By Alexandra Morell, MD
Endometrial cancer is the most common gynecologic cancer and the fourth most common overall cancer in women in the United States.1 Nationwide, there are approximately 65,000 new endometrial cancer cases and more than 12,500 deaths annually. Mortality rates from endometrial cancer have increased over the last three decades, which likely is multifactorial and related to increased obesity rates, changes in reproductive trends, and lack of recent medical advances in the treatment of this cancer type.1,2
Historical Classification of Endometrial Cancer
Historically, endometrial cancer has been divided into two subtypes: type 1 endometrial cancers and type 2 endometrial cancers.3 Type 1 endometrial cancers represent more than 75% of cases and are characterized as hormonally driven and histologically low grade (endometrioid adenocarcinoma). These tumors typically derive from a precursor endometrial intraepithelial neoplasia, previously known as complex endometrial hyperplasia with atypia. Type 1 cancers are typically diagnosed at an early stage and represent a favorable prognosis.
In contrast, type 2 endometrial cancers are histologically high grade (clear cell and papillary serous carcinomas) and are thought to derive from a precursor endometrial intraepithelial carcinoma lesion. Type 2 cancers are more aggressive, often diagnosed at a later stage, and represent a poor prognosis.
Molecular Classification of Endometrial Cancer
In recent years, there has been a transition in classification of endometrial cancers with a focus on molecular profiles as opposed to histology alone. In 2013, the Cancer Genome Atlas Network (TCGA) published an integrative genomic and proteonomic analysis of 373 endometrial carcinomas.4 Based on these results, four subtypes of endometrial cancer were identified: deoxyribonucleic acid (DNA) polymerase epsilon (POLE) ultramutated, microsatellite unstable hypermutated (MSI), copy number high (CN high), and copy number low (CN low).
To better apply these subtypes to a clinical setting, the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) was developed to use molecular profiles clinically.5 ProMisE resulted in four distinct endometrial cancer subtypes (similar to the TCGA classifications), which include POLE mutated, mismatch repair deficient (MMR-D), p53 mutant, and no specific molecular profile (NSMP).
In the ProMisE algorithm, the p53 mutant group is a surrogate for CN high and the NSMP group is a surrogate for CN low. The ProMisE algorithm recommends performing mismatch repair protein immunohistochemistry (IHC), POLE exonuclease domain mutant (EDM) hotspot sequencing, and p53 IHC to clinically classify endometrial cancers into their respective subgroups.
POLE hotspot gene mutations are present in approximately 10% of endometrial cancers.5 POLE is involved in maintaining accurate DNA replication by removing incorrectly paired nucleotides.6 POLE mutations most commonly are found with endometrioid histology.5 Of the four molecular subtypes of endometrial cancer, tumors that are POLE ultramutated have the most favorable prognosis, irrespective of tumor grade.
Mismatch repair genes (MLH1, PMS2, MSH2, and MSH6) also are important in maintaining high-fidelity, error-prone DNA replication.7 Mutations in these genes lead to repeated sections of DNA alterations termed microsatellite instability. Microsatellite instability is present in approximately one-third of endometrial cancers. This can result from somatic gene mutations from MLH1 hypermethylation or from germline gene mutations, such as in Lynch syndrome. MSI unstable tumors typically are endometrioid, and MSI-mutated endometrial cancers tend to have an intermediate prognosis.5
A serious histology is more commonly seen with p53 abnormal tumors. This is the most aggressive molecular subtype, representing a poor prognosis. Tumors that are microsatellite stable, p53 wild-type, and without POLE mutations are categorized as NSMP. These tumors have moderate mutational load and low copy number alterations. These tumors often are endometrioid histology and frequently are estrogen and progesterone receptor positive. NSMP classified endometrial cancers have an intermediate prognosis.
Most commonly, an endometrial cancer will fall into only one of the molecular classifications; however, a small subset of endometrial cancers may have more than one molecular feature.8 In this case, POLE followed by MMR status followed by p53 expression tends to determine prognosis. Therefore, if a tumor has both a POLE mutation and is p53 mutant, a patient likely still will have a favorable prognosis because of the POLE mutation despite also having a p53 mutation.
Clinical Relevance
The most recent endometrial cancer staging guidelines from 2023 have incorporated these molecular classifications.9
For example, an endometrial cancer involving less than 50% of the endometrium that is p53 wild-type, mismatch repair deficient, and does not harbor a POLE mutation would be staged as a 1A2mMMRd endometrial cancer, with the “m” designation indicating a molecular classification. Alternatively, an endometrial cancer involving less than 50% of the endometrium that is p53 wild-type, microsatellite stable, and without a POLE mutation would be staged as a 1A2mpNSMP endometrial cancer.
In addition, defining these endometrial cancer molecular subtypes has clinical relevance because they have prognostic value, are highly reproducible among pathologists, and likely will affect treatment algorithms in the future.10 Two recent clinical trials have led to U.S. Food and Drug Administration approval for pembrolizumab and dostarlimab, both immune checkpoint inhibitors, in advanced and recurrent endometrial cancer, with more pronounced improvement in progression-free survival in patients with mismatch repair deficient tumors.11,12 Ongoing studies are evaluating de-escalation of therapy for patients with POLE mutations and escalation of treatment for patients with p53 mutations.10
Alexandra Morell, MD, is Adjunct Instructor, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY.
References
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.
2. Giaquinto AN, Broaddus RR, Jemal A, Siegel RL. The changing landscape of gynecologic cancer mortality in the United States. Obstet Gynecol. 2022;139(3):440-442.
3. Hernandez E; American College of Obstetricians and Gynecologists. ACOG Practice Bulletin number 65: Management of endometrial cancer. Obstet Gynecol. 2006;107(4):952.
4. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
5. Talhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 2015;113(2):299-310.
6. Church DN, Briggs SE, Palles C, et al. DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22(14):2820-2828.
7. León-Castillo A, Gilvazquez E, Nout R, et al. Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas. J Pathol. 2020;250(3):312-322.
8. Stelloo E, Jansen AM, Osse EM, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017;28(1):96-102.
9. Berek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. Int J Gynecol Obstet. 2023;162(2):383-394.
10. Jamieson A, Bosse T, McAlpine JN. The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer. Ther Adv Med Oncol. 2021;13:17588359211035959.
11. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
12. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
The classification of endometrial cancer is evolving, transitioning from histological subtypes to molecular profiling. Four key molecular subtypes (POLE ultramutated, MSI unstable, p53 mutant, and NSMP) guide prognosis and treatment. The integration of molecular features into staging highlights their clinical relevance for improving diagnostic accuracy and therapeutic strategies.
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