Lung Cancer Chemoradiation: Predictors of Survival

描述（由申请人提供）：在过去几十年中，非小细胞肺癌（NSCLC）的治疗疗效仅略有改善。放化疗仍然有一个狭窄的治疗指数，反应率是不可预测的，即使在控制了已知的预测因素的阶段，组织学，等级和性能状态。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NSCLC治疗的基石。辐射诱导的毒性同样是不可预测的和剂量限制性的。来自体外研究的数据显示，辐射抗性与不良预后相关，并且与辐射抗性细胞系相比，辐射敏感细胞系表现出更大的初始损伤，并且修复这种损伤更慢。由相互作用的基因调控的细胞事件可能部分解释了这种不可预测的结果。我们假设个体间遗传差异影响铂类药物治疗的疗效和毒性，并且这种遗传信息可用于预测个体药物反应。在这项建议中，我们将建立在现有的案件确定基础设施，以实现以下具体目标：1。我们将构建一个包含1400例接受铂类药物联合其他药物+放疗治疗的晚期NSCLC（不可手术的III期和IV期）患者的特征明确的队列。该样本将包括800例前瞻性入组的患者和600例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，我们已经获得或将获得有关吸烟史、饮食摄入、家族癌症史、既往病史、体重减轻、体能状态、肿瘤特征、治疗毒性和疗效的详细基线信息，以及完整的患者随访数据。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淋巴细胞的功能性彗星试验，第一种评估辐射诱导损伤的基本切除修复（BER）和双链断裂修复（DSB），第二种主要评估铂诱导损伤的核苷酸切除修复（NER）。通过这些试验，我们将测试宿主的内在修复能力影响药物敏感性的假设。具体来说，我们假设降低的NER能力与对铂治疗的反应改善相关（由于修复铂加合物的能力降低）。此外，我们假设BER和/或DSB修复能力降低，因为它转化为快速分裂细胞修复损伤的能力降低，与急性和晚期辐射毒性的风险较高相关;然而，BER和/或DSB修复能力降低与生存率提高相反。3.与表型检测平行，我们将在所有1400例患者中采用基于途径的方法来评估DNA修复途径相关基因（特别是NER、BER和DSB）多态性的频率。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、耐药性和毒性受多个相关基因变异调控的假设。我们还将检验修复基因型与Aim 2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-如诊断和治疗开始时的吸烟情况，人口统计学因素，选择微量营养素的不良饮食摄入，体重减轻，体能状态和肿瘤特征-与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，该模型将整合并优先考虑这些相关的流行病学和分子结果预测因子。本研究的统一主题是细胞对放疗和化疗遗传毒性效应的易感性的内在差异调节毒性和结果。这项多变量预后研究可能具有长期预后潜力，根据患者的遗传组成，允许更大的个体化治疗，从而提高疗效和降低发病率。

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.