Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice

Abstract

HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely-at least in part-resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases-85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component-were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients' medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended, due to the significant heterogeneity of HER2 protein expression. Keywords: endometrial serous carcinoma; fluorescent in situ hybridization; HER2 testing; heterogeneity; immunohistochemistry The significance of human epidermal growth factor receptor 2 (HER2/Neu, ERBB2) amplification and HER2 protein overexpression has been well established in the pathogenesis and targeted therapy of breast cancer and more recently in gastric and gastroesophageal junction carcinomas. 1-3 Tumorspecific HER2 testing guidelines have been developed to reflect the unique biological features of each of these tumor types and to predict the clinical response to HER2-targeted therapy. [4][5][6][7] Although HER2/neu has been studied in endometrial cancer for over 15 years, standard testing methods or scoring guidelines are yet to be developed. The reported rates of HER2 overexpression in endometrial serous carcinoma range between 14 and 80%, due to-at least in part-the significant ...

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

“…Previous reports suggest that a subset of uterine serous carcinomas is reliant upon HER2/neu amplification as a driver pathway [10]. Recent reports suggest that HER2/neu is amplified in approximately 33% of cases [12]. Overexpression of HER2/neu is associated with a worse prognosis and a more aggressive tumor phenotype in a number of cancers including USC [13][14][15][16][17].…”

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

“…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.…”

“…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).…”

“…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).…”

“…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). Taken together, these data suggest that while a significant subset of USC patients may potentially benefit from current HER2/neu-targeted therapies such as trastuzumab (Herceptin, Genentech/Roche), a novel HER2/neu-targeting antibody-drug conjugate (ADC) active against USC with heterogeneous or moderate (2þ) to low (1þ) HER2/neu expression might significantly expand the number of treatment-eligible patients.…”