PO.CL01.07 · 临床研究

纵向肿瘤指导的无细胞DNA全基因组测序联合转录组分析捕捉可切除胃食管癌的肿瘤负荷动态

Longitudinal tumor-informed cell-free DNA whole genome sequencing coupled with transcriptomic analysis captures tumor burden dynamics in resectable gastroesophageal cancer

编号 1140 展板 21 时间 4/19 02:00–05:00 区域 Section 44 主讲 Blair Landon, BS;PhD

分会场 Liquid Biopsies: Circulating Nucleic Acids 1

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作者与单位 Authors & Affiliations

Blair V. Landon¹, Jaime Wehr¹, Rachel Keogh¹, Noushin Niknafs¹, Christopher Cherry¹, Nisha Rao¹, Gavin Pereira¹, Mark Sausen², Richard J. Battafarano³, Stephen C. Yang³, Stephen Broderick³, Jinny Ha³, Russell K. Hales⁴, K. Ranh Voong⁴, Kristen A. Marrone¹, Chen Hu¹, Josephine L. Feliciano¹, Ali H. Zaidi⁵, Ronan J. Kelly⁶, Vincent K. Lam¹, Valsamo (Elsa) K. Anagnostou¹

¹The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD,²Labcorp, Baltimore, MD,³Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,⁴Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD,⁵Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA,⁶The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX

摘要 Abstract

中文摘要

引言：循环肿瘤DNA（ctDNA）已被确立为在整个癌症诊疗过程中检测残留病灶和监测治疗反应的有前景的生物标志物，然而其用于评估对新辅助免疫检查点抑制（ICI）治疗反应的效用仍在研究中。我们采用肿瘤指导的无细胞DNA（cfDNA）全基因组测序（WGS）方法，对接受新辅助ICI治疗的胃食管癌进行分子层面的肿瘤负荷动态监测，并基于ctDNA状态将临床结局与基线肿瘤的转录组评估相关联。方法：我们对接受新辅助ICI及放化疗后行手术切除的可切除胃食管癌患者（NCT03044613）的肿瘤（n=28）、配对白细胞（WBC，n=28）及系列血浆样本（n=97）进行了WGS。利用肿瘤和WBC的序列数据识别肿瘤特异性单核苷酸变异（SNV）。采用高质量SNV通过随机森林机器学习模型确定血浆中ctDNA的存在。在四个时间点（基线、ICI第1周期后、ICI第2周期后及术前）评估ctDNA状态和肿瘤分数（TF）。结果与肿瘤无关基因panel的ctDNA靶向NGS（n=32例患者，n=152份样本）进行比较，并与临床结局相关联。此外，对基线肿瘤样本（n=28）进行bulk RNA测序（RNAseq）并用于基因集富集分析（GSEA）。结果：术前ctDNA TF高于中位数的患者，其总生存期（OS）显著短于ctDNA TF低于中位数或ctDNA不可检出的患者（logrank p < 0.0001）。在通过肿瘤无关靶向NGS panel检测为术前不可检出的患者中，通过肿瘤指导WGS方法可检出ctDNA的个体，其OS在数值上短于ctDNA不可检出的个体（logrank p=0.1）。同样地，术前cfDNA TF降低≥95%的患者具有更长的无复发生存期（logrank p=0.002）和OS（logrank p= 0.0001）。基线肿瘤RNAseq数据的GSEA显示，在通过肿瘤指导WGS方法检出基线ctDNA的个体的肿瘤中，G2/M细胞周期检查点和E2F靶点富集（FDR校正p=2.31e-12），提示cfDNA TF检测捕捉了血流中的细胞更新。采用肿瘤无关方法按ctDNA检出进行分层的分析中，未观察到增殖和细胞周期进程相关基因集的上调。结论：肿瘤指导的cfDNA WGS分析能够准确捕捉新辅助免疫治疗期间的肿瘤负荷动态和细胞更新，为进一步的治疗干预和优化开启了机会窗口。

