Using MRI and circulating tumor DNA to improve the interpretation of response to immunotherapy and targeted therapy in CNS metastases

项目总结/摘要 使用免疫疗法或靶向疗法治疗脑转移瘤的兴趣越来越大， 包括癌症引起的软脑膜疾病然而，解释对以下问题的反应可能具有挑战性： 治疗或了解对治疗的反应或抵抗模式，因为连续组织样品是 很难从大脑中获得。因此，迫切需要鉴定非侵入性的反应标记物或 在这一未充分研究的患者人群中评估了对新疗法的耐药性。 在这项提议中，Aim 1将联合收割机结合循环肿瘤DNA和复杂的MRI扫描，以改善我们的诊断。 能够解释接受PD-1抑制剂pembrolizumab治疗的脑转移患者的反应。与 帕博利珠单抗，MRI上对比增强的增加可以是肿瘤进展或炎症， 通过治疗成功重新激活免疫系统。我们假设，通过结合定量的 通过MRI扫描测量肿瘤负荷，特别是循环肿瘤DNA，我们将能够消除 从伪进展到真正进展，此外，了解反应/耐药机制。 目的2将使用循环肿瘤DNA阐明脑转移瘤的克隆进化， 靶向治疗，允许非侵入性手段来了解反应和耐药模式。目标3将 解决了准确确定软脑膜炎患者放射学反应的临床挑战 癌症的疾病。与我们对脑实质转移瘤的假设相似，我们预计， ctDNA到MRI将提高我们更可靠地测量LMD对治疗的反应的能力。

Project Summary/Abstract There is increasing interest in using immunotherapy or targeted therapy to treat brain metastases, including leptomeningeal disease from cancer. However, it can be challenging to interpret response to treatment or to understand patterns of response or resistance to treatment since serial tissue samples are difficult to obtain from the brain. Thus, there is a critical need to identify noninvasive makers of response or resistance to new therapies being evaluated in this understudied patient population. In this proposal, Aim 1 will combine circulating tumor DNA with sophisticated MRI scans to improve our ability to interpret response of brain metastases patients treated with pembrolizumab, a PD-1 inhibitor. With pembrolizumab, increase in contrast enhancement on MRI can be tumor progression or inflammation from successful re-activation of the immune system with treatment. We hypothesize that by combining a quantitative measure of tumor burden, specifically circulating tumor DNA, with MRI scans, we will be able to disambiguate true progression from pseudoprogression and, moreover, to understand mechanisms of response/resistance. Aim 2 will use circulating tumor DNA to shed light on the clonal evolution of brain metastases in response to targeted therapy, allowing for noninvasive means to understand response and resistance patterns. Aim 3 will address the clinical challenge of accurately determining radiographic response in patients with leptomeningeal disease from cancer. Similar to our hypothesis for parenchymal brain metastases, we expect that adding ctDNA to MRI will improve our ability to more reliably measure LMD response to treatment.