Lung Cancer Prognosis: FLT PET and DNA Hypermethylation

肺癌预后：FLT PET 和 DNA 高甲基化

• 批准号: 7249430
• 负责人: HUBERT J VESSELLE
• 金额: $ 52.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249430
• 关键词: Address; Adjuvant Chemotherapy; Behavior; Biological Assay; Biological Markers; Blood; Cancer Etiology; Cancer Patient; Cancer Prognosis; Candidate Disease Gene; Caring; Cell Proliferation; Cessation of life; Collection; DNA; Data; Deoxyglucose; Detection; Development; Disease; Distant; Enrollment; Evaluation; Excision; Facility Construction Funding Category; Genes; Hypermethylation; Image; Invasive; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Methylation; Microscopic; Modification; Morbidity - disease rate; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Paraffin; Participant; Pathology; Patients; Pilot Projects; Plasma; Polymerase Chain Reaction; Positron-Emission Tomography; Postoperative Period; Primary Neoplasm; Publishing; Recruitment Activity; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Research Personnel; Resectable; Resected; Risk; Sensitivity and Specificity; Staging; Standards of Weights and Measures; Time; Tissues; Tumor Tissue; United States; Universities; Washington; X-Ray Computed Tomography; base; bisulfite; chemotherapy; cost; follow-up; interest; novel; novel strategies; outcome forecast; prognostic; programs; radiotracer; size; tumor; uptake

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States. Thirty percent of patients with NSCLC are classified as stage I or II at time of presentation and undergo primary surgical resection with curative intent. However, as a result of initially undiagnosed microscopic metastases, over 50% will develop recurrent disease within two years of surgery. Recent studies have demonstrated that post-resection chemotherapy increases survival of stage I/II patients. But chemotherapy is associated with considerable morbidity and cost. Thus, an accurate method is needed for identifying patients at high risk of recurrence who would benefit most from such additional therapy, while sparing the patients at low risk of recurrence. Currently there is no way of preoperatively and non-invasively identifying the subset of stage I/II NSCLC patients who will recur post resection. Current preoperative staging of NSCLC by 2-[F-18]fluoro-2-deoxy- D-glucose (FDG) Positron Emission Tomography (PET) imaging and Computed Tomography does not permit identification of microscopic metastases. Further, although several studies have suggested that FDG uptake in the primary tumor could predict survival, these studies did not adjust uptake values for size of primary tumor, which is a well-established predictor of survival. When such adjustments are made, FDG uptake is no longer prognostic. Thus new approaches for non-invasive and preoperative prognostic assessment of NSCLC patients are needed. In the proposed study we hypothesize that the uptake of the new radiotracer, 3'-deoxy-3'- [F18]fluorothymidine (FLT), at PET, used in combination with detection of a panel of hypermethylated genes can provide a sensitive and specific approach to identification of stage I/II NSCLC patients at high risk of recurrence after surgical resection. Support for our hypothesis concerning the prognostic utility of FLT used in combination with tissue and/or blood-based biomarkers comes from 1) our pilot studies demonstrating that primary tumor FLT uptake strongly correlates with cellular proliferation, a known predictor of prognosis; 2) studies demonstrating the relationship between detection of 20 hypermethylated genes (in tissue or plasma) and the presence and behavior of cancers including NSCLC. This prognostic information will permit individualization and optimization of therapy for the 41,000 early stage NSCLC patients undergoing surgical resection each year in the United States.

描述(申请人提供)：非小细胞肺癌(NSCLC)是美国癌症死亡的主要原因。30%的NSCLC患者在发病时被归类为I期或II期，并接受了具有治愈意图的初次手术切除。然而，由于最初未诊断的微小转移，超过50%的患者将在手术后两年内复发。最近的研究表明，术后化疗可提高I/II期患者的存活率。但化疗与相当高的发病率和成本有关。因此，需要一种准确的方法来识别高复发风险的患者，谁将从这种额外的治疗中受益最大，同时避免低复发风险的患者。 目前还没有办法在手术前和非侵入性地确定哪些I/II期NSCLC患者会在手术后复发。目前非小细胞肺癌的术前分期采用2-[F-18]氟-2-脱氧-D-葡萄糖(FDG)正电子发射断层扫描(PET)和计算机断层扫描(CT)不能识别微小转移。此外，尽管一些研究表明原发肿瘤中FDG摄取可以预测生存，但这些研究并没有调整原发肿瘤大小的摄取值，这是一个公认的生存预测指标。当做出这样的调整时，FDG摄入量不再是一个可预测的指标。因此，需要对非小细胞肺癌患者进行无创性和术前预后评估的新方法。 在拟议的研究中，我们假设在PET中摄取新的放射性示踪剂3‘-脱氧-3’-[F18]氟胸苷(Flt)，结合一组高甲基化基因的检测，可以提供一种敏感和特异的方法来识别手术切除后复发风险高的I/II期NSCLC患者。支持我们关于Flt与组织和/或血液为基础的生物标记物联合使用的预后效用的假设来自1)我们的试点研究表明，原发肿瘤Flt摄取与细胞增殖密切相关，这是一个已知的预后预测指标；2)研究表明，检测到20个高甲基化基因(在组织或血浆中)与包括NSCLC在内的癌症的存在和行为之间的关系。这一预后信息将使美国每年接受手术切除的41,000名早期非小细胞肺癌患者的治疗个体化和最优化。