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，每年诊断为神经母细胞瘤的>1500名患者中有一半患有高风险疾病，这些病例中有一半在一线治疗后会复发或进展。复发性神经母细胞瘤是侵袭性的，并且通常是耐药的。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，这是昂贵的，侵入性的，并且对经常需要麻醉的儿童来说是负担。这些缺点限制了监测的频率。需要更灵敏、侵入性更小和毒性更小的监测技术。突变谱经常在复发肿瘤中发生变化，这可能解释治疗抗性并提供额外的药物靶点。然而，成像无法提供有关分子特征的信息。液体活检检测是微创的，允许频繁采样，并灵敏地检测肿瘤衍生的DNA和信使RNA循环在外周血中的肿瘤分子标志物。MONALISA旨在缩小现有差距，并建立液体活检作为标准护理，以监测复发性/难治性神经母细胞瘤，作为其他儿科癌症的蓝图。可靠、早期评估分子进展或复发是MONALISA中提出的实用随机临床试验的主要目的。我们开发了一种数字决策支持工具，以帮助肿瘤学家使用新的监测和应用患者报告的结果，以整合患者的观点，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早期发现事件，以及是否可以通过早期诊断和治疗干预实现更好的总生存率。这是迈向个性化医疗的重要一步，将支持在治疗过程中进行可靠的疾病监测。“这项行动是癌症使命项目”诊断和治疗（诊断）”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).”