REal Word aPpLicAtion of Molecular Based Endometrial Cancer Classification

Despite the high incidence, endometrial cancer represents a low mortality neoplasma due to the high prevalence of early-stage diagnosis (90%). Concerning the uterine-confined disease (FIGO 2009 and 2023 stage I-II), molecular-based classification has showed an unprecedent impact on the treatment algorithm leading to a full integration into the latest staging classification. The first evidence of the prognostic value of molecular subgroups came from the TCGA data in which patients were subdivided into: patients with POLE gene alterations, MMR deficient (MMRd), patients with TP53 gene mutations, absence of one of these alterations (NSMP). The use of molecular classification reveals distinct prognostic groups ranging from an excellent prognosis (POLE mutated) to those with a worst prognosis (p53 mutated). Therefore, according to the ESGO guidelines, in patients with stage I-II POLE mutated endometrial cancer, the recurrence rate is so low as to justify omitting adjuvant treatment in favor of observation alone. Several groups have applied a diagnostic algorithm using five immunohistochemical markers (p53, MLH1, MSH2, MSH6 and PMS2) and a molecular test (analysis of mutations in the exonuclease domain of POLE) to identify prognostic groups similar to the molecular classification of TCGA. The feasibility of this approach has been confirmed by many publications that have all consistently reported prognostic relevance especially in high-grade and high-risk tumours in several independent cohorts and prospective clinical trials. In conclusion, despite the validation of immunohistochemical evaluation in place of molecular evaluation, the need to perform a more complex evaluation to define POLE status makes its implementation not yet ubiquitous. The integration of molecular analysis of the POLE mutations remains challenging across the centers involved in the management of endometrial cancer. REPLACE is a national, cross-sectional survey that will census all Italian gynaecology centres (≈ 264) involved in the endometrial cancer treatment into: (i) quantify POLE testing adoption, (ii) describe diagnostic methodologies, (iii) map treatment de-escalation strategies triggered by POLE status, and (iv) explore management pathways where POLE is unavailable. Findings will highlight implementation gaps and inform future network initiatives.