Lung Cancer Chemoradiation: Predictors of Survival

肺癌放化疗：生存的预测因素

• 批准号: 7939475
• 负责人: Xifeng Wu
• 金额: $ 24.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939475
• 关键词: Acute; Apoptotic; Base Excision Repairs; Biological Assay; Body Weight decreased; Cancer Patient; Carboplatin; Cell Cycle; Cell Cycle Regulation; Cell Line; Cells; Characteristics; Cisplatin; Clinical; Comet Assay; DNA Repair Pathway; Data; Demographic Factors; Development; Diagnosis; Dietary intake; Disease; Dose; Dose-Limiting; Double Strand Break Repair; Drug resistance; Enrollment; Event; Excision Repair; Exhibits; Family Cancer History; Frequencies; Genes; Genetic; Genetic Polymorphism; Genotype; Histology; In Vitro; Individual; Interview; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Medical; Medical History; Micronutrients; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Non-Small-Cell Lung Carcinoma; Nucleotide Excision Repair; Outcome; Paclitaxel; Pathway interactions; Patients; Performance Status; Pharmaceutical Preparations; Phenotype; Platinum; Platinum Compounds; Platinum adduct; Predisposition; Quality of life; Radiation; Radiation Toxicity; Radiation induced damage; Radiation therapy; Relapse; Research; Research Infrastructure; Resistance; Risk; Risk Assessment; Sampling; Smoking; Smoking History; Staging; Testing; Therapeutic Index; Toxic effect; Translating; Treatment Efficacy; Variant; analog; base; cancer therapy; chemotherapy; clinically relevant; clinically significant; cohort; dosage; drug efficacy; drug metabolism; drug sensitivity; epidemiologic data; experience; follow-up; gene therapy; high risk; improved; insight; outcome forecast; prognostic; prospective; repaired; resistance mechanism; response; tumor; uptake

DESCRIPTION (provided by applicant): The efficacy of treatment for non-small cell lung cancer (NSCLC) has improved only marginally over the past few decades. Chemoradiotherapy continues to have a narrow therapeutic index, and response rates are unpredictable, even after controlling for the known predictors of stage, histology, grade, and performance status. Drug resistance presents a major obstacle in NSCLC treatment. Platinum agents, specifically cisplatin and carboplatin, are the cornerstones of NSCLC therapy. Radiation induced toxicity is similarly unpredictable and dose limiting. Data from in vitro studies show that radioresistance is associated with poor prognosis and that, compared to radioresistant lines, radiosensitive cell lines exhibit greater initial damage and repair this damage more slowly. Cellular events that are modulated by sets of interacting genes may partly explain such unpredictable outcomes. We hypothesized that interindividual genetic differences impact the efficacy and toxicity of platinum-based therapy and that this genetic information can be used to predict individual drug response. In this proposal, we will build upon an existing case ascertainment infrastructure to achieve the following specific aims: 1. We will construct a well-characterized cohort of 1400 advanced NSCLC (inoperable stages III and IV) patients treated with platinum drugs combined with other agents + radiation. This sample will consist of 800 patients prospectively enrolled and 600 patients retrospectively identified through participation in our ongoing studies. By personal interview and medical chart review, we have obtained or will obtain detailed baseline information on smoking history, dietary intake, family cancer history, previous medical history, weight loss, performance status, tumor characteristics, treatment toxicity and efficacy, and complete patient follow up data. 2. To evaluate the intrinsic repair capacity of the prospective cases, we will use two functional lymphocyte-based comet assays, the fir it of which assesses basic excision repair (BER) and double-strand break repair (DSB) of radiation-induced damage, and the second of winch assesses mainly nucleotide excision repair (NER) of platinum-induced damage. Through these assays, we will test the hypothesis that the host's intrinsic repair capacity influences drug sensitivity. Specifically, we hypothesize that reduced NER capacity is associated with improved response to platinum therapy (due to decreased ability to repair platinum adducts). Further, we hypothesize that reduced BER and/or DSB repair capacity, because it translates to a decreased ability to repair damage to rapidly dividing cells, is associated with higher risk of acute and late-term radiation toxicity; however, reduced BER and/or DSB repair capacity is conversely associated with improved survival. 3. In parallel with the phenotypic assays, we will assume a pathway-based approach in all 1400 patients to evaluate frequencies of polymorphisms in genes involved in DNA repair pathways, specifically NER, BER, and DSB. We will also evaluate frequencies of polymorphisms in pathways relevant for the activity or disposition of platinum analogs and taxols, including drug metabolism, multidrug resistance, cellular uptake, and select genes in cell cycle control and apoptotic pathways. We will test the hypothesis that therapy response, resistance, and toxicity are modulated by variants in multiple relevant genes. We will also test the hypothesis that there are correlations between the repair genotypes and the phenotype data from Aim 2. 4. We will integrate clinical and epidemiologic data - such as smoking at diagnosis and treatment initiation, demographic factors, poor dietary intake of select micronutrients, weight loss, performance status, and tumor characteristics - with the genetic data from the studies described above. We will develop a quantitative multivariate risk assessment model that will incorporate and prioritize these relevant epidemiologic and molecular predictors of outcome. The unifying theme of this study is that intrinsic differences in the susceptibility of cells to the genotoxic effects of radiotherapy and chemotherapy modulate toxicity and outcome. This multivariate prognostic study could have long-term prognostic potential by allowing greater individualization of therapy, based on the genetic makeup of the patient, thereby both increasing efficacy and reducing morbidity.

