A clinically applicable molecular-based classification for endometrial cancers

By A. Talhouk, M. McConechy, S. Leung, H. Li-Chang, J. Kwon, Nataliya Melnyk, Winnie Yang, J. Senz, Niki Boyd, A. Karnezis and 3 more. British Journal of Cancer, 2015

861 citations recorded by the source corpus.

Background:Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.Methods:Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.Results:Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for ‘copy-number’ status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined ‘high-risk’ group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.Conclusions:Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

Subfields: Cancer Research, Obstetrics and Gynecology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/59e06854c162d1c282509800ce7264f0c83c5cab

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In Cancer Research

In Obstetrics and Gynecology

In Pulmonary and Respiratory Medicine

Remi A. Nout

Citations in the corpus

Confirmation of ProMisE: A simple, genomics‐based clinical classifier for endometrial cancer (2017, methodology): “The Harell C-index was used to evaluate the ability of ProMisE to discriminate outcomes in new patients from the confirmation cohort using model parameters developed in the discovery cohort.(8) The ProMisE molecular subgroups were characterized in the confirmation cohort using descriptive statistics”
Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer—Combined Analysis of the PORTEC Cohorts (2016, methodology): “Using methods broadly available in clinical practice, these four subgroups can be easily determined by their surrogate markers: p53, microsatellite instability (MSI), and POLE resulting in a practically and clinically useful molecular classification tool (11, 12).”
FIGO staging of endometrial cancer: 2023 (2023, positive): “41 Perhaps the most impactful molecular classification is that proposed by The Cancer Genome Atlas (TCGA), 31 Several studies have demonstrated the prognostic value of this TCGA-surrogate approach.”
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.”
Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series (2018, methodology): “aspx) [15], we previously reported on the ‘discovery’ [10] and ‘confirmation’ [16] cohorts encompassing over 450 cases.”