PO.CL01.09 · 临床研究

使用超灵敏的肿瘤指导型结构变异检测方法对转移性乳腺癌进行连续ctDNA监测

Serial ctDNA monitoring in metastatic breast cancer using an ultrasensitive tumor informed structural variant based assay

编号 3864 展板 25 时间 4/20 02:00–05:00 区域 Section 45 主讲 Mitchell Elliott, BS;MD

分会场 Liquid Biopsies: Circulating Nucleic Acids 3

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作者与单位 Authors & Affiliations

Mitchell J. Elliott¹, June Roh¹, Kareena Thakur¹, Sasha Main², Karen Howarth³, Sofia Birkeälv³, Jennifer Yen³, Völundur Hafstad³, Wendy Levin⁴, Vikash Kumar¹, Long Nguyen¹, Meredith Li¹, Scott Victor Bratman⁵, Eitan Amir¹, Philippe L. Bedard⁶, Lillian L. Siu⁷, Hal Berman⁸, David Cescon⁹

¹Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada,²Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada,³SAGA Dx, Lund, Sweden,⁴SAGA Dx, Morrisville, NC,⁵The Governing Council of The University of Toronto, Toronto, ON, Canada,⁶UHN-Toronto General Hospital, Toronto, ON, Canada,⁷UHN Princess Margaret Cancer Centre, Toronto, ON, Canada,⁸Department of Pathology, Toronto General Hospital, Toronto, ON, Canada,⁹Princess Margaret Cancer Centre, Toronto, ON, Canada

摘要 Abstract

中文摘要

背景：循环肿瘤DNA（ctDNA）动态变化与转移性乳腺癌（mBC）的治疗反应相关，但使用肿瘤指导型超灵敏检测方法所产生的证据仍然有限。此外，跨不同受体亚型以及历经多线治疗的连续ctDNA监测格局仍未得到充分描述。再者，基于结构变异（SV）的ctDNA检测在此背景下的性能尚未确立。将ctDNA验证为mBC中可靠的反应和进展生物标志物，尤其是在治疗转换过程中，可提供临床应用价值。方法：我们在接受标准治疗系统性疗法的mBC患者中开展了一项单中心回顾性研究。前瞻性地在入组时、影像学再分期事件时（±30天）以及疾病进展时采集连续血液样本。使用一种超灵敏的、基于全基因组测序（WGS）的肿瘤指导型SV数字PCR检测对ctDNA进行回顾性分析。从病历中获取临床数据、跨连续治疗线的真实世界无进展生存期（rwPFS）和总生存期（OS）。结果：28/100例患者获得了结果（18例ER+/HER2-、6例TNBC、4例HER2+），贡献了120个可评估时间点（每位患者中位3个，范围1-18个），中位随访时间为12.2个月（范围2.0-16.3）。患者接受了中位2线转移性治疗（范围1-8）。经正交验证的指纹图谱包含中位13个SV（范围4-16）。在所有采样时间点中，77%（92/120）检测到ctDNA，其中34%（31/92）的阳性结果落在超灵敏范围内（变异等位基因分数≤0.01%或≤100 ppm）。连续ctDNA监测密切反映了每位患者的治疗进程。值得注意的是，没有一例经放射科医师判定的进展是在治疗中最低点ctDNA先升高之前发生的。四例患者（1例ER+/HER2-、1例TNBC、2例HER2+）ctDNA不可检测，中位rwPFS为27个月（范围20-40），且仍在接受治疗，无rwPFS或OS事件。研究仍在持续入组，继续进行连续血浆采集并使rwPFS/OS数据逐步成熟。结论：这些初步发现证明了使用肿瘤指导型超灵敏SV检测在真实世界异质性mBC队列中进行ctDNA监测的可行性。ctDNA动态变化在连续治疗线中密切追踪治疗反应，早期信号提示ctDNA清除至超灵敏检测阈值以下与疾病控制延长相关。落在超灵敏范围内的时间点占比很高，凸显了检测灵敏度对转移性监测的重要性。将展示来自完整队列的更新结果，包括与所有配对影像学再分期事件的相关性。

查看英文原文 English abstract

Background: Circulating tumor DNA (ctDNA) dynamics correlate with treatment response in metastatic breast cancer (mBC), yet evidence generated using tumor-informed, ultrasensitive assays remains limited. In addition, the landscape of serial ctDNA monitoring across different receptor subtypes and through multiple lines of therapy remains poorly characterized. Furthermore, the performance of structural variant (SV) based ctDNA detection has not been established in this setting. Validating ctDNA as a reliable biomarker of response and progression in mBC, particularly across treatment transitions, could provide clinical utility. Methods: We conducted a single-center retrospective study in patients with mBC receiving standard-of-care systemic therapy. Serial blood samples were collected prospectively at enrollment, radiographic restaging events (+/-30 days), and at disease progression. ctDNA was analyzed retrospectively using an ultrasensitive, whole genome sequencing (WGS)-based, tumor-informed SV digital PCR assay. Clinical data, real-world progression-free survival (rwPFS) across sequential lines of therapy, and overall survival (OS) were obtained from the medical record. Results: Results were available for 28/100 patients (18 ER+/HER2-, 6 TNBC, 4 HER2+), contributing 120 evaluable timepoints (median 3 per patient, range 1-18) with a median follow-up of 12.2 months (range 2.0-16.3). Patients received a median of 2 lines of metastatic therapy (range 1-8). Orthogonally validated fingerprints contained a median of 13 SVs (range 4-16). ctDNA was detected in 77% (92/120) of all sampled timepoints, with 34% (31/92) of positives falling within the ultrasensitive range (variant allele fraction ≤0.01% or ≤100 ppm). Serial ctDNA monitoring closely mirrored each patient's treatment course. Notably, no radiologist-adjudicated progression occurred without a preceding rise in ctDNA from on-treatment nadir. Four patients (1 ER+/HER2-, 1 TNBC, 2 HER2+) had undetectable ctDNA with a median rwPFS of 27 months (range 20-40) and remain on therapy without rwPFS or OS events. Accrual is ongoing, with continued serial plasma collection and maturing rwPFS/OS data. Conclusion: These preliminary findings demonstrate the feasibility of ctDNA monitoring in a real-world, heterogeneous mBC cohort using a tumor-informed, ultrasensitive SV-based assay. ctDNA dynamics closely tracked treatment response across sequential lines of therapy, and early signals suggest that ctDNA clearance below the ultrasensitive detection threshold is associated with prolonged disease control. The high proportion of timepoints within the ultrasensitive range underscores the relevance of assay sensitivity for metastatic monitoring. Updated results from the full cohort, including correlation with all matched radiographic restaging events will be presented.

利益披露 Disclosure

M. J. Elliott, Gilead Other, honoraria. J. Roh, None.. K. Thakur, None.. S. Main, None. K. Howarth, SAGA Dx Employment. S. Birkeälv, SAGA Dx Employment. J. Yen, SAGA Dx Employment. V. Hafstad, SAGA Dx Employment. W. Levin, SAGA Dx Employment. V. Kumar, None.. L. Nguyen, None.. M. Li, None. E. Amir, Novartis Other, honoraria. H. Berman, None. D. Cescon, AstraZeneca ). Guardant Health ). Gilead ). GlaxoSmithKline ). NeoGenomics ). Knight ). Merck ). Pfizer ). Roche ). Patent (US62/675,228) Patent.

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