描述（由申请人提供）：在过去的几十年中，非小细胞肺癌（NSCLC）的治疗效果仅略有改善。即使在控制了阶段、组织学、分级和体力状态的已知预测因素之后，放化疗的治疗指数仍然很窄，并且反应率是不可预测的。耐药性是NSCLC治疗的主要障碍。铂类药物，特别是顺铂和卡铂，是非小细胞肺癌治疗的基石。辐射引起的毒性同样是不可预测的并且剂量有限。体外研究的数据表明，放射抗性与不良预后相关，并且与放射抗性细胞系相比，放射敏感性细胞系表现出更大的初始损伤，并且修复这种损伤的速度更慢。由一组相互作用的基因调节的细胞事件可以部分解释这种不可预测的结果。我们假设个体间的遗传差异影响铂类治疗的疗效和毒性，并且该遗传信息可用于预测个体药物反应。在本提案中，我们将建立在现有病例确定基础设施的基础上，以实现以下具体目标： 1. 我们将构建一个由 1400 名接受铂类药物联合其他药物联合治疗的晚期 NSCLC（无法手术的 III 期和 IV 期）患者组成的特征明确的队列+ 辐射。该样本将包括 800 名前瞻性纳入的患者和 600 名通过参与我们正在进行的研究回顾性确定的患者。通过个人访谈和病历审查，我们已经或将获得有关吸烟史、饮食摄入量、家族癌症史、既往病史、体重减轻、体能状态、肿瘤特征、治疗毒性和疗效以及完整患者随访的详细基线信息上数据。 2. 为了评估潜在病例的内在修复能力，我们将使用两种基于功能性淋巴细胞的彗星试验，其中首先评估辐射引起的损伤的基本切除修复（BER）和双链断裂修复（DSB） ，绞车的第二个主要评估铂引起的损伤的核苷酸切除修复（NER）。通过这些测定，我们将检验宿主的内在修复能力影响药物敏感性的假设。具体来说，我们假设 NER 能力降低与铂类治疗反应改善相关（由于修复铂类加合物的能力降低）。此外，我们假设 BER 和/或 DSB 修复能力的降低，因为它意味着修复快速分裂细胞损伤的能力降低，与急性和晚期辐射毒性的较高风险相关；然而，BER 和/或 DSB 修复能力的降低与生存率的提高相反。 3. 在进行表型分析的同时，我们将对所有 1400 名患者采取基于通路的方法，以评估参与 DNA 修复通路的基因多态性频率，特别是 NER、BER 和 DSB。我们还将评估与铂类似物和紫杉醇的活性或处置相关的途径中多态性的频率，包括药物代谢、多药耐药性、细胞摄取以及细胞周期控制和细胞凋亡途径中的选择基因。我们将检验治疗反应、耐药性和毒性是由多个相关基因的变异调节的假设。我们还将测试修复基因型与目标 2 中的表型数据之间存在相关性的假设。 4. 我们将整合临床和流行病学数据 - 例如诊断和治疗开始时吸烟、人口因素、特定微量营养素的饮食摄入不良、体重减轻、体能状态和肿瘤特征 - 以及来自上述研究的遗传数据。我们将开发一个定量的多变量风险评估模型，该模型将纳入并优先考虑这些相关的流行病学和分子结果预测因素。这项研究的统一主题是细胞对放疗和化疗的基因毒性作用的敏感性的内在差异调节毒性和结果。这项多变量预后研究可以根据患者的基因组成进行更大程度的个体化治疗，从而提高疗效并降低发病率，从而具有长期预后潜力。