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

描述(申请人提供)：曲妥珠单抗是一种针对受体酪氨酸激酶HER2的单抗，最近被证明可以提高晚期或转移性胃腺癌患者的总体存活率。胃腺癌是世界上第二常见的癌症。只有当胃癌HER2阳性(定义为免疫化学(IHC)3+)或HER2通过荧光原位杂交(FISH)扩增时，患者才有资格接受曲妥珠单抗治疗。不幸的是，IHC或FISH似乎不能准确地测量HER2，部分原因是胃癌中肿瘤的异质性。事实上，回顾我们自己的机构经验，IHC或FISH发现HER2阳性胃癌的比率很低。不准确地确定HER2状态的主要问题是，假阴性结果将错误地排除患者接受有效的胃癌治疗。我们的研究小组开发了一种新的放射性标记成像研究，可能会改善对胃癌患者HER2状态的测量。我们将曲妥珠单抗与螯合剂DOTA偶联，并用放射性同位素~(64)Cu标记，可通过正电子发射断层扫描(PET)进行检测。这种放射免疫标记显像仪，64CuDOTA-曲妥珠单抗-PET，被设计用来评估HER2在体内的功能性表达。因此，我们可以对胃癌患者中HER2阳性的癌细胞进行成像和量化。这一高度创新的方法已经在转移性乳腺癌患者中进行了测试，表明HER2阳性病变可以被准确识别，并表明64Cu-DOTA-曲妥珠单抗-PET是安全和耐受性良好的。我们假设64Cu-DOTA-曲妥珠单抗-PET将改进HER2在胃癌中表达的检测和量化，每年有近100万患者受到影响。我们的主要目的是证明64Cu-DOTA-曲妥珠单抗-PET在确定HER2状态方面比IHC或FISH的标准组织活检更准确。在这项建议中，我们将确定64Cu-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HER2阳性组织，以及64Cu-DOTA-曲妥珠单抗-PET是否提供了有别于IHC或FISH的HER2表达测量。最终，我们的长期目标是组织一项使用64CuDOTA-曲妥珠单抗-PET的临床试验，以更准确地确定患者接受抗HER2治疗的资格。我们提出了以下目标：特定目标I：招募胃腺癌患者参加一项64Cu-DOTA-曲妥珠单抗-PET成像试验。特定目的II：比较免疫组织化学和FISH定量检测HER2在胃癌患者体内的表达，以及活体64Cu-DOTA-曲妥珠单抗-PET技术。

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.