LAUSR

Molecular profiling of endometrial carcinoma according to The Cancer Genome Atlas (TCGA) points toward a paradigm shift from morphological to molecular classification. TCGA and many subsequent studies confirm the existence of four specific types of endometrial carcinoma: POLE ultramutated (±7%); mismatch repair deficient (MMRD)/hypermutated (±28%); copy number low (±39%); and copy number high/p53 mutated (±26%). To facilitate clinical use, alternatives to genome sequencing, such as the Proactive Molecular Risk Classifier for Endometrial Cancer, have been developed. This allows endometrial carcinoma to be assigned to one of the four types based on MMR protein and p53 immunohistochemistry and POLE mutation analysis. Based on this approach, the TCGA groups consistently exhibit prognostic relevance with POLE ultramutated tumors having an excellent outcome and copy number high having a poor outcome, while the other groups have an intermediate prognosis. Moreover, this molecular classification to some extent negates the wellknown interobserver variability in morphological typing of endometrial carcinoma, especially highgrade. In the recently published ESGOESTROESP endometrial carcinoma guidelines, the integration of TCGA molecular classification with traditional morphological classification has been proposed if results are available. However, in our opinion, there are still important gaps in knowledge that need to be addressed prior to integrating the molecular classification fully into clinical recommendations. One important question is how does preoperative molecular profiling impact surgical staging? Merged data of general endometrial carcinoma cohorts, including information on FIGO stage and TCGA types, 2 5 6 shows that information on stage is insufficiently available for all cohorts with respect to numbers and patterns of spread. Striking is the fact that over 10% of POLE mutated tumors are ≥FIGO stage II at diagnosis and together with the MMRD and copy number low group account for 65% of advanced endometrial carcinoma. Therefore, the TCGA classification does not help surgeons to decide when and how to stage endometrial carcinoma. Subsequently, where currently, positive lymph nodes are the most important prognostic factor, the prognostic effect of upstaging for each molecular type is currently unknown. Another important question is “what is the appropriate adjuvant treatment, if needed, for each molecular type?”. For example, while chemotherapy may be beneficial for copy number high neoplasms, immune checkpoint inhibitors may be effective for MMRD tumors. However, the clinical benefit in the adjuvant and metastatic setting for each molecular type has not been proven yet. A high risk for relapse does not equal the fact that adjuvant treatment is effective. In summary, we should be careful when integrating the current TCGA data, which were retrospectively collected, too quickly into current practice. We encourage collaborative prospective observational studies that integrate surgical staging information with followup, and genomic classification to address the first question. The second question can only be solved by properly designed prospective randomized clinical studies. It is our opinion that molecular classification will be complementary to traditional pathological examination since parameters such as lymphovascular invasion, cervical and nodal involvement, and depth of myometrial invasion can only be determined using traditional methods.