Abstract
48 Background: HER2 is overexpressed in gastric and gastroesophageal junction (GEJ) tumors. Though treatment of these tumors with the HER2-targeted agent trastuzumab offers clinical benefit, patients ultimately progress. Signaling by HER2/HER3 heterodimers following activation by HER3’s ligand heregulin has been shown to be a resistance mechanism to trastuzumab. The objective of this study was to quantitate HER2, HER3 and heregulin in gastric and GEJ tumor samples to determine whether these tumors express components for signaling through this complex and thus have potential for developing trastuzumab resistance. Methods: A novel immunofluorescent assay was used to quantitate HER2 and cytokeratin in 236 gastric and GEJ tumors. Using image analysis, each cell within a section was classified as tumor or non-tumor based on cytokeratin level. HER2 fluorescence was also quantitated in each cell and converted to number of HER2 receptors per cell using a standard curve from an array of cell lines with defined HER2. The assay’s single cell output enables an assessment of HER2 heterogeneity in any tissue. In those tumors overexpressing HER2, HER3 and heregulin were quantitated using immunofluorescence as for HER2 and by RT-PCR. Results: In concordance with published data, HER2 was overexpressed in ~10% of gastric and ~20% of GEJ tumors. HER2-overexpressing tumors could be divided into two groups with levels of HER2 consistent with IHC scores of 2+ and 3+ as assessed by clinical assays. All HER2-overexpressing samples also expressed HER3 and heregulin. Heregulin expression was detected in both tumor cells and/or in adjacent stroma. Conclusions: HER3 and heregulin are present in HER2-overexpressing gastric and GEJ tumors. To evaluate the importance of HER3 and heregulin in these patients, a randomized open label second line Phase 2 trial has been initiated with MM-111, a HER2/HER3 bispecific antibody that inhibits HER3 activity in HER2-overexpressing cells by blocking heregulin binding. HER2, HER3 and heregulin expression will be retrospectively analyzed in tumor samples from patients in this trial, providing further insight into the role of this complex in gastric and GEJ cancer.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
