Role of ctDNA change as a response measure in the EA1183 patient population and how ctDNA changes correlate with metabolic response by serial FDG PET/CT

项目总结： 骨显性(BD)和仅骨性(BO)转移性乳腺癌(MBC)患者 患者群体1，2他们经常被排除在使用RECIST 1.1作为主要反应的临床试验之外 评估，因为骨损伤被归类为不可测量的、非靶向损伤3。当前以血液为基础 生物标记物，如肿瘤标记物(CA15.3、CA27.29和CEA)在 评估MBC患者对治疗的反应。因此，有必要采取更好的措施。 对BD MBC患者的治疗反应。EA1183功能是一项前瞻性的多中心临床试验 由NCI批准，由ECOG-ACRIN赞助，旨在评估系列FDG-PET/CT对 评估BD MBC的反应。这项试验将测试肿瘤代谢变化对临床预测的能力。 无进展生存(PFS)和骨骼相关事件发生时间(TRE)的有意义的结果。 CtDNA的测量和表征为非侵入性评估这两种疾病提供了一种选择 肿瘤生物学中基因组变化的负担和出现。我们建议将基于液体的肿瘤 监测(通过连续采集循环肿瘤DNA、ctDNA)和FDG-PET/CT成像以确定 这些生物标志物，单独或联合，可以预测BO或BD患者的治疗反应 参加EA1183功能试验的MBC。我们还将评估FDG-PET/CT， CtDNA，或两者兼而有之，最早可以在治疗后4周预测PFS。我们假设成像的整合 (FDG-PET/CT)和液体为基础的液体活检(CtDNA)分析可以确定治疗反应的特征 对于BO和BD患者，MBC提前于目前使用的方法，最早可能在4周内。这 R01提案将为EA1183中的其他目标提供支持，这是我们提案的目标：1)至 评估系列ctDNA测量中定性和定量变化预测PFS和SRE时间的能力 在BO或BD患者中，MBC在EA1183开始新的系统治疗；2)确定早期代谢 全身治疗开始后4周FDG-PET/CT评估骨转移灶的变化可预测PFS 3)探讨ctDNA变化与BO和BD MBC的关系。 FDG-PET/CT评价代谢反应及与ctDNA结合能力的检测 在新的系统治疗开始后4周和12周预测PFS和SRE。这项研究的结果 将为BD MBC生成强大的响应端点，以提供临床试验和指南 对这类MBC患者的临床实践。

Project Summary: Patients with bone dominant (BD) and bone only (BO) metastatic breast cancer (MBC) represent a large patient population1,2 who are often excluded from clinical trials using RECIST 1.1 as the primary response assessment because bone lesions are classified as non-measurable, non-target lesions3. Current blood-based biomarkers such as tumor markers (CA15.3, CA27.29 and CEA) have similarly shown limited utility in assessing response to therapy in patients with MBC. There is therefore an important need for better measures of therapeutic response for patients with BD MBC. EA1183 FEATURE is a prospective, multicenter clinical trial approved by the NCI and sponsored by ECOG-ACRIN designed to evaluate the value of serial FDG-PET/CT to assess response in BD MBC. The trial will test the ability of tumor metabolic changes to predict the clinically meaningful outcomes of progression free survival (PFS) and time to skeletal-related event (tSRE). Measurement and characterization of ctDNA provides an option of non-invasively evaluating both disease burden and emergence of genomic changes in tumor biology. We propose to integrate fluid-based tumor monitoring (by serial collection of circulating tumor DNA, ctDNA) and FDG-PET/CT imaging to determine if these biomarkers, separately or combined, can predict a response to therapy for in patients with BO or BD MBC participating in the EA1183 FEATURE trial. We will also assess the extent to which FDG-PET/CT, ctDNA, or both can predict PFS as early as 4 weeks into therapy. We hypothesize that integration of imaging (FDG-PET/CT) and fluid-based, liquid biopsy (ctDNA) assays may permit characterization of therapy response for patients with BO and BD MBC in advance of currently used methods, possibly as early as 4 weeks. This R01 proposal will provide support for additional objectives in EA1183, which are the aims of our proposal: 1.) to assess ability of qualitative and quantitative changes in serial ctDNA measures to predict PFS and time to SRE in patients with BO or BD MBC beginning new systemic therapy in EA1183; 2) to determine if early metabolic changes in bone metastases assessed by FDG-PET/CT at 4 weeks after start of systemic therapy predict PFS and tSRE in patients with BO or BD MBC; 3) to evaluate the relationship between changes in ctDNA and metabolic response as assessed by FDG-PET/CT and to test the combined ability of FDG-PET/CT and ctDNA at 4 and 12 weeks after the start of new systemic therapy to predict PFS and SRE. The outcome of this study will be the generation of robust response endpoints for BD MBC to provide access to clinical trials and guide clinic al practice for the large group of patients with this type of MBC.