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Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives

ABSTRACT: Endometrial cancer is the most common gynecological cancer in developed countries, and its incidence has increased. The majority of patients with endometrial cancer have an early disease and favorable prognosis; however, a significant proportion of endometrial cancer, which mainly comprises high-grade or type II endometrial cancer such as serous, clear cell, and carcinosarcoma, shows advanced/recurrent disease and dismal prognosis. Novel therapeutic development is required for patients with aggressive endometrial cancers. Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2 (HER2) overexpression/gene amplification in 20%-40% of patients with type II endometrial cancer. Historically, HER2 targeted therapy has been developed for various major cancers, including breast and gastric cancer. Notably, recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change. Simultaneously, an optimized HER2 test for endometrial cancer as companion diagnostics should be established. In this review, we summarize the recent findings on endometrial cancer, current treatment, optimized HER2 testing, key clinical trials on HER2 targeted therapy, and future directions in aggressive endometrial cancer, including serous carcinoma and carcinosarcoma.

SUBMITTER: Saito A

PROVIDER: S-EPMC8546653 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Infertility and adverse gynecological outcomes such as preeclampsia and miscarriage represent significant female reproductive health concerns. The spatiotemporal expression of growth factors indicates that they play an important role in pregnancy. The goal of this study is to define the role of the ERBB family of growth factor receptors in endometrial function. Using conditional ablation in mice and siRNA in primary human endometrial stromal cells, we identified the epidermal growth factor receptor (Egfr) to be critical for endometrial function during early pregnancy. While ablation of Her2 or Erbb3 led to only a modest reduction in litter size, mice lacking Egfr expression are severely subfertile. Pregnancy demise occurred shortly after blastocyst implantation due to defects in decidualization including decreased proliferation, cell survival, differentiation and target gene expression. To place Egfr in a genetic regulatory hierarchy, transcriptome analyses was used to compare the gene signatures from mice with conditional ablation of Egfr, wingless-related MMTV integration site 4 (Wnt4) or boneless morphogenic protein 2 (Bmp2); revealing that not only are Bmp2 and Wnt4 key downstream effectors of Egfr, but they also regulate distinct physiological functions. In primary human endometrial stromal cells, marker gene expression, a novel high content image-based approach and phosphokinase array analysis were used to demonstrate that EGFR is a critical regulator of human decidualization. Furthermore, inhibition of EGFR signaling intermediaries WNK1 and AKT1S1, members identified in the kinase array and previously unreported to play a role in the endometrium, also attenuate decidualization. These results demonstrate that EGFR plays an integral role in establishing the cellular context necessary for successful pregnancy via the activation of intricate signaling and transcriptional networks, thereby providing valuable insight into potential therapeutic targets.

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Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives

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