查看英文原文 English abstract

Introduction: Circulating tumor DNA (ctDNA) has been established as a promising biomarker for detecting residual disease and monitoring therapy response across the cancer care continuum, however its utility to assess response to neoadjuvant immune checkpoint inhibition (ICI) is still being investigated. We utilized a tumor-informed cell-free DNA (cfDNA) whole genome sequencing (WGS) approach to molecularly monitor tumor burden dynamics and link clinical outcomes with transcriptomic assessment of baseline tumors based on ctDNA status in gastroesophageal cancer treated with neoadjuvant ICI. Methods: We performed WGS on tumor (n=28), matched white blood cell (WBC, n=28), and serial plasma samples (n=97) from patients with resectable gastroesophageal cancer treated with neoadjuvant ICI and chemoradiation prior to surgical resection (NCT03044613). Tumor and WBC sequence data was used to identify tumor-specific single nucleotide variants (SNVs). High quality SNVs were utilized to determine the presence of ctDNA in plasma through a random forest machine learning model. ctDNA status and tumor fraction (TF) were assessed across four timepoints (baseline, post-ICI cycle 1, post-ICI cycle 2, and pre-operatively). Results were compared with tumor-naïve gene panel ctDNA targeted NGS (n=32 patients, n=152 samples) and correlated with clinical outcomes. Additionally, bulk RNA sequencing (RNAseq) was performed on baseline tumor samples (n=28) and utilized for gene set enrichment analyses (GSEA). Results: Patients with pre-operative ctDNA TF above the median had a significantly shorter overall survival (OS) compared to those with ctDNA TF below the median or undetectable ctDNA (logrank p < 0.0001). Among patients who were undetectable pre-operatively via the tumor-naïve targeted NGS panel, individuals with detectable ctDNA via the tumor-informed WGS approach attained a numerically shorter OS compared to individuals with undetectable ctDNA (logrank p=0.1). Similarly, patients with ≥95% reduction in cfDNA TF pre-operatively had longer recurrence-free (logrank p=0.002) and OS (logrank p= 0.0001). GSEA of RNAseq data from baseline tumors revealed enrichment of G2/M cell cycle checkpoint and E2F targets in tumors from individuals with detectable baseline ctDNA via the tumor-informed WGS approach (FDR-adjusted p=2.31e-12), suggesting that cfDNA TF detection captures cellular turnover in the blood stream. The upregulation of proliferation and cell cycle progression-associated gene sets was not observed in stratified analyses by ctDNA detection utilizing the tumor-naïve approach. Conclusions: Tumor-informed cfDNA WGS analyses accurately capture tumor burden dynamics and cellular turnover during neoadjuvant immunotherapy, opening a window of opportunity for further therapeutic intervention and optimization.

利益披露 Disclosure

B. V. Landon, None.. J. Wehr, None. R. Keogh, Merck Sharp & Dohme Travel. N. Niknafs, None. C. Cherry, CM Cherry Consulting Other, Founder. N. Rao, None.. G. Pereira, None. M. Sausen, Labcorp Employment, Stock. R. J. Battafarano, None.. S. C. Yang, None. S. Broderick, AstraZeneca Other, Consultant. Bristol Myers Squibb Other, Consultant. J. Ha, None. R. K. Hales, AstraZeneca Other, Honoraria. K. Voong, AstraZeneca Other, Consultant. K. A. Marrone, AstraZeneca ), Other, Consultant, Honoraria. Amgen Other, Consultant. Daiichi Sankyo/Lilly Other, Consultant. Janssen Other, Consultant. Mirati Therapeutics ), Other, Consultant. Regeneron Other, Consultant. Bristol Myers Squibb ). Puma Biotechnology Other, Consultant. C. Hu, Belay Diagnostics Other, Consultant. Johnson & Johnson Other, Consultant. J. L. Feliciano, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ). Pfizer ). Coherus Other, Consultant. Daiichi Sankyo Other, Consultant. Genentech Other, Consultant. Janssen Other, Consultant. Eli Lilly Other, Consultant. Regeneron Other, Consultant. Takeda Other, Consultant. A. H. Zaidi, BilliontoOne ), Other, Consultant. Delfi Diagnostics ), Other, Consultant. Gilead Sciences Other, Consultant. PrognomiQ ), Other, Consultant. Previse Stock, Other, Consultant. Eli Lilly ). Genece Health ). Roche ). Myriad Genetics ). Tempus ). Tg Therapeutics Stock. Gritstone Bio Stock. R. J. Kelly, Amgen Other, Consultant. Astellas Other, Consultant. AstraZeneca Other, Consultant. Beigene Other, Consultant. Bristol Myers Squibb ), Other, Consultant. Cardinal Health Other, Consultant. Daiichi Sankyo Other, Consultant. Eisai Other, Consultant. Eli Lilly ), Other, Consultant. EMD Serono Other, Consultant. Exact Sciences Other, Consultant. Grail Other, Consultant. Illumina Other, Consultant. Ipsen Other, Consultant. Merck Other, Consultant. Novartis Other, Consultant. Novocure Other, Consultant. OncoHost Other, Consultant. Phillips Other, Consultant. Takeda and Toray Other, Consultant. V. K. Lam, Iovance Biotherapeutics Other, Consultant. 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 ). V. K. Anagnostou, AstraZeneca ), Other, Advisory Board Member. Bristol Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Advisory Board Member. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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