Revolutionizing Endometrial Cancer Classification: The Impact of the Endometrial Promise Classifier

NSMP endometrial cancer is the most common molecular type of endometrial cancer, and although most patients with this cancer type have excellent outcomes there is tremendous variability in prognosis. Earlier this year, we published a study which demonstrated that two key features, tumor grade and estrogen receptor status, enable stratification of clinical outcomes within NSMP endometrial cancers and can be used to direct care.

To discuss the development of the Endometrial ProMisE Molecular Classifier, and the new NSMP study further, we are delighted to have Dr. Jessica McAlpine and Dr. Amy Jamieson, esteemed gynecological cancer surgeons at Vancouver General Hospital, who have been instrumental in the development and implementation of this innovative tool.

Together, they will share insights on how this classifier is revolutionizing the classification of endometrial cancer and its clinical significance for patients.

Note: this conversation was edited for length and clarity

Q1 – What is an Endometrial ProMisE Classifier and how did we get here?

Dr. Jessica McAlpine: The traditional system of categorizing tumors based on histomorphology, or how they look under a microscope, has worked well in ovarian cancer but has been problematic in endometrial cancer. Expert pathologists often disagree on how to classify tumors, particularly high-grade ones, leading to inconsistent pathology diagnoses, challenges in interpretations of treatment efficacy in clinical trials, and inability to accurately provide prognostic information. This hindered research and patient care, and highlighted the need for a more objective and reproducible classification system.

In 2013, a breakthrough came with The Cancer Genome Atlas project (TCGA), a study that provided in-depth profiling of endometrial cancer. However, methods used by the TCGA were not practical and were not able to be transferred to the clinic. Our team started to work on developing a pragmatic classifier that could use standard pathology material to identify four molecular subtypes of endometrial cancer with prognostic value. The four subtypes:1) POLE mutated (POLEmut), 2) mismatch repair deficient (MMRd), 3) p53 abnormal (p53abn) and 4) no specific molecular profile (NSMP). We utilized simple immunohistochemistry and focused sequencing, and with the help of Imagia Canexia Health, incorporated the POLE test. Taken together, these molecular features enable classification and can be executed reliably by any pathology lab.

Q2 – What was the clinical significance of the Endometrial Promise Classifier and its impact on patient care?

Dr. Amy Jamieson: The clinical significance of the Endometrial Promise Classifier has been tremendous. The World Health Organization recommended its incorporation into routine endometrial cancer pathology reporting in 2020, and the same year the European clinical management guidelines had changed to incorporate molecular classification for treatment decisions with other international organizations following (NCCN, FIGO). Molecular classification has impacted patient care by guiding preoperative imaging, surgical decisions, and treatment plans.

Q3 – Can you walk us through the highlights of your most recent publication on Modern Pathology?

Dr. Amy Jamieson: The aim of the study was to identify key features associated with outcomes in endometrial cancers with a specific molecular subtype called NSMP, which has diverse features and clinical outcomes. The study looked at over a thousand cases of NSMP endometrial cancers and analyzed various clinical, pathological, immunohistochemical, and genetic features.

Through this analysis, we found that two critical features, tumor grade and estrogen receptor status could stratify prognosis. Patients with low-risk NSMP subset, which included grade 1 or 2 tumors and estrogen receptor positive tumors, had excellent outcomes with a very low five-year disease recurrence rate of 1.6% across all stages and 1.4% for stage 1. The majority (84%) of NSMP endometrial cancers fell into this low-risk group, which is exciting as it represents a large proportion of patients with excellent outcomes. Combining these ‘low-risk NSMP’ cases with one of the other relatively  less common molecular subtypes POLEmut endometrial cancers, together encompass 50% of all endometrial cancer patients with excellent outcomes who may not need any adjuvant treatment (ie who do not need chemotherapy or radiation)

Dr. Jessica McAlpine:  Exactly–adding to that, I think this hints to the next frontier in care. We’re so fussed about making sure that we treat those patients who need additional therapy, but you cannot overstate the impact of not having to give someone toxic radiation and toxic chemotherapy with long-term consequences. As a clinician, that makes us really excited if you can safely identify people who after surgery has been performed could step away from any additional therapy and just be followed with routine visits.

The ProMisE classifier has revolutionized the classification of endometrial cancer, providing a more objective and reproducible system that has a significant impact on patient care. With its incorporation into clinical practice and guidelines, it has become an invaluable tool for gynecological cancer surgeons, medical oncologists and radiation oncologists in making informed treatment decisions for patients with endometrial cancer. The future looks promising as more countries and organizations adopt this innovative classifier to ensure access and equity, further improving patient outcomes in the field of gynecologic cancers.

Thank you Dr. Jamieson and Dr. McAlpine for taking the time to discuss this important topic. For additional information about this study, please reach out to media@imagiacanexia.com.

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