Endometrial cancer

Vicky Makker, Helen MacKay, Isabelle Ray-Coquard, Douglas A Levine, Shannon N Westin, Daisuke Aoki, Ana Oaknin, Vicky Makker, Helen MacKay, Isabelle Ray-Coquard, Douglas A Levine, Shannon N Westin, Daisuke Aoki, Ana Oaknin

Abstract

Although endometrial cancer management remains challenging, a deeper understanding of the genetic diversity as well as the drivers of the various pathogenic states of this disease has led to development of divergent management approaches in an effort to improve therapeutic precision in this complex malignancy. This comprehensive review provides an update on the epidemiology, pathophysiology, diagnosis and molecular classification, recent advancements in disease management, as well as important patient quality-of-life considerations and emerging developments in the rapidly evolving therapeutic landscape of endometrial cancers.

© 2021. Springer Nature Limited.

Figures

Figure 1.. Uterine anatomy.
Figure 1.. Uterine anatomy.
The endometrium is the inner lining of the uterus. Endometrial cancer arises from the endometrial glandular epithelium.
Figure 2.. Incidence and mortality of cancers…
Figure 2.. Incidence and mortality of cancers of the corpus uteri.
A∣ Worldwide incidence of cancers of the corpus uteri. B∣ Worldwide mortality of cancers of the corpus uteri. Data from the Globocan Registry.
Figure 3.
Figure 3.
Molecular subgroup of EC. A. Genomic features of the four molecular subgroups of endometrial cancer (EC) identified by The Cancer Genome Atlas project. B. The frequency of mutations in specific EC-associated genes varies between molecular subgroups. MSI, microsatellite instability; Mb, megabase; CN, copy number. From The Cancer Genome Atlas Research Network; Nature 2013;497(7447):67-73. Springer Nature.
Figure 4.. Crosstalk endometrial cancer’s cell, TAMs…
Figure 4.. Crosstalk endometrial cancer’s cell, TAMs and microenvironment.
Infiltrating monocytes are recruited to tumor foci via chemokines such as CCL2 and CCL5 which induced accumulation of tumour-associated macrophages (TAMs). Tumors produce CSF-1, which acts as both a chemoattractant and a mitogen for circulating monocytes which differentiate into TAMs. TAMs produce angiogenic factors such as VEGF to stimulate tumor-associated blood vessel growth. Through the expression of the immune checkpoint ligands PD-L1/2 and secretion of immunosuppressive factors like prostaglandins, TAMs create an immunosuppressive environment by acting on T cells. Reciprocally, TAMs remodel the extracellular matrix via matrix metalloproteases (MMPs) to create an environment that is a niche for cancer stem cells and conducive for the epithelial-mesenchymal transition (EMT), which leads to metastasis. Amino acid metabolism in TAMs causes metabolic starvation of T cells via IDO1/2 pathway. IL-10 and TGFβ secreted by TAMs promote regulatory T cells (Treg) activity, leading to immunosuppression. Fibroblasts and myofibroblasts, activated by the binding 17-β-estradiol and its receptor ERα, secret cell-cycle-related proteins (MAD2L1, CDKN1A and CEBPβ) and growth factors (IGF and TGF), leading to EMT, which reduces cell-cell adhesion and triggers the ability of cells to escape from apoptosis, migrate and invade. The contemporary loss of E-cadherin and the up-regulation of β-catenin drive the EMT process leading to the alteration of the endometrial architecture and the subsequent multistep process towards endometrial cancer (EC). Fibroblasts and myofibroblasts act as sentinel and amplifier of estrogens on the neighboring endometrium. They are characterized by an opposite expression of E-cadherin/β-catenin compared to the epithelium.
Figure 5.. Staging of endometrial cancer.
Figure 5.. Staging of endometrial cancer.
Endometrial cancer is staged according to 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria. This staging system comprises four stages (I-IV): tumour limited to the corpus uteri (Stage I; panel a), tumor invasion of cervical stroma but confined to the uterus (stage II; panel b), local and/or regions tumor spread (stage III; panel c) and tumour invasion of bladder and/or bowel mucosa and/or distant metastases (stage IV; panel d).
Figure 6.. Histological features of endometrial cancer.
Figure 6.. Histological features of endometrial cancer.
A. POLE ultramutated. B. Microsatellite Instability High. C. Copy number high. D. Copy number low. Image credit to Dr. Lora H. Ellenson, Chief Attending, GYN pathology.
Figure 7.. Progression-free survival of EC.
Figure 7.. Progression-free survival of EC.
Survival varies according to the molecular subtype of endometrial cancer (EC). Copy-number high EC is associated with the poorest prognosis out of all subtypes, whereas the ultramutated subtype is associated with high survival. Adapted from From The Cancer Genome Atlas Research Network; Nature 2013;497(7447):67-73. Springer Nature.
Figure 8.. PORTEC-4a Trial Schema.
Figure 8.. PORTEC-4a Trial Schema.
This was a multicenter randomized phase III trial in high-intermediate risk endometrial cancer investigating the role of an integrated clinicopathological and molecular risk profile to determine adjuvant management with options of no adjuvant therapy, vaginal brachytherapy, or external-beam radiotherapy-based profile compared to standard adjuvant vaginal brachytherapy. G1: Grade 1; G2: Grade 2; G3: Grade 3; LVSI: lymphovascular space invasion; POLEm: POLE mutant; MMRp: mismatch repair proficient; wt: wildtype; MMRd: mismatch repair deficient; CTNBB1m: CTNBB1 mutant; TP53m: TP53 mutant

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      Phase I study that established monotherapy activity of the PD-1 inhibitor dostarlimab in endometrial cancer.

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      Phase III trial of lenvatinib and pembrolizumab in advanced endometrial cancer that led to the FDA approval (non MSI-H/MMRd) and EMA approval (all endometrial cancer) of this combination therapy in patients previously treted with platinum-based chemotherapy in any setting.

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