Molecular Classification of Endometrial Carcinoma: Protocol for a Cohort Study.

Background: Endometrial carcinoma (EC) is the most common gynecologic malignancy in developed countries and the fourth most frequent in women worldwide. The cornerstone of treatment for EC is surgery. Clinicopathological features are currently used to help determine the individual risk of recurrence and the need for adjuvant treatment after surgery. Nonetheless, there is significant interobserver variability in assigning histologic subtype when using a morphological classification, revealing the need for a more unified approach. The Cancer Genome Atlas (TCGA) project identified 4 distinct prognostic EC subtypes based on genomic abnormalities. Surrogate assays including 3 immunohistochemical markers (p53, MSH6, and PMS2) and 1 molecular test (mutation analysis of the exonuclease domain of DNA polymerase epsilon; POLE) allowed the development and validation of a simplified molecular classifier that correlates with the TCGA classification, has prognostic value, and can easily be used in clinical practice. This molecular classification categorizes EC in 4 subtypes: POLE mutated, mismatch repair-deficient, p53 abnormal, and no specific molecular profile. Applying this classification in clinical practice will help tailor adjuvant treatment decisions.

Objective: The aim of this study is to retrospectively apply this novel molecular classification to a cohort of patients with EC treated in a comprehensive cancer center, to assess its applicability in clinical practice, to evaluate clinical outcomes by molecular subtypes, and to assess its prognostic value.

Methods: In this retrospective cohort study, patients with primary EC diagnosed during and after 2013 and treated or followed at our institution, after definite surgery, will be included. Demographic and clinicopathological data will be obtained from electronic health records and from pathology reports. Laboratory methods will include immunohistochemical study of p53 and mismatch repair proteins, as well as POLE mutational analysis by genetic sequencing. The primary end point is recurrence-free survival and secondary end points are disease-specific survival and overall survival. A descriptive analysis of variables will be carried out. Survival analysis will be performed using the Kaplan-Meier method and the groups will be compared using the log-rank test.

Results: This protocol was reviewed and approved by the Instituto Português de Oncologia do Porto, Portugal, ethics committee in October 2021; patient selection from our cancer registry began the same month. A total of 160 patients will be included. This work will present real-life results that will allow a better understanding of the Portuguese EC population and the distribution of the molecular subgroups throughout. We will use these results to understand the prognostic value of this classification in our population and its role in adjuvant therapy decisions. This study is anticipated to conclude in December 2022.

Conclusions: This study will provide important information regarding these women's outcomes according to this new molecular classification and will support its use when discussing a patient's need for adjuvant treatment.

International Registered Report Identifier (irrid): PRR1-10.2196/34461.