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.

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

“…ERK5 also participates in the proliferative signaling in response to activation of HER2 receptors in breast cancer cells, [ 40 ], and ERK5 inhibition sensitizes these cells to anti-HER2 treatments [ 41 ]. 20%-40% of patients with advanced non-endometrioid EC show HER2 overexpression [ 42 ], and Trastuzumab added to standard chemotherapy improved survival of patients with HER + aggressive serous EC, according to a recent phase 2 study [ 43 ]. Thus, it will be relevant to investigate whether ERK5 also mediates HER2 signaling in aggressive EC, and whether ERK5 inhibition could be of help to sensitize these cells to anti-HER2 therapies.…”

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

“…ERK5 also participates in the proliferative signaling in response to activation of HER2 receptors in breast cancer cells, [33], and ERK5 inhibition sensitizes these cells to anti-HER2 treatments [34]. 20%-40% of patients with advanced non-endometrioid EC show HER2 overexpression [35], and Trastuzumab added to standard chemotherapy improved survival of patients with HER + aggressive serous EC, according to a recent phase 2 study [36]. Thus, it will be relevant to investigate whether ERK5 also mediates HER2 signaling in aggressive EC, and whether ERK5 inhibition could be of help to sensitize these cells to anti-HER2 therapies.…”

Endometrial cancer: molecular classification and future treatments

“…16 60 Human epidermal growth factor receptor 2/neu Human epidermal growth factor receptor 2 (HER2/neu) is a receptor tyrosine protein kinase (erbB-2) that is encoded by the ERBB2 gene and is overexpressed in roughly 20-60% of uterine serous carcinomas, 30-60% of uterine clear cell carcinomas, and offers a therapeutic target. 61 Trastuzumab is a humanised monoclonal antibody that targets HER2/neu, with demonstrated efficacy in other tumours with HER2/neu overexpression including breast and gastric cancers. 61 Initial evaluation in a phase 2 trial of 286 patients of single agent trastuzumab in advanced and recurrent endometrial cancer overexpressing HER2/neu showed no progression-free or overall survival benefit.…”

“…61 Trastuzumab is a humanised monoclonal antibody that targets HER2/neu, with demonstrated efficacy in other tumours with HER2/neu overexpression including breast and gastric cancers. 61 Initial evaluation in a phase 2 trial of 286 patients of single agent trastuzumab in advanced and recurrent endometrial cancer overexpressing HER2/neu showed no progression-free or overall survival benefit. 62 However, trastuzumab in combination with standard-of-care carboplatin and paclitaxel in uterine serous carcinomas with HER2/neu overexpression has demonstrated efficacy.…”