstract
- 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.<br />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.<br />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).<br />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.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Area Under Curve
DNA Polymerase II genetics
Endometrial Neoplasms mortality
Endometrial Neoplasms therapy
Female
Genes, p53
Humans
Middle Aged
Mutation
Neoplasm Grading
Neoplasm Staging
Poly-ADP-Ribose Binding Proteins genetics
Prognosis
Randomized Controlled Trials as Topic
Recurrence
Risk Assessment
Survival Analysis
Biomarkers, Tumor
Endometrial Neoplasms diagnosis
Endometrial Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 22
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 27006490
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-2878