A FEASIBILITY PET STUDY OF HER2 RECEPTORS IN BREAST CANCER USING 89ZR-TRASTUZUMAB

使用 89ZR-曲妥珠单抗对乳腺癌 HER2 受体进行可行性宠物研究

• 批准号: 8635832
• 负责人: FARROKH DEHDASHTI
• 金额: $ 31.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635832
• 关键词: Address; Adverse effects; Animals; Antigen Targeting; Behavior; Binding; Biodistribution; Biological; Biopsy; Cancer Etiology; Cancer Patient; Clinical Data; Country; Detection; Development; Diagnostic; Disease; Dose; ERBB2 gene; Evaluation; Extracellular Domain; Feasibility Studies; Fluorescent in Situ Hybridization; Goals; Growth; Half-Life; Heterogeneity; Human; Image; Image Analysis; Imaging Device; Immunohistochemistry; Immunotherapy; In Vitro; Individual; Label; Lesion; Malignant Neoplasms; Measurable; Metastatic Lesion; Methods; Molecular and Cellular Biology; Monoclonal Antibodies; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Patients; Pilot Projects; Positron; Positron-Emission Tomography; Primary Lesion; Property; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Recurrence; Resistance; Resolution; Risk; Safety; Sampling Errors; Site; Staining method; Stains; Therapeutic Monoclonal Antibodies; Time; Tracer; Trastuzumab; Treatment Effectiveness; Tumor Burden; Visual; Woman; Xenograft procedure; Zirconium; base; burden of illness; chemotherapy; cost; dosimetry; improved; in vitro Assay; in vivo; malignant breast neoplasm; mortality; novel; outcome forecast; pre-clinical; public health relevance; radiotracer; receptor; receptor expression; response; tumor; tumor xenograft; uptake; zirconium oxide

Title A Feasibility PET Study of HER2 Receptors in Breast Cancer Using 89Zr-Trastuzumab Project Summary The use of monoclonal antibodies (MAbs) for treatment of oncologic patients is rapidly expanding while the imaging tools for evaluation of the specific tumor antigens targeted by these therapies lagged behind. Breast cancer remains the leading cause of cancer mortality among women in Western countries. HER2-amplified breast cancers, which consist of 20-30% of breast cancers, are associated with a more aggressive growth rate, increased risk of metastasis and worse overall survival compared with HER2-negative breast cancers. The identification of HER2 amplification as the driver mutation in these cancers and the subsequent development of trastuzumab, a MAb directed against the extracellular domain of the HER2 receptor, have dramatically improved the prognosis in these patients. However, only half of HER2-positive patients receiving first-line trastuzumab and chemotherapy for metastatic disease have objective responses. This suggests that the presence of HER2 positivity by current in vitro assays is not an accurate predictor of response to therapy, possibly related to within-patient tumor heterogeneity. PET using radiolabeled antibodies (Immuno-PET) is a novel option for non-invasive identification of the presence of specific targets throughout the body, tracing and quantification of monoclonal antibodies binding to the target and ultimately helping in better understanding of in vivo behavior and effectiveness of treatment with MAbs in individual patients. In this application, we are proposing a feasibility study using Zirconium-89 (89Zr) labeled trastuzumab in breast cancer. Because of its longer physical half-life that matches the biological half-life of a MAb (i.e., the mean half-life of trastuzumab is 5.8 days), 89Zr is preferred to 68Ga- (t1/2 = 1.13 h) and 64Cu- (t1/2 = 12.7 h) for radiolabeling of MAbs. In studies with tumor xenografts, significantly greater 89Zr-trastuzumab uptake has been detected in HER2- positive than in HER2-negative tumor sites. In a small study of patients with HER2-positive breast cancer, high image quality with optimal biodistribution and excellent tumor uptake have been demonstrated with 89Zr- trastuzumab-PET. We are proposing to perform a pilot study with goals of demonstrating the feasibility of imaging breast cancer patients with 89Zr-trastuzumab-PET, evaluating the relationship between tumor 89Zr- trastuzumab uptake and in vitro status of HER2, assessing the safety of 89Zr-trastuzumab and determining the human dosimetry of this radiopharmaceutical.

标题 ~(89)Zr-曲妥珠单抗用于乳腺癌HER2受体的PET研究 项目摘要 用于治疗肿瘤患者的单抗的使用正在迅速扩大，而 用于评估这些疗法靶向的特定肿瘤抗原的成像工具落后。乳房 癌症仍然是西方国家女性癌症死亡的主要原因。HER2基因扩增 乳腺癌占乳腺癌的20%-30%，与更具侵略性的生长速度有关， 与HER2阴性乳腺癌相比，转移风险增加，总体生存率更差。这个 HER2扩增在这些癌症中的驱动突变及其后续发展 曲妥珠单抗，一种针对HER2受体胞外区的单抗，显著地 改善了这些患者的预后。然而，只有一半的HER2阳性患者接受一线治疗 曲妥珠单抗和化疗对转移性疾病有客观反应。这表明， 目前的体外检测HER2阳性并不能准确预测治疗反应， 可能与患者体内肿瘤的异质性有关。使用放射性标记抗体的宠物(免疫PET)是一种 用于非侵入性识别全身特定目标的存在的新选项，跟踪和 与靶标结合的单抗的定量，最终有助于更好地了解in 单抗在个体患者体内的行为和治疗效果。在此应用程序中，我们是 提出了一项使用~(89)Zr标记曲妥珠单抗治疗乳腺癌的可行性研究。因为它的 与单抗的生物半衰期相匹配的更长的物理半衰期(即曲妥珠单抗的平均半衰期为 5.8d)，~(89)Zr标记单抗优于~(68)Ga~-(t~(1/2)=1.13h)和~(64)Cu~-(t~(1/2)=12.7h)。在……里面 对肿瘤移植瘤的研究，在HER2-HER2中检测到显著更高的89Zr-曲妥珠单抗摄取 阳性表达高于HER2阴性肿瘤部位。在一项针对HER2阳性乳腺癌患者的小型研究中， 具有最佳生物分布和良好的肿瘤摄取的图像质量已被证实。 曲妥珠单抗-PET。我们建议进行一项初步研究，目的是证明 用~(89)Zr-曲妥珠单抗-PET对乳腺癌患者进行显像，评价肿瘤~(89)Zr~(-1)与肿瘤的关系 曲妥珠单抗对HER2的摄取和体外状态，评价89Zr-曲妥珠单抗的安全性，并测定 这种放射性药物的人体剂量测定。