MONALISA: A SIOPEN pragmatic clinical trial to MOnitor NeuroblastomA relapse with LIquid biopsy Sensitive Analysis

高危神经母细胞瘤占儿童癌症相关死亡的15%。在欧盟每年被诊断为神经母细胞瘤的1500名患者中，有一半患有高危疾病，这些患者中有一半在一线治疗后会复发或进展。复发的神经母细胞瘤具有侵袭性，通常对治疗有抵抗力。监测疾病复发和治疗反应对这些患者的生存机会至关重要。目前用于监测的标准护理是成像技术和骨髓评估，这些技术成本高昂，具有侵入性，对儿童来说是一种负担，他们经常需要麻醉。这些缺点限制了监控的频率。需要更灵敏、更少侵入性和毒性更低的监测技术。在复发的肿瘤中，突变谱经常发生变化，这可能解释治疗耐药性，并提供额外的可药物靶点。然而，成像不能提供有关分子特征的信息。液体活组织检查是微创的，允许频繁采样，并灵敏地检测外周血中循环的肿瘤衍生DNA和信使RNA中的肿瘤分子标志物。Monalisa的目标是弥合现有的差距，并建立液体活检作为监测复发/难治性神经母细胞瘤的标准护理，作为其他儿科癌症的蓝图。在Monalisa上提出的实用随机临床试验的主要目的是对分子进展或复发进行可靠的早期评估。我们开发了一种数字决策支持工具来帮助肿瘤学家使用新的监测和应用患者报告的结果来整合患者的观点，并评估微创液体活检诊断对生活质量的影响。我们将确定是否可以使用液体活检监测更早地发现事件，以及早期诊断和治疗干预是否能够提高总体存活率。走向个性化医疗的这一重要步骤将支持正在治疗的可靠的疾病监测。“这项行动是癌症使命关于‘诊断和治疗(诊断)’项目集群的一部分。”

High-risk neuroblastoma accounts for 15% of cancer related-deaths in children. Half of the >1500 patients yearly diagnosed with neuroblastoma in the EU have high-risk disease, which will relapse or progress in half these cases after first-line treatment. Relapsed neuroblastoma is aggressive and often therapy-resistant. Monitoring for disease relapse and therapy response is crucial for the survival chance of these patients. The current standard-of-care for monitoring are imaging technologies and bone marrow assessment, which are costly, invasive and a burden for children, who often require anesthesia. These drawbacks limit how often is monitored. More sensitive, less invasive and less toxic monitoring techniques are needed. The mutational spectrum often changes in recurring tumors, which may explain therapy resistance and provide additional druggable targets. Imaging, however, provides no information about molecular characteristics. Liquid biopsy tests are minimally invasive, allow frequent sampling and sensitively detect tumor molecular markers in tumor-derived DNA and messenger RNA circulating in peripheral blood. MONALISA aims to close existing gaps and establish liquid biopsies as standard-of-care to monitor relapsed/refractory neuroblastoma, as a blueprint for other pediatric cancers. Reliable, early assessment of molecular progression or relapse is the main aim of the pragmatic randomized clinical trial proposed in MONALISA. We develop a digital decision support tool to help oncologists use the new monitoring and apply patient-reported outcomes to integrate patient viewpoints and assess the effect of minimally invasive, liquid biopsy diagnostics on quality of life. We will establish whether events can be detected earlier using liquid biopsy monitoring, and whether better overall survival is enabled by earlier diagnosis and treatment interventions. This essential step towards personalized medicine will support reliable disease monitoring under treatment. “This action is part of the Cancer Mission cluster of projects on ‘‘Diagnostics and Treatment (diagnostics).”