Improving Endometrial cancer assessment by combining the new techniqUe of GENomic profiling with surgical Extra Uterine Disease Assessment

Endometrial cancer (EC) is the most common gynaecologic malignancy in developed
countries. In Belgium, ~1500 patients are diagnosed with EC each year. Current
treatment for EC includes a hysterectomy with bilateral salpingo-oophorectomy.
Further surgical staging procedures (lymphadenectomy, peritoneum, and/or
omentum biopsies) can be performed, might detect metastases, and determine the
disease stage. The type and extent of this surgical staging depend on a
pre-operative risk assessment and guides adjuvant treatment (chemo- or
radiotherapy). However, this pre-operative risk assessment based on histology
and imaging is relatively inaccurate. This strategy is far from optimal for
several reasons. First, preoperative histology presents high intersubjective
variability leading to poor reproducibility in the assignment of histotype,
particularly in high-grade tumours.(1) Moreover, its concordance between
preoperative histology and final histology is poor, as it does not correspond
in ~33% of cases, most likely due to superficial sampling and tumour
heterogeneity.(2,3) In addition, preoperative imaging modalities are expensive,
time-consuming, hampered by non-perfect accuracies, require specialized
expertise, or present limitations in reproducibility and availability.(4) As a
result, this leads to an incorrect risk estimation of metastases at diagnosis
in EC patients. In particular, the risk of metastasis in low- and
intermediate-risk patients (representing 80% of EC patients) is underestimated,
as 10-15% of these patients develop recurrent disease.(5-8) Also, not all
intermediate-high and high-risk patients present with metastases at diagnosis,
and ~50% of these patients do not recur. The suboptimal risk estimation of
metastases at diagnosis results in an important over- and undertreatment of
patients (2, 3) and inaccurate clinical trials.(9,10) Thus, there is an urgent
need to develop risk stratification strategies that will better predict the
presence and localization of metastases in EC patients, and therefore more
efficiently tailor surgical staging procedures.
In 2013 The Cancer Genome Atlas (TCGA) Research Network developed a new
molecularly driven classification system, that divides EC tumours into four
molecular subgroups (POLE-ultra mutated (POLE), p53 abnormal (p53abn), mismatch
repair deficient (MMRd), and nonspecific molecular profile (NSMP). The
molecular classification has shown to surpass histologic subtyping and grading
to more efficiently predict prognosis and has the potential to represent a
paradigm shift in the management of EC patients.(11)
However, the relation between the four molecular subgroups and the risk of
tumour spread beyond the uterus at diagnosis has insufficiently been
investigated so far. It has been stated that the future is molecular and that
surgical staging will be of reduced relevance. As a result, the new
classification is being quickly incorporated, and the use of staging surgery to
assess the presence of metastases dissuaded. This is incomprehensible, as the
presence and localization of metastases (disease stage) have until now been the
most important predictor of prognosis, and its impact on each of the four risk
subgroups is so far not known.
We believe that the future is in integrating morphologic and molecular
findings, so the preoperative diagnosis will also support accurate surgical
decision making. If the new molecular classification is fully implemented
without knowing the importance of the disease stage at diagnosis in each of the
molecular subgroups, it will be extremely difficult, if not impossible, to
investigate this in the future. By replacing the traditional classification
(based on histotype and stage) with the molecular classification alone, we will
lose important information and therefore propose to integrate stage and
molecular classification.

EUGENIE aims to bridge the knowledge gap. As up till now disease stage was the
most important prognostic factor, we aim to improve the molecular risk
classification system by integrating the disease stage into the molecular
subgroups. As a first step, we will prospectively collect the unique data of a
large cohort of EC patients who are all fully staged. We will then evaluate if
the disease stage is associated with the molecular type. This will determine
the indicated surgical procedure in each subgroup. Secondly, we will assess how
the information on stage combined with molecular type relates to prognosis.
These data will inform us about the need for adjuvant treatment for each
combination of stage and molecular subgroup. The results of the project will
eventually lead to an integrated, personalized management of all EC patients.

EUGENIE is a prospective multicentre study including 1,000 EC patients.
Patients will be included during the first four years of the study and the
follow-up will be two-six years. Patients with FIGO stage I-IV EC will be
enrolled. A surgical staging procedure will be performed, including a
hysterectomy with bilateral salpingo-oophorectomy (BSO) and assessment of lymph
nodal and peritoneal/omental metastases. The molecular classification will be
determined on the tumor sample. Adjuvant treatment will be proposed based on
patient characteristics, pathology, and stage, according to European guidelines
and local practice. Follow-up is as in routine practice and will be documented
at least for two years after treatment. The primary objective is to determine
the association between molecular classification and the disease stage. The
secondary objective is the association between disease stage in each of the
molecular subgroups and prognosis.

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Extent of the burden and risk associated with participation are minimal.

There is an urgent need to develop risk stratification strategies that will
better predict the presence and localization of metastases in EC patients, and
therefore more efficiently tailor surgical staging procedures.