PO.CL01.07 · 临床研究

可切除癌症新辅助免疫检查点抑制期间肿瘤指导和肿瘤未知ctDNA残留病灶检测的分析和临床灵敏度

Analytical and clinical sensitivity of tumor-informed and tumor-naïve ctDNA residual disease detection during neoadjuvant immune checkpoint inhibition in resectable cancers

编号 1129 展板 10 时间 4/19 02:00–05:00 区域 Section 44 主讲 Paul Lee, BS

分会场 Liquid Biopsies: Circulating Nucleic Acids 1

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作者与单位 Authors & Affiliations

Paul K. Lee¹, Blair V. Landon¹, Ezgi Oner¹, Jaime Wehr¹, Qiong Meng¹, Amna Jamali¹, Mimi Najjar², Gavin Pereira¹, Samira Hosseini-Nami¹, Rachel Keogh¹, Chen Hu¹, Ronan J. Kelly³, Joshua E. Reuss⁴, Patrick M. Forde⁵, Mark Sausen⁶, Vincent K. Lam¹, Robert B. Scharpf¹, Noushin Niknafs¹, Valsamo (Elsa) Anagnostou¹

¹Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD,²Cleveland Clinic, Cleveland, OH,³Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX,⁴Department of Hematology/Oncology, Georgetown University, Washington, DC,⁵Trinity St. James’s Cancer Institute, Trinity College Dublin, Dublin, Ireland,⁶Labcorp, Baltimore, MD

摘要 Abstract

中文摘要

背景：循环肿瘤DNA（ctDNA）已成为新辅助免疫治疗期间微创检测残留病灶的关键生物标志物。然而，由于灵敏度有限以及现有检测方法的实际限制，其融入常规临床决策仍受制约。方法：我们对来自32例可手术胃食管（GE）癌患者（NCT03044613）和30例可切除胸膜间皮瘤（PM；NCT03918252）患者的520份生物样本（56份肿瘤、105份白细胞[WBC]、359份血浆）进行了多模态匹配的肿瘤、白细胞（WBC）和循环游离DNA（cfDNA）二代测序（NGS）。ctDNA残留病灶分析在基线、每个周期新辅助免疫治疗前以及术前进行。对于肿瘤指导方法，将匹配的肿瘤、WBC和cfDNA的全基因组测序（WGS）数据（覆盖度分别为80x、40x和30x）通过随机森林机器学习模型整合，并使用非癌性cfDNA参考集校准，以确定cfDNA肿瘤分数（TF）。同时，我们对cfDNA和WBC进行了正交的肿瘤未知、固定基因panel靶向纠错NGS（30,000x），过滤种系和克隆性造血变异。结果：总体而言，肿瘤指导检测显示出显著更高的灵敏度，表现为在所有评估时间点的ctDNA检出率均高于肿瘤未知检测。在GE队列中，肿瘤指导检测在基线、周期2、周期3和术前分别为22/25（88%）、20/25（80%）、18/26（69%）和5/21（24%）的患者检出ctDNA。相比之下，肿瘤未知检测在相应时间点分别为13/30（43%）、12/30（40%）、11/30（37%）和5/25（20%）检出ctDNA。在可检出的病例中，两种方法的cfDNA TF高度一致（R=0.85，p<0.001）。在PM队列中，肿瘤指导检测在基线、周期2、周期3和术前分别为12/26（46%）、11/25（44%）、7/21（33%）和13/25（52%）检出ctDNA。在GE队列中证明肿瘤指导方法具有更高分析灵敏度后，我们仅在肿瘤指导检测可检出ctDNA的病例中应用肿瘤未知方法。其中，在相应时间点分别为6/14（43%）、6/13（46%）、5/8（63%）和7/15（47%）检出ctDNA。在两种方法均可检出ctDNA的时间点，cfDNA TF一致（R=0.63，p=0.002）。术前肿瘤指导ctDNA残留病灶与较短的无进展生存期相关（log-rank，p=0.0059）。结论：基于WGS的肿瘤指导液体活检可可靠地测量新辅助免疫治疗期间的ctDNA残留病灶，与肿瘤未知方法相比灵敏度更高，支持其临床价值。

