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

项目摘要： 骨主导型（BD）和仅骨（BO）转移性乳腺癌（MBC）患者代表了一个大的 患者人群1，2通常被排除在使用RECIST 1.1作为主要缓解的临床试验之外 评估，因为骨病变被归类为不可测量的非靶病变3。当前基于血液 生物标志物如肿瘤标志物（CA15.3、CA27.29和CEA）在肿瘤治疗中同样显示出有限的效用。 评估MBC患者对治疗的反应。因此，迫切需要采取更好的措施 BD MBC患者的治疗反应。EA 1183 FEATURE是一项前瞻性、多中心临床试验 由NCI批准并由ECOG-ACRIN赞助，旨在评估连续FDG-PET/CT的价值， 在BD MBC中评估缓解。该试验将测试肿瘤代谢变化预测临床疗效的能力。 无进展生存期（PFS）和至发生肿瘤相关事件的时间（tSRE）的有意义结局。 ctDNA的测量和表征提供了非侵入性评估这两种疾病的选择， 肿瘤生物学中基因组变化的负担和出现。我们建议将液体肿瘤 监测（通过连续收集循环肿瘤DNA，ctDNA）和FDG-PET/CT成像，以确定是否 这些生物标志物，单独或组合，可以预测BO或BD患者对治疗的反应 MBC参与EA 1183 FEATURE试验。我们还将评估FDG-PET/CT， ctDNA，或两者都可以预测PFS早在治疗4周。我们假设， （FDG-PET/CT）和基于液体的液体活检（ctDNA）测定可允许表征治疗反应 对于BO和BD MBC患者，可能早于目前使用的方法4周。这 R 01提案将为EA 1183中的其他目标提供支持，这些目标是我们提案的目标：1.）到 评估连续ctDNA测量的定性和定量变化预测PFS和至SRE时间的能力 在EA中开始新的全身治疗的BO或BD MBC患者中1183; 2）确定早期代谢 全身治疗开始后4周通过FDG-PET/CT评估的骨转移变化可预测PFS BO或BD MBC患者中ctDNA和tSRE的变化; 3）评估ctDNA和tSRE变化之间的关系， 通过FDG-PET/CT评估代谢反应，并测试FDG-PET/CT和ctDNA的联合能力 在开始新的全身治疗后4周和12周，预测PFS和SRE。本研究的结果 将为BD MBC生成稳健的缓解终点，以提供临床试验和指南 临床实践的大组患者这种类型的MBC。

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.