HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges

Abstract

Context.-In the era of targeted cancer therapy, there is growing interest in developing novel therapeutic strategies against endometrial carcinoma, especially its most biologically aggressive variant, serous adenocarcinoma. Several publications have demonstrated that a significant proportion of uterine serous carcinomas show HER2 overexpression and/or amplification, suggesting that HER2 may be a promising therapeutic target. Case reports have already shown clinical response to trastuzumab, a humanized monoclonal immunoglobulin (Ig) G1 antibody against HER2, and patients are currently being enrolled in a multi-institutional prospective randomized trial to evaluate the therapeutic efficacy of trastuzumab.Objective.-To review current data on HER2 testing and targeted therapy against HER2/neu in endometrial carcinoma. Data Sources.-Review of the literature and personal experience of the authors.Conclusions.-Parallel to the clinical studies, there is a need to develop standardized criteria for HER2 testing in endometrial carcinoma that reflect the unique biological and pathogenetic features of these tumors and correlate with clinical response to therapy. This article presents a comprehensive review of the current state of HER2-based therapy and HER2 testing in endometrial carcinoma.

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression

“…Despite the over-expression of HER2 in a significant subset of USC (10,11) and the publication of encouraging case reports using trastuzumab in combination with chemotherapy on a limited number of patients with recurrent disease (28)(29)(30), single-agent trastuzumab 4 mg/kg in week 1 then 2 mg/kg weekly until disease progression in stage III/IV or recurrent endometrial cancers failed to demonstrate significant clinical activity at the phase II level (GOG-181B) (24). While the negative results of the Gynecologic Oncology Group study have been challenged due to the many shortcomings in the design of the GOG181B trial (31), these negative clinical findings do suggest that a significant number of endometrial cancer patients may potentially harbor disease endowed with primary resistance to trastuzumab secondary to PI3KCA mutations and/or caused by a highly heterogeneous HER2/neu expression (10,11).…”

“…While the negative results of the Gynecologic Oncology Group study have been challenged due to the many shortcomings in the design of the GOG181B trial (31), these negative clinical findings do suggest that a significant number of endometrial cancer patients may potentially harbor disease endowed with primary resistance to trastuzumab secondary to PI3KCA mutations and/or caused by a highly heterogeneous HER2/neu expression (10,11). Importantly, our preclinical data with SYD985 clearly demonstrate that PI3K-mutated/T-resistant USC primary cell lines may be highly sensitive to this novel ADC and that SYD985 may be significantly more effective than T-DM1 in inducing bystander killing of low/negative HER2/ neu-expressing USC cells admixed with HER2/neu-positive tumors.…”

“…With no direct ligand identified to date, HER-2/neu functions as a preferred partner for heterodimerization with other members of the EGFR family (namely HER-1 or ErbB1, HER-3 or ErbB3 and HER-4 or ErbB4), and thus plays an important role in coordinating the complex ErbB signaling network that is responsible for regulating cell growth and differentiation (6)(7)(8)(9). Recent data from large USC series demonstrated that HER2 overexpression (i.e., HER2/neu 3þ expression by IHC or c-erbB2 gene amplification by FISH) is present in about 35% of the patients with an additional 40% to 50% USC patients harboring tumors with 2þ or 1þ HER2/neu expression by IHC (10,11). Importantly, in these studies, a striking heterogeneity in HER2/neu protein expression was found with 53% of the HER2/neu 3þ positive USC samples demonstrating large areas of disease with low to negligible HER2/neu expression (10).…”

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

“…Overexpression of Her2 is found in 22% of breast cancers, 28% of pulmonary adenocarcinoma, 17% of colorectal adenocarcinomas, 11% of pulmonary squamous, and 11% of gastric adenocarcinomas (37). Her2 overexpression is also found in ovarian and aggressive forms of uterine cancer (38)(39)(40). Recent evidence has implicated Her2 signaling in resistance to the EGFR-targeted cancer drug cetuximab (41).…”

HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

“…Numerous studies have supported that HER2 is a promising target for the treatment of endometrial tumors not curable with surgery or radiation [35], the majority of which are high grade EnCa. The general conclusion of these studies is that tumors harboring HER2 protein over-expression with concurrent gene amplification will likely be the most responsive to anti-HER2 therapies [36]. Unfortunately, the available clinical data do not yet provide support for this rational position.…”