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abstract
See editorial on pages The promise of molecular staging for the future, this issue.
Molecular profiling is becoming increasingly powerful in characterizing
cancers. This technology should be used to augment the traditional
anatomic and histologic staging of all cancers and particularly of
endometrial cancers.
Abstract
BACKGROUND
Classification
of endometrial carcinomas (ECs) by morphologic features is
irreproducible and imperfectly reflects tumor biology. The authors
developed the Proactive Molecular Risk Classifier for Endometrial Cancer
(ProMisE), a molecular classification system based on The Cancer Genome
Atlas genomic subgroups, and sought to confirm both feasibility and
prognostic ability in a new, large cohort of ECs.
METHODS
Immunohistochemistry
(IHC) for the presence or absence of mismatch repair (MMR) proteins (to
identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE
EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense
mutations; p53 wt and p53 abn, respectively) were performed on 319 new
EC samples. Subgroups were characterized and assessed relative to
outcomes. The prognostic ability of ProMisE was compared with that of
current risk-stratification systems (European Society of Medical
Oncology [ESMO]).
RESULTS
ProMisE
decision-tree classification achieved categorization of all cases and
identified 4 prognostic subgroups with distinct overall,
disease-specific, and progression-free survival (P < .001). Tumors with POLE
EDMs had the most favorable prognosis, and those with p53 abn the worst
prognosis, and separation of the 2 middle survival curves (p53 wt and
MMR-D) was observed. There were no significant differences in survival
between the ESMO low-risk and intermediate-risk groups. ProMisE improved
the ability to discriminate outcomes compared with ESMO risk
stratification. There was substantial overlap (89%) between the p53 abn
and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.
CONCLUSIONS
Molecular
classification of ECs can be achieved using clinically applicable
methods and provides independent prognostic information beyond
established clinicopathologic risk factors available at diagnosis.
Consistent, biologically relevant categorization enables stratification
for clinical trials and/or targeted therapy, identification of women who
are at increased risk of having Lynch syndrome, and may guide clinical
management.
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