Radiolabeled Trastuzumab to Improve Diagnosis and Staging of HER2+ Gastric Cancer

描述（由申请人提供）：曲妥珠单抗是一种靶向受体酪氨酸激酶HER 2的单克隆抗体，最近显示可改善晚期或转移性胃腺癌患者的总生存期，胃腺癌是全球第二大常见癌症。仅当胃癌为HER 2阳性（定义为免疫化学（IHC）3+）或通过荧光原位杂交（FISH）扩增HER 2时，患者才有资格接受曲妥珠单抗治疗。不幸的是，IHC或FISH似乎是测量HER 2的不精确方法，部分原因是胃癌中的肿瘤异质性。事实上，回顾我们自己的机构经验，通过IHC或FISH发现HER 2阳性胃癌的发生率很低。HER 2状态不准确的主要问题是假阴性结果将错误地排除患者接受有效的胃癌治疗。我们的研究团队开发了一种新的放射性标记成像研究，可以改善胃癌患者HER 2状态的测量。我们将曲妥珠单抗与螯合剂DOTA结合，并用放射性同位素64 Cu标记，可以通过正电子发射断层扫描（PET）检测。这种放射免疫缀合物成像模式，64 Cu-DOTA-曲妥珠单抗-PET，旨在评估体内功能性HER 2表达。因此，我们可以对胃癌患者中的HER 2阳性癌细胞进行成像和定量。这种高度创新的方法已经在转移性乳腺癌患者中进行了测试，证明可以准确识别HER 2阳性病变，并揭示64 Cu-DOTA-曲妥珠单抗-PET是安全的，耐受性良好。我们假设64 Cu-DOTA-曲妥珠单抗-PET将改善胃癌中HER 2表达的检测和定量，胃癌每年折磨近100万患者。我们的主要目的是证明64 Cu-DOTA-曲妥珠单抗-PET比标准组织活检（IHC或FISH）更准确地确定HER 2状态。在该提议中，我们将确定64 Cu-DOTA-曲妥珠单抗-PET是否可以克服胃癌组织的异质性并帮助定位HER 2阳性组织，以及64 Cu-DOTA-曲妥珠单抗-PET是否提供不同于IHC或FISH的HER 2表达的测量。最终，我们的长期目标是组织一项使用64 Cu-DOTA-trastuzumab-PET的临床试验，以更准确地确定患者接受抗HER 2治疗的资格。我们提出了以下目标：具体目标I：在64 Cu-DOTA-曲妥珠单抗-PET成像试验中招募胃腺癌患者。具体目标二：在胃癌患者中比较采用体内64 Cu-DOTA-曲妥珠单抗-PET技术进行的HER 2表达的IHC和FISH定量。

DESCRIPTION (provided by applicant): 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.