A clinically applicable molecular-based classification for endometrial cancers

Abstract

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.

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

“…POLE mutation status could be used for stratification of patients and clinical trials to enable evaluation within this unique subgroup. The integration of testing for POLE mutation status into endometrial classification and risk assessment will ultimately help guide endometrial carcinoma management and provide important prognostic information to the women with this disease (45). However, our preliminary data suggest that continuing our current standard of care is advisable.…”

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

“…Both serous carcinoma and clear cell carcinoma are estrogen-independent endometrial cancers of type II (53). In 2013, the CGA published a comprehensive genomic analysis of 373 patients with these two types of endometrial cancer (54), and a novel classification of endometrial cancers was proposed based on genomic alterations, in contrast to the conventional classification system based on tissue type and estrogen stimulation (55). The novel classification system is based on polymerase ε (POLE) gene abnormalities, microsatellite instability (MSI) and chromosomal copy number, and includes four subgroups, as follows: POLE ultramutated, MSI hypermutated, genome copy-number low and genome copy-number high (Fig.…”

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

“…Integrated genomic characterization by The Cancer Genome Atlas (TCGA) defined four distinct endometrial carcinoma subgroups with possible prognostic value (10). 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). In relatively small series of unselected endometrial carcinomas, the combination of both the clinicopathologic and molecular classification improved the clinicopathologic risk assessment (12).…”