Molecular classification of endometrial carcinomas (EC) divides these neoplasms into four distinct subgroups based on their molecular background. Given its clinical significance, genetic examination is becoming integral to the diagnostic process. This study aims to share our experience with the molecular classification of EC using immunohistochemistry (IHC) and next-generation sequencing (NGS). We included all ECs diagnosed at two institutions from 2020 to the present. All cases were prospectively examined by IHC for MMR proteins and p53, followed by NGS using a customized panel covering 18 genes, based on which ECs were classified into four molecular subgroups: POLE mutated, hypermutated (MMR deficient), no specific molecular profile (NSMP), and TP53 mutated. The cohort comprised 270 molecularly classified ECs: 18 (6.6%) POLE mutated, 85 (31.5%) hypermutated, 137 (50.7%) NSMP, and 30 (11.1%) TP53 mutated. Twelve cases (4.4%) were classified as 'multiple classifier' EC. Notably, most of these cases with available follow-up (6/9) behaved aggressively. Within the POLEmut EC group, 3/4 cases had advanced tumors, including one patient who died of the disease. Similarly, in the MMRd/TP53mut group, 3/5 patients with available follow-up had metastatic disease, leading to death of the patient in 1 case. ECs of NSMP showed multiple genetic alterations, with the most common mutations being PTEN (44% within the group of NSMP), followed by PIK3CA (30%), ARID1A (21%), and KRAS (9%). Our findings suggest that combining immunohistochemistry with NGS offers a more reliable classification of ECs, including 'multiple classifier' cases, which, based on our observations, tend to exhibit aggressive behavior. Additionally, our data highlight the complex genetic background of NSMP ECs, which can facilitate further stratification of tumors within this group and potentially help select patients for dedicated clinical trials.

Biopticka Laboratory Ltd Plzen Czech Republic

Department of Gynaecology and Obstetrics Faculty of Medicine in Plzen University Hospital Plzen Charles University Plzen Czech Republic

Department of Pathology Faculty of Medicine in Plzen University Hospital Plzen Charles University Plzen Czech Republic

Faculty of Medicine in Plzen Charles University Plzen Czech Republic

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Kandoth C, Schultz N, Cherniack AD et al (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497:67–73 PubMed DOI

Corr B, Cosgrove C, Spinosa D, Guntupalli S (2022) Endometrial cancer: molecular classification and future treatments. BMJ Med 1:e000152 PubMed DOI PMC

Vermij L, Smit V, Nout R, Bosse T (2020) Incorporation of molecular characteristics into endometrial cancer management. Histopathology 76:52–63 PubMed DOI

Who classification of tumours editorial board female genital tumours [Internet] (2020) Lyon (France): International Agency for Research on Cancer. (WHO classification of tumours series, 5th edn. vol 4. Available from: https://tumourclassification.iarc.who.int/chapters/34

Concin N, Matias-Guiu X, Vergote I et al (2021) ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 31:12–39 PubMed DOI

Oaknin A, Bosse TJ, Creutzberg CL et al (2022) Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 33:860–877 PubMed DOI

Berek JS, Matias-Guiu X, Creutzberg C et al (2023) FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 162:383–394 PubMed DOI

Momeni-Boroujeni A, Nguyen B, Vanderbilt CM et al (2022) Genomic landscape of endometrial carcinomas of no specific molecular profile. Mod Pathol 35:1269–1278 PubMed DOI PMC

Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826 PubMed DOI PMC

Šteiner P, Andreasen S, Grossmann P et al (2018) Prognostic significance of 1p36 locus deletion in adenoid cystic carcinoma of the salivary glands. Virchows Arch 473:471–480 PubMed DOI

Ooi A, Oyama T, Nakamura R et al (2015) Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Mod Pathol 28:861–871 PubMed DOI

Stelloo E, Bosse T, Nout RA et al (2015) Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol 28:836–844 PubMed DOI

Talhouk A, McAlpine JN (2016) New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract 3:14 PubMed DOI PMC

Talhouk A, McConechy MK, Leung S et al (2017) Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer 123:802–813 PubMed DOI

León-Castillo A, Gilvazquez E, Nout R et al (2020) Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas. J Pathol 250:312–322 PubMed DOI PMC

Stelloo E, Nout RA, Osse EM et al (2016) Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 22:4215–4224 PubMed DOI

Talhouk A, McConechy MK, Leung S et al (2015) A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 113:299–310 PubMed DOI PMC

León-Castillo A, Britton H, McConechy MK et al (2020) Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 250:323–335 PubMed DOI PMC

Bosse T, Nout RA, McAlpine JN et al (2018) Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups. Am J Surg Pathol 42:561–568 PubMed DOI PMC

Brett MA, Atenafu EG, Singh N et al (2021) Equivalent survival of p53 mutated endometrial endometrioid carcinoma grade 3 and mutated endometrial endometrioid carcinoma grade. Int J Gynecol Pathol 40:116–123 PubMed DOI

Cui J, Chen X, Zhai Q et al (2023) A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer: a case report. Diagn Pathol 18:19 PubMed DOI PMC

https://www.endometrium.cz/doc/trusight-oncology-500-and-ht-data-sheet-1170-2018-010%20003.pdf

McAlpine JN, Chiu DS, Nout RA et al (2021) Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: an individual patient data meta-analysis. Cancer 127:2409–2422 PubMed DOI

Veneris JT, Lee EK, Goebel EA et al (2019) Diagnosis and management of a recurrent polymerase-epsilon (POLE)-mutated endometrial cancer. Gynecol Oncol 153:471–478 PubMed DOI

Dong D, Lei H, Liu D et al (2021) POLE and mismatch repair status, checkpoint proteins and tumor-infiltrating lymphocytes in combination, and tumor differentiation: identify endometrial cancers for immunotherapy. Front Oncol 11:640018 PubMed DOI PMC

Mehnert JM, Panda A, Zhong H et al (2016) Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J Clin Invest 126:2334–2340 PubMed DOI PMC

Wang F, Zhao Q, Wang YN et al (2019) Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol 5:1504–1506 PubMed DOI PMC

Slomovitz BM, Jiang Y, Yates MS et al (2015) Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33:930–936 PubMed DOI PMC

Barra F, Evangelisti G, Ferro Desideri L et al (2019) Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs 28:131–142 PubMed DOI

Konstantinopoulos PA, Lee EK, Xiong N et al (2023) A phase II, two-stage study of Letrozole and Abemaciclib in estrogen receptor-positive recurrent endometrial cancer. J Clin Oncol 41:599–608 PubMed DOI

Mirza MR, Bjorge L, Marme F et al (2020) LBA28 A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. Ann Oncol 31:S1160 DOI

Moroney MR, Woodruff E, Qamar L et al (2021) Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer. Mol Carcinog 60:511–523 PubMed DOI

Aghajanian C, Filiaci V, Dizon DS et al (2018) A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 150:274–281 PubMed DOI PMC