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

基因检测指导儿科癌症护理和随访：使用蒽环类药物相关的心脏毒性作为未来的模型

• 批准号: 9789024
• 负责人: Jennifer M. Yeh
• 金额: $ 40.34万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789024
• 关键词: Adult; Aftercare; American Society of Clinical Oncology; Annual Reports; Anthracyclines; Benefits and Risks; Cancer Control; Cancer Model; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Death; Cardiotoxicity; Caring; Chest; Child; Child Care; Childhood; Childhood Cancer Survivor Study; Childhood Cancer Treatment; Clinical; Clinical Course of Disease; Clinical Data; Clinical Research; Cohort Studies; Congestive Heart Failure; Data; Diagnosis; Disease; Dose; Epidemiology; Excess Mortality; Future; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic screening method; Genomics; Genotype; Health; Heart Diseases; Individual; Life Expectancy; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical Genetics; Methods; Modeling; Morbidity - disease rate; Nature; Outcome; Patients; Pediatric Oncology; Pediatric Oncology Group; Penetrance; Predisposition; Prevalence; Publishing; Quality of life; Radiation therapy; Randomized Clinical Trials; Recommendation; Research; Resources; Risk; Risk Factors; Risk Marker; Saint Jude Children' s Research Hospital; Source; Statistical Methods; Subgroup; Survival Rate; Survivors; Testing; Time; Toxic effect; Translating; Treatment-related toxicity; Uncertainty; Work; adverse outcome; anticancer research; base; cancer care; cancer diagnosis; cancer genomics; cancer therapy; care outcomes; childhood cancer survivor; clinical care; clinical practice; clinical risk; cohort; cost; disorder control; evidence base; flexibility; follow-up; genetic information; genetic risk assessment; genetic risk factor; genetic variant; high risk; improved; improved outcome; individualized medicine; models and simulation; mortality risk; novel; novel strategies; personalized care; personalized medicine; personalized strategies; precision medicine; predictive modeling; premature; prospective; screening guidelines; treatment risk; Adult; Aftercare; American Society of Clinical Oncology; Annual Reports; Anthracyclines; Benefits and Risks; Cancer Control; Cancer Model; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Death; Cardiotoxicity; Caring; Chest; Child; Child Care; Childhood; Childhood Cancer Survivor Study; Childhood Cancer Treatment; Clinical; Clinical Course of Disease; Clinical Data; Clinical Research; Cohort Studies; Congestive Heart Failure; Data; Diagnosis; Disease; Dose; Epidemiology; Excess Mortality; Future; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic screening method; Genomics; Genotype; Health; Heart Diseases; Individual; Life Expectancy; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical Genetics; Methods; Modeling; Morbidity - disease rate; Nature; Outcome; Patients; Pediatric Oncology; Pediatric Oncology Group; Penetrance; Predisposition; Prevalence; Publishing; Quality of life; Radiation therapy; Randomized Clinical Trials; Recommendation; Research; Resources; Risk; Risk Factors; Risk Marker; Saint Jude Children' s Research Hospital; Source; Statistical Methods; Subgroup; Survival Rate; Survivors; Testing; Time; Toxic effect; Translating; Treatment-related toxicity; Uncertainty; Work; adverse outcome; anticancer research; base; cancer care; cancer diagnosis; cancer genomics; cancer therapy; care outcomes; childhood cancer survivor; clinical care; clinical practice; clinical risk; cohort; cost; disorder control; evidence base; flexibility; follow-up; genetic information; genetic risk assessment; genetic risk factor; genetic variant; high risk; improved; improved outcome; individualized medicine; models and simulation; mortality risk; novel; novel strategies; personalized care; personalized medicine; personalized strategies; precision medicine; predictive modeling; premature; prospective; screening guidelines; treatment risk

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.

项目摘要/摘要 最近的基因组进步已经确定了种系风险标志物预测治疗风险的潜力 - 在接受癌症治疗的儿童的相关毒性。尽管小儿癌症治疗的进展已导致 生存率，长期发病率和早期死亡率的显着提高强调了对 新的方法可以最大程度地减少晚期毒性，同时保持疾病控制；使用遗传标记 预测风险和变化疗法代表了减少不良结果的潜在策略。遗传风险 评估对患者进行个性化治疗的可能性引起了极大的兴奋 承担风险增加或降低的人。例如，癌症幸存者队列的研究表明 充血性心力衰竭的风险增加了五倍，心脏过早死亡的风险增加了七倍。 最近发表了临床实践建议，用于对治疗的个性化适应和 基于儿童癌症患者的遗传性心脏风险特征的监测 治疗。但是，围绕着遗传信息可能转化为成功的大量不确定性 改善了癌症儿童的护理和结果。此外，儿童癌和长期的稀有性 观察晚期结果所需的延迟限制了前瞻性试验的可行性，以评估精度 医学护理和随访方法。我们建议采用决策分析建模方法 确定基因检测如何为临床护理提供依据，包括初始癌症治疗和治疗后护理 基于个人对心脏毒性的敏感性。我们将开发出一种新颖的灵活的微观仿真模型 儿童期癌症的临床疗程，以展示与童年有关的全部健康结果 癌症，包括最初的疾病控制和与治疗有关的晚期毒性，然后纳入遗传数据 评估对这些结果的影响。这个建模框架将整合来自多个的数据 资源，包括儿童癌症幸存者研究（CCSS）至（1） 被诊断出癌症的儿童； （2）确定利用遗传变异测试的临床影响 在指导癌症护理方面的心脏毒性； （3）评估遗传标记的考虑如何改善后续 为高危幸存者提出心脏筛查建议。我们的目的是描绘 围绕模型参数的不确定性及其对建模结果的影响 引导方法，推断心脏毒性风险的统计方法以及严格的方法 不确定性分析。通过唯一利用CCSS数据来表征与终身治疗有关的 心脏毒性风险，我们提出的研究将建立一个新的分析框架来评估 在儿科肿瘤学中使用基因检测的不确定性和权衡，并构成了 了解遗传风险测试对其他毒性的影响。