查看英文原文 English abstract

Background: Circulating tumor DNA (ctDNA) has become a key biomarker for minimally invasive detection of residual disease during neoadjuvant immunotherapy. However, its integration into routine clinical decision-making remains limited by modest sensitivity and the practical constraints of current assays. Methods: We performed multi-modality matched tumor, white blood cell (WBC), and cell-free DNA (cfDNA) next-generation sequencing (NGS) of 520 biospecimens (56 tumor, 105 WBC, 359 plasma) from 32 patients with operable gastroesophageal (GE) cancer (NCT03044613) and 30 patients with resectable pleural mesothelioma (PM; NCT03918252). ctDNA residual disease analyses were performed at baseline, before each cycle of neoadjuvant immunotherapy, and preoperatively. For the tumor-informed approach, whole genome sequencing (WGS) data of matched tumor, WBC, and cfDNA (80x, 40x, and 30x coverage) were integrated through a random forest machine learning model and calibrated using a reference set of noncancerous cfDNA to determine cfDNA tumor fraction (TF). In parallel, we performed orthogonal tumor-naïve, fixed-gene-panel targeted error-correction NGS of cfDNA and WBC (30,000x), filtering germline and clonal hematopoiesis variants. Results: Overall, the tumor-informed assay showed significantly higher sensitivity, evidenced by a higher ctDNA detection rate at all evaluated timepoints compared to the tumor-naïve assay. In the GE cohort, the tumor-informed assay detected ctDNA for 22 of 25 (88%), 20 of 25 (80%), 18 of 26 (69%), and 5 of 21 (24%) patients at baseline, cycle 2, cycle 3, and preoperatively, respectively. By contrast, 13 of 30 (43%), 12 of 30 (40%), 11 of 30 (37%), and 5 of 25 (20%) had detectable ctDNA by the tumor-naïve assay at corresponding timepoints. In detectable cases, cfDNA TFs were highly concordant between approaches (R = 0.85, p < 0.001). In the PM cohort, 12 of 26 (46%), 11 of 25 (44%), 7 of 21 (33%), and 13 of 25 (52%) had ctDNA detected by the tumor-informed assay at baseline, cycle 2, cycle 3, and preoperatively, respectively. Having demonstrated higher analytical sensitivity with the tumor-informed approach in the GE cohort, we applied the tumor-naïve approach only in cases with detectable ctDNA by the tumor-informed assay. Of these, 6 of 14 (43%), 6 of 13 (46%), 5 of 8 (63%), and 7 of 15 (47%) had ctDNA detected at corresponding timepoints. cfDNA TFs were concordant at timepoints when ctDNA was detectable by both approaches (R = 0.63, p = 0.002). Tumor-informed ctDNA residual disease preoperatively was associated with shorter progression-free survival (log-rank, p = 0.0059). Conclusion: Tumor-informed WGS-based liquid biopsies reliably measure ctDNA residual disease during neoadjuvant immunotherapy, demonstrating greater sensitivity compared to a tumor-naïve approach, supporting their clinical value.

利益披露 Disclosure

P. K. Lee, None.. B. V. Landon, None.. E. Oner, None.. J. Wehr, None.. Q. Meng, None.. A. Jamali, None.. M. Najjar, None.. G. Pereira, None.. S. Hosseini-Nami, None. R. Keogh, Merck Sharp & Dohme Travel. C. Hu, Belay Diagnostics Other, Consultant. Johnson & Johnson Other, Consultant. R. J. Kelly, Astellas Other, Consultant. AstraZeneca Other, Consultant. Bristol Myers Squibb ), Other, Consultant. Daiichi Sankyo Other, Consultant. Eisai Other, Consultant. Eli Lilly ), Other, Consultant. EMD Serono Other, Consultant. Exact Sciences Other, Consultant. Grail Other, Consultant. Ipsen Other, Consultant. Merck Other, Consultant. Novartis Other, Consultant. Novocure Other, Consultant. Phillips Other, Consultant. Takeda Other, Consultant. Toray Other, Consultant. Amgen Other, Consultant. Beigene Other, Consultant. Cardinal Health Other, Consultant. Exact Sciences, Illumina, OncoHost Other, Consultant. J. E. Reuss, AstraZeneca ), Other, Consultant. Bristol Myers Squibb Other. Daiichi Sankyo Other, Consultant. Seagen Other, Consultant. Gilead Other, Consultant. Janssen Other, Consultant. Novocure Other, Consultant. Regeneron ), Other, Consultant. Summit Therapeutics Other, Consultant. Pfizer Other, Consultant. Lilly Other, Consultant. Natera Other, Consultant. Merck Other, Consultant. EMD Serono Other, Consultant. Genentech/Roche ), Other, Consultant. Boehringer Ingelheim Other, Consultant. Verastem ). Nuvalent ). Arcus ). Revolution Medicines, Amgen, Duality Bio ). P. M. Forde, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ), Other, Consultant. Novartis ), Other, Consultant. Regeneron ), Other, Consultant. Kyowa ). BioNTech ), Other, Consultant. AbbVie Other, Consultant. Amgen Other, Consultant. Ascendis Other, Consultant. ChromaCode Other, Consultant. Daiichi Sankyo Other, Consultant. F-Star Other, Consultant. Genelux Other, Consultant. Gilead Other, Consultant. Gilead Other, Consultant. iTeos Other, Consultant. Novocure Other, Consultant. Tavotek Other, Consultant. Teva, Genentech, Sanofi, Surface, Janssen, G1, Merck Other, Consultant. Polaris, Flame Other, Data and Safety Monitoring Board. M. Sausen, Labcorp Employment, Stock. V. K. Lam, Anheart Therapeutics Other, Consultant. Takeda Other, Consultant. Seattle Genetics ), Other, Consultant. Bristol Myers Squibb ), Other, Consultant. AstraZeneca ), Other, Consultant. Guardant Health Other, Consultant. GlaxoSmithKline ). Merck ). Iovance Biotherapeutics Other, Consultant. R. B. Scharpf, Delfi Diagnostics Stock, Patent, Other, Founder, Consultant. Artemyx Stock, Other, Founder, Consultant. N. Niknafs, None. V. Anagnostou, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Consultant. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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