Genetic testing to guide pediatric cancer care and follow up: using anthracycline-associated cardiac toxicity as a model for the future

项目摘要/摘要 最近的基因组学进展已经确定了生殖系风险标记预测治疗风险的可能性- 接受癌症治疗的儿童的相关毒性。尽管儿科癌症治疗的进展已经导致 存活率、长期发病率和早期死亡风险的显著增加强调了 在保持疾病控制的同时将晚期毒性降至最低的新方法；使用遗传标记 预测风险和改变疗法是减少不良后果的一种潜在策略。遗传风险 评估引起了人们对个性化治疗的可能性的极大兴奋 风险增加或减少的人。例如，对癌症幸存者队列的研究表明， 充血性心力衰竭的风险增加五倍，心脏过早死亡的风险增加七倍。 最近发表了针对治疗和治疗的个体化适应的临床实践建议 基于接受蒽环类药物治疗的儿童癌症患者的遗传心脏风险谱监测 心理治疗。然而，相当大的不确定性围绕着遗传信息如何成功地转化为 改善对癌症儿童的护理和预后。此外，儿童癌症的罕见和长期的 观察晚期结果所需的潜伏期限制了评估精密度的前瞻性试验的可行性。 以医学的方式进行护理和随访。我们建议使用决策分析建模方法来 确定基因检测如何为临床治疗提供信息，包括癌症初始治疗和治疗后护理 基于个体对心脏毒性的敏感性。我们将开发一种新的、灵活的微模拟模型 儿童癌症的临床病程，以预测与儿童有关的全部健康结果 癌症，包括最初的疾病控制和与治疗相关的晚期毒性，然后纳入遗传数据 评估对这些结果的影响。该建模框架将集成来自多个 资源，包括儿童癌症幸存者研究(CCSS)到(1)预测以下项目的长期结果 诊断为癌症的儿童；(2)确定利用基因变异检测对儿童的临床影响 心脏毒性在指导癌症治疗中的作用；以及(3)评估考虑遗传标记如何改善随访- 提高对高危幸存者的心脏筛查建议。我们的目标是描绘 围绕模型参数的不确定性及其对建模结果的影响 自举方法，推断心脏毒性风险的统计方法，以及严格的方法 不确定度分析。通过独特地利用CCSS数据来表征与终身治疗相关的 心脏毒性风险，我们提议的研究将建立一个新的分析框架来评估 围绕在儿科肿瘤学中使用基因检测的不确定性和权衡，并形成了 了解基因风险测试对其他毒性的影响。

PROJECT SUMMARY/ABSTRACT Recent genomic advances have identified a potential for germline risk markers to predict risk of treatment- related toxicity in children treated for cancer. Although advances in pediatric cancer treatment have led to remarkable increases in survival rates, long-term morbidity and early mortality risks underscore the need for new approaches that minimize late toxicities while maintaining disease control; using genetic markers to predict risk and change therapy represents a potential strategy to reduce adverse outcomes. Genetic risk assessment has created great excitement about the possibility of individualized therapy adapted for patients who carry increased or decreased risk. For example, research in cancer survivor cohorts have demonstrated a five-fold increased risk of congestive heart failure and a seven-fold increased risk of premature cardiac death. Clinical practice recommendations have recently been published for individualized adaptation of treatment and surveillance based upon genetic cardiac-risk profile in childhood cancer patients receiving anthracycline therapy. However, considerable uncertainty surrounds how successfully genetic information may translate into improved care and outcomes for children with cancer. Further, the rarity of childhood cancer and the long latency needed to observe late outcomes limit the feasibility of prospective trials to evaluate a precision- medicine approach to care and follow-up. We propose to employ a decision-analytic modeling approach to determine how genetic testing may inform clinical care, both of initial cancer therapy and post-treatment care based on individual susceptibility for cardiotoxicity. We will develop a novel, flexible microsimulation model of the clinical course of childhood cancer to project the full spectrum of health outcomes relevant to the childhood cancer, including initial disease control and treatment-related late toxicities, and then incorporate genetic data to assess the impact upon these outcomes. This modeling framework will integrate data from multiple resources, including the Childhood Cancer Survivors Study (CCSS) to (1) project long-term outcomes for children diagnosed with cancer; (2) determine the clinical impact of utilizing genetic variant testing for cardiotoxicity in guiding cancer care; and (3) assess how consideration of genetic markers can improve follow- up cardiac screening recommendations for at-risk survivors. We aim to portray the scope and nature of the uncertainties that surround model parameters and their impact on modeled outcomes by employing bootstrapping methods, statistical methods to extrapolate cardiotoxicity risks, and rigorous approaches to uncertainty analysis. By uniquely leveraging the CCSS data to characterize the lifelong treatment-related cardiotoxicity risks, our proposed research will establish a novel analytic framework for evaluating the uncertainties and tradeoffs surrounding the use of genetic testing in pediatric oncology, and form the basis for understanding the impact of genetic risk testing for other toxicities.