Endometrial cancer is not a single entity but rather a very heterogeneous group of diseases.
Historically, endometrial cancer patients have been classified as endometrioid (type I) or
non-endometrioid (type II) according to the dualistic Bokhman model- However, this approach
has been limited in accurately predicting prognosis and guiding treatment owing to
heterogeneity within subtypes, inadequate incorporation of molecular and genetic information,
and high interobserver variability .
In the last ten years, after the publication of The Cancer Genome Atlas (TCGA)[5], the
molecular classification of endometrial cancer into four molecular subtypes [(i)
POLE/ultramutated group (POLE mutated), (ii) mismatch repair
deficiency/microsatellite-instable, hypermutated group (MMRd/MSI-H), (iii) copy-number-high,
TP53-mutant (CNH/p53abn), and (iv) copy-number-low, TP53-wild-type (CNL, or No Specific
Mutational Profile [NSMP])] has rapidly gained interest. Recently, the European Societies of
Gynaecological Oncology, Radiotherapy and Oncology, and Pathology (ESGO-ESTRO-ESP), the
European Society of Medical Oncology (ESMO), the National Comprehensive Cancer Network
(NCCN), and the new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging
system have promoted the use of (surrogate) molecular classification. Retrospective studies
supported the value of adopting molecular classification to offer reliable data on
prognostication and adjuvant treatment decisions. Although no prospective data are available,
current guidelines promote the use of molecular profiles to tailor adjuvant treatment after
surgery. As only a few retrospective studies have investigated the association between
molecular profiles and response to various adjuvant treatments, it is important to note that
data are limited. Interestingly, the growing adoption of molecular profiling led to the
detection of a subgroup of tumors called multiple classifiers, characterized by multiple (two
or three) molecular features. According to the guidelines, tumors with a POLE mutation should
be considered POLEmut, regardless of other molecular features, whereas MMRd/MSI-H tumors with
a p53 abnormality should be considered MMRd/MSI-H. Data on these patients is limited and
fragmentary. The aforementioned consensus is based solely on a large retrospective cohort of
multiple classifiers collected by Leon-Castillo et al.. Hence, to fill this literature gap,
the investigators designed this retrospective study, which aimed to collect multiple
classifiers patients to improve knowledge on this emerging category.