Abstract
The breadth of HER2 expression by primary human ovarian cancers remains controversial, which questions its suitability as a universal antigen in this malignancy. To address these issues, we performed extensive HER2 expression analysis on a wide panel of primary tumors as well as established and short-term human ovarian cancer cell lines. Conventional immunohistochemical (IHC) analysis of multiple tumor sites in 50 cases of high-grade ovarian serous carcinomas revealed HER2 overexpression in 29% of evaluated sites. However, more sensitive detection methods including flow cytometry, western blot analysis and q-PCR revealed HER2 expression in all fresh tumor cells derived from primary ascites or solid tumors as well as all established and short-term cultured cancer cell lines. Cancer cells generally expressed HER2 at higher levels than that found in normal ovarian surface epithelial (OSE) cells. Accordingly, genetically-engineered human T cells expressing an HER2-specific chimeric antigen receptor (CAR) recognized and reacted against all established or primary ovarian cancer cells tested with minimal or no reactivity against normal OSE cells. In conclusion, all human ovarian cancers express immunologically-detectable levels of HER2, indicating that IHC measurement underestimates the true frequency of HER2-expressing ovarian cancers and may limit patient access to otherwise clinically meaningful HER2-targeted therapies.
Highlights
The ERBB2 proto-oncogene encodes a transmembrane protein tyrosine kinase receptor involved in the development and progression of many cancers including ovarian cancer [1,2]
HER2 protein expression is most commonly detected via semiquantitative IHC analysis on paraffin embedded tissues using established protocols employed for the assessment of breast cancer patients being considered for anti-HER2 Herceptin treatment [9]
Our results demonstrate that all ovarian cancer (OvCa) samples express HER2, and that this level of expression is sufficient to elicit immune recognition
Summary
The ERBB2 proto-oncogene encodes a transmembrane protein tyrosine kinase receptor involved in the development and progression of many cancers including ovarian cancer [1,2]. HER2 overexpression is associated with an increased risk of progression and death especially among women with FIGO stage I and II OvCa [6]. No correlation has been found between the presence of HER2 overexpression and FIGO stage, suggesting that activation of HER2 overexpression is broad and can occur both in early and late stages of disease [7]. These qualities would appear to make HER2 an attractive molecule for targeted immunotherapies in women with HER2positive ovarian cancer, where naturally-occurring CD4+ and CD8+ T cell responses have been observed [8]. The extent to which HER2 is expressed by OvCas remains controversial, as the rate of HER2-positive OvCas reported in the literature ranges from 4.9% to 52.5%
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