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Molecular subtypes of endometrial carcinoma: Molecular, pathologic, and clinical features[1-19]

Molecular subtypes of endometrial carcinoma: Molecular, pathologic, and clinical features[1-19]
TCGA category Molecular classification Molecular features (diagnostic tests) Pathology features Clinical features Outcomes Treatment options
POLE "ultramutated"
(approximately 7% of TCGA)		 POLEmut
(approximately 7 to 9% of all ECs)
  • Markedly high TMB
  • >100 mut/Mb
  • SCNA very low
  • PTEN mutations (94%)
  • (POLE EDM or hotspot sequencing)
 Commonly high grade, LVSI, aggressive features, "ambiguous morphology" prominent TIL, EEC G3-2-1* but can be any Presents in younger, often thinner women Highly favorable (>96% five-year survival)
  • Observation only may be reasonable, even if high-risk features. Clinical trials are needed to establish safety and efficacy.
  • Checkpoint inhibitors for rare advanced/recurrent
MSI "hypermutated"
(approximately 28% of TCGA)		 MMRd
(26 to 30% of all ECs)
  • 10 to 100 mut/Mb
  • SCNA low
  • PTEN (88%), PIK3CA (54%), ARID1A (37%) mutations
  • (MMR IHC: PMS2, MSH6, ±MSH2, and MLH1; or MSI assay)
 LVSI and higher grade, prominent TIL, MELF, EEC G2/3-1* but can be any Lynch syndrome association Intermediate
  • Radiation
  • Checkpoint inhibitors if advanced/recurrent
Copy-number low
(approximately 39% of TCGA)		 p53wt/NSMP
(45 to 50% of all ECs)
  • Low TMB (<10 mut/Mb)
  • SCNA low
  • PTEN (77%), PIK3CA (53%), CTNNB1 (52%), ARID1A (42%) mutations
  • ER+ PR+
  • (p53 IHC: wt [normal expression] and absence of POLEmut or MMRd)
 Squamous differentiation, low TIL, mostly low-grade EEC G1-2-3* Often presents in younger individuals with higher BMI or exogenous estrogen Intermediate-favorable
  • Hormonal therapy
  • PI3K/mTOR inhibitors?
Copy-number high
(approximately 26% of TCGA)		 p53abn
(13 to 18% of all ECs)
  • Low TMB (<10 mut/Mb)
  • SCNA high
  • PIK3CA (47%), PPP2R1A (22%), FBXW7 (22%) mutations
  • (p53 IHC: abnormal or TP53 mutation)
 LVSI, high cytonuclear atypia, mostly high grade, mostly serous but approximately 25% EEC G3 Presents in older, thinner, women; commonly advanced stage Poor (approximately 50% five-year survival)
  • Chemotherapy
  • HER2-targeted or HRD-targeted therapy?
Summary of EC classification, outlining original TCGA categories and subsequent TCGA-inspired analogous pragmatic molecular classifiers now in use (eg, ProMisE, PORTEC trials). For each molecular subtype, the associated molecular, pathologic, clinical features, and clinical outcomes are shown. Potential treatment selections (conventional and targeted) for each molecular subtype are also shown with clinical trials in progress for further validation.[1-18]
TCGA: The Cancer Genome Atlas; POLE: DNA polymerase epsilon, catalytic subunit; mut: mutation; EC: endometrial cancer; TMB: tumor mutational burden; Mb: megabase; SCNA: somatic copy number alteration; PTEN: phosphatase and tensin homolog; EDM: exonuclease domain mutations; LVSI: lymphovascular space invasion; TIL: tumor-infiltrating lymphocytes; EEC: endometrioid endometrial cancer; G: grade; MSI: microsatellite instability; MMRd: mismatch repair deficient; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; ARID1A: AT-rich interaction domain 1A; IHC: immunohistochemistry; PMS2: postmeiotic segregation 2; MSH6: mutL homolog 6; MSH2: mutL homolog 2; MLH1: mutL homolog 1; MELF: microcystic elongated and fragmented; p53wt: p53 wild type; NSMP: no specific molecular profile; CTNNB1: catenin beta 1; ER: estrogen receptor; PR: progesterone receptor; BMI: body mass index; PI3K: phosphoinositide 3-kinase; mTOR: mechanistic target of rapamycin; p53abn: abnormal p53 expression on IHC; TP53: tumor protein 53; PPP2R1A: protein phosphatase 2, structural/regulatory subunit alpha; FBXW7: F-box and WD repeat domain containing 7; HER2: human epidermal growth factor receptor 2; HRD: homologous recombination deficiency.
* In order of frequency.
References:
  1. Creutzberg CL, Leon-Castillo A, De Boer SM, et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on adjuvant therapy. Ann Oncol 2019; 30:mdz394.
  2. Stelloo E, Bosse T, Nout RA, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol 2015; 28:836.
  3. Stelloo E, Nout RA, Osse EM, et al. Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer - combined analysis of PORTEC cohorts. Clin Cancer Res 2016; 15:4215.
  4. McConechy MK, Talhouk A, Leung S, et al. Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis. Clin Cancer Res 2016; 22:2865.
  5. McAlpine J, Leon-Castillo A, Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol 2018; 244:538.
  6. Van Gool IC, Rayner E, Osse EM, et al. Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues. Clin Cancer Res 2018; 24:3197.
  7. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.
  8. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372:2509.
  9. Talhouk A, Derocher H, Schmidt P, et al. Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma. Clin Cancer Res 2019; 25:2537.
  10. Ashley CW, Da Cruz Paula A, Kumar R, et al. Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression. Gynecol Oncol 2019; 152:11.
  11. de Jonge MM, Auguste A, van Wijk LM, et al. Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas. Clin Cancer Res 2019; 25:1087.
  12. Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. J Clin Oncol 2018; 36:2044.
  13. Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497:67.
  14. Talhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 2015; 113:299.
  15. Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer 2017; 123:802.
  16. McAlpine J, Nout R, Kommoss S, et al. Survival benefit in women with endometrial cancers harboring POLE may be independent of adjuvant therapy. International Gynecologic Cancer Society Kyoto, Japan 2018. Int J Gynecol Cancer 2018; 28:0.
  17. Santin AD, Bellone S, Buza N, et al. Regression of Chemotherapy-Resistant Polymerase ε (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab. Clin Cancer Res 2016; 22:5682.
  18. Eggink FA, Van Gool IC, Leary A, et al. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology 2017; 6:e1264565.
  19. León-Castillo A, de Boer SM, Powell ME, et al. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. J Clin Oncol 2020; :JCO2000549.
Courtesy of Jessica McAlpine, MD, and Jutta Huvila, MD, PhD.
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