Trastuzumab, the monoclonal antibody targeting the receptor tyrosine kinase HER2, was recently shown to improve the overall survival of patients with advanced or metastatic gastric adenocarcinoma, the 2nd most common cancer worldwide. Patients were eligible to receive trastuzumab only if the gastric cancer was HER2- positive, which was defined as immunochemistry (IHC) 3+ or if HER2 was amplified by fluorescence in situ hybridization (FISH). Unfortunately, IHC or FISH appear to be inexact methods to measure HER2 partly because of tumor heterogeneity in gastric cancers. Indeed, review of our own institutional experience has revealed a low rate of HER2-positive gastric cancers by IHC or FISH. The major problem with inaccurate determination of HER2 status is that false negative results will erroneously exclude patients from receiving effective gastric cancer therapy. Our research team has developed a novel radiolabeled imaging study that may improve the measurement of HER2 status in patients with gastric cancer. We have conjugated trastuzumab with the chelating agent DOTA and labeled it with the radioisotope 64Cu, which can be detected by positron emission tomography (PET). This radioimmunoconjugate imaging modality, 64Cu-DOTA-trastuzumab-PET, was designed to assess functional HER2 expression in vivo. As such, we may image and quantify HER2-positive cancer cells in patients with gastric cancer. This highly innovative approach has been tested in patients with metastatic breast cancer, demonstrating that HER2-positive lesions can be accurately identified and revealing that 64Cu-DOTA- trastuzumab-PET is safe and well tolerated. We hypothesize that 64Cu-DOTA-trastuzumab-PET will improve the detection and quantification of HER2 expression in gastric cancer, which afflicts nearly 1 million patients each year. Our primary objective is to show that 64Cu-DOTA-trastuzumab-PET is more accurate than standard tissue biopsy with IHC or FISH for determining HER2 status. In this proposal we will determine whether 64Cu-DOTA-trastuzumab-PET can overcome the heterogeneity of gastric cancer tissues and help localize HER2-positive tissues and if 64Cu- DOTA-trastuzumab-PET provides a measure of HER2 expression that is distinct from IHC or FISH. Ultimately, our long-term goal is to organize a clinical trial using 64Cu-DOTA-trastuzumab-PET to more accurately determine the eligibility of patients to receive anti-HER2 therapy. We propose the following aims:
Specific Aim I : To enroll patients with gastric adenocarcinoma in a 64Cu-DOTA-trastuzumab-PET imaging trial.
Specific Aim II : To compare IHC and FISH quantification of HER2 expression with an in vivo 64Cu-DOTA- trastuzumab-PET technique in patients with gastric cancer.

Public Health Relevance

The monoclonal antibody trastuzumab has been recently shown to improve survival of patients with advanced gastric cancer. Unfortunately, the current methods to determine eligibility for trastuzumab (i.e., HER2 overexpression) are inexact. Our team has developed a radiolabeled imaging study that will improve the accuracy of measuring HER2, which may translate into helping the lives of tens of thousands of patients each year.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Zhang, Huiming
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City of Hope/Beckman Research Institute
United States
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