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: 10231094
• 负责人: Jennifer M. Yeh
• 金额: $ 40.01万
• 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/10231094
• 关键词: Adult; Aftercare; American Society of Clinical Oncology; Annual Reports; Anthracycline; 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; 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 testing; 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.

项目总结/文摘