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（由申请人提供）：非小细胞肺癌（NSCLC）是美国癌症死亡的主要原因。 30% 的 NSCLC 患者在就诊时被归类为 I 期或 II 期，并接受初次手术切除以达到治愈目的。然而，由于最初未诊断出微小转移，超过 50% 的患者会在手术后两年内出现复发性疾病。最近的研究表明，切除后化疗可提高 I/II 期患者的生存率。但化疗会带来相当大的发病率和费用。因此，需要一种准确的方法来识别复发风险高的患者，他们将从这种额外治疗中获益最多，同时避免复发风险低的患者。 目前还没有办法在术前和非侵入性地识别切除后会复发的 I/II 期 NSCLC 患者亚群。目前通过 2-[F-18]氟-2-脱氧-D-葡萄糖 (FDG) 正电子发射断层扫描 (PET) 成像和计算机断层扫描对 NSCLC 进行术前分期无法识别微观转移。此外，虽然一些研究表明原发肿瘤中 FDG 的摄取可以预测生存，但这些研究没有根据原发肿瘤的大小调整摄取值，而原发肿瘤的大小是公认的生存预测因子。进行此类调整后，FDG 的摄取量不再具有预测作用。因此，需要对 NSCLC 患者进行非侵入性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)，与一组高甲基化基因的检测结合使用，可以提供灵敏且特异的检测结果。识别手术切除后复发高风险的 I/II 期 NSCLC 患者的方法。支持我们关于 FLT 与组织和/或血液生物标志物联合使用的预后效用的假设来自 1) 我们的初步研究表明，原发性肿瘤 FLT 摄取与细胞增殖密切相关，细胞增殖是已知的预后预测因子； 2) 研究证明 20 个高甲基化基因（在组织或血浆中）的检测与癌症（包括非小细胞肺癌）的存在和行为之间的关系。这些预后信息将有助于为美国每年接受手术切除的 41,000 名早期 NSCLC 患者提供个体化治疗和优化治疗。