Abstract
Abstract Endometrial cancer is the most common gynecologic malignancy and the majority of patients are cured with surgery alone. A substantial subset of patients, however, present with high grade uterine papillary serous carcinoma (UPSC) and these patients account for a disproportionate degree of the recurrence, chemoresistance and death associated with endometrial cancer. Novel treatment strategies incorporating molecularly targeted therapies would be of great value in effective clinical management of these tumors. HER2 (ErbB2) hyperactivity has been associated with 10-20% of UPSC, though efforts to target this signature with trastuzumab have yielded no response in a recent prospective trial. In breast cancer, HER2/HER3 (ErbB2/ErbB3) dimerization has been associated with trastuzumab resistance. The expression profile of HER3 in UPSC is currently unknown. The objective of this investigation was to characterize HER2 and HER3 expression in a UPSC series and correlate these findings with clinical outcomes including survival. Under an IRB approved protocol, we identified 33 patients who underwent initial surgical staging at our institution between 2000 and 2009 with archival formalin fixed, paraffin embedded blocks and complete clinical follow up data. These tumor samples were subjected to immunohistochemistry (IHC) for HER2 and HER3 as well as fluorescent in situ hybridization (FISH) to assess the amplification status of the HER2 gene. Non-parametric tests were utilized to test correlation between detected levels of HER2 or HER3 protein expression and HER2 gene amplification and survival analysis was performed using the Kaplan-Meier method. HER2 gene amplification was observed in 34% of the cohort while HER2 protein over-expression, defined as 2+ or 3+ staining, was found in 59% of samples tested. HER2 gene amplification was associated with high HER2 protein expression (p < 0.05). Moreover, HER2 gene amplification was significantly associated with a decreased overall survival (p < 0.05). Finally, HER3 over-expression, defined as 2+ or 3+ staining, was observed in 52% of the entire cohort and HER3 protein levels exhibited a significant inverse relationship to HER2 protein expression and HER2 gene amplification (p < 0.05). These findings suggest that HER2 and HER3 signaling may function independently of one another in UPSC. The observed alterations in HER2 and HER3 expression levels constitute clinically relevant and prevalent signatures in UPSC that merit further investigation to determine the potential benefits of therapies targeting the epidermal growth receptor pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4556. doi:1538-7445.AM2012-4556
Published Version
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