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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.

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Fig. 1: Overview of endometrial cancer origin, development and molecular classification.
Fig. 2: Minimally invasive sampling methods for endometrial cancer (EC) patients.
Fig. 3: Molecular-based risk/treatment stratification strategies for endometrial cancer (EC) patients.
Fig. 4: Functional grouping of genes in which aberrations are acquired in metastases of endometrial cancer.

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Acknowledgements

The authors apologize to those authors whose work we could not cite owing to space limitations. This work was supported by the Intramural Research Program of the National Human Genome Research Institute at NIH (HG200338 and HG200379) to D.W.B.

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The authors contributed equally to all aspects of the article.

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Correspondence to Daphne W. Bell.

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D.W.B. receives royalty income from US patent no. 7,294,468 ‘Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments’, which is licensed to Esoterix Genetic Labs LLC. M.E.U. has no competing interests.

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Supplementary information

Glossary

Carcinosarcoma

Tumour comprising both carcinoma and sarcoma.

Hysterectomy

Surgical removal of the uterus.

Epithelial-to-mesenchymal transition

(EMT). Process by which epithelial cells acquire characteristics of mesenchymal cells, including but not limited to decreased cell-to-cell adhesion, decreased polarity and increased motility.

Carcinomas

Cancer caused by uncontrolled proliferation of epithelial cells.

Complex atypical hyperplasia

(CAH). When occurring in the endometrium, precancerous changes in the epithelial cells lining the uterus, characterized by abnormal growth and the acquisition of somatic genomic aberrations.

Ovarian insufficiency

Loss of normal ovarian function.

Mismatch repair

(MMR). Type of DNA repair that corrects base–base mismatches and insertions/deletions.

Atrophic endometrium

Thin layer of nonproliferative epithelial cells lining the uterus; characteristic of postmenopausal women.

Serous endometrial intraepithelial carcinoma

(SEIC). Noninvasive malignant precursor to serous endometrial cancer.

Sarcoma

Cancer caused by uncontrolled proliferation of connective tissue.

The Cancer Genome Atlas

(TCGA). NIH-funded initiative that molecularly characterized over 20,000 primary cancer and matched normal samples, covering 33 cancer types.

Progression-free survival

(PFS). Length of time a patient lives without objective worsening of disease.

Microsatellite instability

(MSI). Alteration of the number of short, repeated sequences of DNA because of a defect in DNA mismatch repair.

Disease-free survival

Length of time a patient lives without signs of disease.

Papanicolaou (Pap) test

Routine screening tool in which cervical cells are collected using a small brush and are analysed microscopically for signs of disease (e.g., irregular cell morphology).

Tao brush

Flexible brush used to sample the inside of the uterus.

Pap brush

Flexible brush used to sample the inside of the cervix.

Next-generation sequencing

(NGS). High-throughput technologies (also known as massively parallel or deep sequencing) that enable faster determination of DNA or RNA base pair codes than previously used technologies (e.g. Sanger sequencing) were capable of.

Uterine lavage

Process by which the uterus is flushed with a sterile solution.

Cologuard

Colorectal cancer screening test that enables patients to collect stool samples in-home; samples are mailed to a lab where they are analysed for the presence of blood and DNA abnormalities.

Lymphovascular space invasion

(LVSI). Spreading of cancer to the lymphatic system or blood vessels.

Carboplatin

Chemotherapy drug that inhibits cell growth and/or causes apoptosis by inducing DNA–DNA and DNA–protein crosslinks.

Paclitaxel

Chemotherapy drug that binds tubulin and inhibits cell division; also induces apoptosis through binding and inhibition of B cell leukaemia 2.

Trastuzumab

Recombinant monoclonal humanized epidermal growth factor receptor 2 antibody.

Tumour-infiltrating lymphocytes

(TILs). White blood cells (immune cells) found within tumour tissue.

TCGA’s Pan-Gyn cohort

The 1,087 invasive breast carcinomas, 308 endocervical adenocarcinomas, 579 high-grade serous ovarian cystadenocarcinomas, 548 uterine corpus endometrial carcinomas and 57 uterine carcinosarcomas molecularly characterized by TCGA.

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Urick, M.E., Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer 19, 510–521 (2019). https://doi.org/10.1038/s41568-019-0177-x

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