Incorporation of molecular characteristics into endometrial cancer management

Abstract

Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high‐grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair‐deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non‐specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this ‘histomolecular’ approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios.

Molecular Subgroups of Endometrial Carcinoma in Romanian Patients

“…According to recent studies, MSI-H/hypermutated tumors which include Lynch syndrome cancers and are represented by loss of MMR (Mismatch Repair) through hypermethylation of one of MMR proteins, comprise 25-30% of endometrial carcinomas [15]. Our study revealed a significant percentage of MSI-H tumors (68%) diagnosed by evaluating loss of MSH6 and/or PMS2 expression, which contradicts various research performed on much larger cohorts [8,15,16]. Other parameters of our study correlated with this molecular subgroup similarly with other conducted studies: higher-grade ECs, endometrioid-type histology, moderate/marked TILs, substantial LVSI [8].…”

“…Our study revealed a significant percentage of MSI-H tumors (68%) diagnosed by evaluating loss of MSH6 and/or PMS2 expression, which contradicts various research performed on much larger cohorts [8,15,16]. Other parameters of our study correlated with this molecular subgroup similarly with other conducted studies: higher-grade ECs, endometrioid-type histology, moderate/marked TILs, substantial LVSI [8].…”

“…This particular molecular subgroup has no specific molecular incriminated driver [19]. Although this largely represented subclass is defined by a low mutational burden, there are numerous studies that show that these have an aggressive clinical behavior [8,18]. Studies show a 65% percentage of this group, but our cohort shows a much higher percentage (74%).…”

“…56% of cases presented with moderate TILs (tumor-infiltrating lymphocytes). Vermij et al [7,8] proved that LVSI in EC patients is connected with an increased risk of lymph node metastasis, locoregional as well as distant recurrences, regardless of stage and histotype. For that matter, LVSI will remain essential in risk stratification schemes, escalating adjuvant treatment regimens in those patients with substantial LVSI.…”

Metabolomic Biomarkers for Detection, Prognosis and Identifying Recurrence in Endometrial Cancer

“…Treatment of EC is usually surgical (hysterectomy and bilateral salpingo-oophorectomy), although a significant minority are offered conservative management in the form of hormonal manipulations, especially women of childbearing age who wish to preserve their fertility [9]. Decisions about adjuvant chemotherapy and radiotherapy are currently based on traditional pathological parameters that lack precision and therefore deny some women with biologically aggressive disease the opportunity to receive life-saving treatments whilst exposing others to unnecessary harms [5,22]. There is, at present, limited evidence to support the routine use of imaging or biochemical testing in the follow-up for EC due mainly to the lack of reliable monitoring tools [5].…”