Clinical actionability of molecular targets in endometrial cancer

Abstract

Endometrial cancer accounts for ~76,000 deaths among women each year worldwide. Disease mortality and the increasing number of new diagnoses make endometrial cancer an important consideration in women's health, particularly in industrialized countries, where the incidence of this tumour type is highest. Most endometrial cancers are carcinomas, with the remainder being sarcomas. Endometrial carcinomas can be classified into several histological subtypes, including endometrioid, serous and clear cell carcinomas. Histological subtyping is currently used routinely to guide prognosis and treatment decisions for endometrial cancer patients, while ongoing studies are evaluating the potential clinical utility of molecular subtyping. In this Review, we summarize the overarching molecular features of endometrial cancers and highlight recent studies assessing the potential clinical utility of specific molecular features for early detection, disease risk stratification and directing targeted therapies.

Figure 1.. Overview of endometrial carcinoma origin, development, and molecular classification.

(a) The image in this panel was deleted to comply with Nature Reviews Cancer policy on self-archiving. Schematic depiction of the initiation and progression of endometrioid (B) and serous (C) endometrial carcinomas (ECs) from the normal and atrophic endometrial glandular epithelium, via precursor lesions (CAH and SEIC). Columnar epithelial cells that have acquired somatic mutations are colored; intratumoral heterogeneity is depicted by differentially colored epithelial cells. PTEN mutation and TP53 mutation are, respectively, early events in the etiology of many endometrioid and serous endometrial carcinomas. In some instances, carcinomas, particularly high-grade carcinomas, undergo an epithelial to mesenchymal transition to give rise to uterine carcinosarcomas, which are biphasic tumors consisting of epithelial carcinoma cells and sarcoma cells (blue). (D) Pie charts showing the distribution (% of tumors) of low grade (grade 1 and grade 2) endometrioid EC, high grade (grade 3) endometrioid EC, and serous EC among the four molecular subgroups delineated in The Cancer Genome Atlas.

Figure 2.. Minimally invasive sampling methods for endometrial cancer (EC) patients. (a.) Tao brush sampling with PapSEEK test:

women testing positive for aneuploidy in any of ~38,000 loci of long interspersed nucleotide elements or mutation in any of 18 genes would be sent for confirmatory testing. PapSEEK testing of Tao brush samples accurately detected EC in 93% of women tested with EC; out of 125 women without EC, none tested positive. (b.) Uterine lavage samples analyzed on a 12 gene next generation sequencing panel detected cancer in 7 women with EC; mutations in the 12 genes were also detected in 51 of 95 women with a non-cancerous uterus. Two images in this Figure were deleted to comply with Nature Reviews Cancer policy on self-archiving.

Figure 3.. Molecular-based risk/treatment stratification strategies for endometrial cancer (EC) patients.

(a.) The TransPORTEC molecular classification system currently being tested in the PORTEC-4a clinical trial and (b.) the Proactive Molecular Risk Classifier for EC (ProMisE). (c.) Distribution of endometrial cancer patients in molecular subgroups. Each cohort consisted of the following EC patients: TCGA (n=232: 186 EEC, 42 SEC, 4 Mixed ECs), TransPORTEC high risk (n=116: 86 high risk EEC, 12 SEC, 18 CCEC), TransPORTEC early stage (n=834 early stage EEC), ProMisE discovery (n=143: 119 EEC, 15 SEC, 8 mixed, 1 undif; 64 ESMO high risk), ProMisE confirmation (n=319; 215 EEC, 5 CCEC, 89 SEC, 10 other; 173 ESMO high risk), ProMisE validation (n=452; 397 EEC, 34 SEC, 21 CCEC/mixed; 131 ESMO high risk), ProMisE young (n= 257 <50 yo: 225 EEC, 17 NEEC, 15 unknown; 21 ESMO high risk). Abbreviations: Clear Cell Endometrial Cancer (CCEC); Catenin Beta 1 (CTNNB1); Exonuclease Domain Mutation (EDM); Exonuclease Domain Wildtype (EDWT); Endometrioid Endometrial Cancer (EEC); European Society of Medical Oncology (ESMO); Immunohistochemistry (IHC); lymphovascular space invasion [G] (LVSI); MicroSatellite Instable (MSI); Mismatch Repair-Deficient (MMR-D); No Specific Molecular Profile (NSMP); polymerase-ε mutated (POLE); Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE); Serous Endometrial Cancer (SEC); The Cancer Genome Atlas (TCGA); Translational Research in Post-Operative Radiation Therapy in Endometrial Carcinoma (TransPORTEC); tumor protein 53 (p53); Undifferentiated (undif); wild-type (WT); year-old (yo).

Figure 4.. Functional grouping of genes in which aberrations are acquired in metastases of endometrial cancer (EC)

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