Florian Janke, Mateo Gasser, Arlou K Angeles, Anja L Riediger, Magdalena Görtz, Louise Appenheimer, Astrid K Laut, Simon Ogrodnik, Sabrina Gerhardt, Albrecht Stenzinger, Marc A Schneider, Michael Thomas, Petros Christopoulos, Holger Sültmann
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Targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) has demonstrated potential clinical utility to support clinical decisions, but requires prior tumor genetic profiling for proper interpretation, and wide adoption remains limited due to high costs.</p><p><strong>Methods: </strong>Tumor-agnostic low-coverage ctDNA whole genome sequencing (lcWGS) was used to longitudinally track genome-wide copy number variations (CNVs) and fragmentation features in advanced NSCLC patients (n = 118 samples from 49 patients) and healthy controls (n = 57). Tumor PD-L1 expression was available for comparison.</p><p><strong>Findings: </strong>Fragmentation features and CNVs were complementary indicators, whose combination significantly increased ctDNA detection compared to single-marker assessments (+ 20.3% compared to CNV analysis alone). Baseline fragment length alterations, but not CNVs, were significantly associated with subsequent progression-free survival (PFS; hazard ratio [HR] = 4.10, p = 6.58e-05) and could improve PFS predictions based on tumor PD-L1 expression alone (HR = 2.70, p = 0.019). Residual CNVs or aberrant fragmentation of ctDNA under ongoing therapy could stratify patients according to the subsequent response duration (median 5.8 vs. 47.0 months, p = 1.13e-06). The integrative analysis of ctDNA fragment characteristics at baseline, tumor PD-L1 expression, and residual ctDNA under ongoing treatment constituted the strongest independent predictor of PFS (p = 6.25e-05) and overall survival (p = 1.3e-03) in multivariable analyses along with other clinicopathologic variables.</p><p><strong>Interpretation: </strong>This study demonstrates the feasibility and potential clinical utility of lcWGS for the tumor-agnostic stratification and monitoring of advanced NSCLC under PD-(L)1 blockade based on CNV and fragmentomic profiling.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"87"},"PeriodicalIF":11.4000,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889826/pdf/","citationCount":"0","resultStr":"{\"title\":\"Low-coverage whole genome sequencing of cell-free DNA to predict and track immunotherapy response in advanced non-small cell lung cancer.\",\"authors\":\"Florian Janke, Mateo Gasser, Arlou K Angeles, Anja L Riediger, Magdalena Görtz, Louise Appenheimer, Astrid K Laut, Simon Ogrodnik, Sabrina Gerhardt, Albrecht Stenzinger, Marc A Schneider, Michael Thomas, Petros Christopoulos, Holger Sültmann\",\"doi\":\"10.1186/s13046-025-03348-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Outcomes under anti-PD-(L)1 therapy have been variable in advanced non-small cell lung cancer (NSCLC) without reliable predictive biomarkers so far. 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Baseline fragment length alterations, but not CNVs, were significantly associated with subsequent progression-free survival (PFS; hazard ratio [HR] = 4.10, p = 6.58e-05) and could improve PFS predictions based on tumor PD-L1 expression alone (HR = 2.70, p = 0.019). Residual CNVs or aberrant fragmentation of ctDNA under ongoing therapy could stratify patients according to the subsequent response duration (median 5.8 vs. 47.0 months, p = 1.13e-06). 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引用次数: 0
摘要
背景：抗pd -(L)1治疗晚期非小细胞肺癌（NSCLC）的结果是可变的，迄今为止没有可靠的预测性生物标志物。循环肿瘤DNA （ctDNA）的靶向下一代测序（NGS）已经证明了支持临床决策的潜在临床效用，但需要事先进行肿瘤遗传分析才能正确解释，并且由于成本高，广泛采用仍然受到限制。方法：采用肿瘤不确定的低覆盖率ctDNA全基因组测序（lcWGS）纵向跟踪晚期NSCLC患者（49例患者的118个样本）和健康对照（57例）的全基因组拷贝数变异（cnv）和片段化特征。肿瘤PD-L1的表达可用于比较。研究结果：片段特征和CNV是互补的指标，与单一标记物评估相比，它们的结合显著增加了ctDNA的检测（与单独的CNV分析相比，增加了20.3%）。基线片段长度改变，而非CNVs，与随后的无进展生存期(PFS；风险比[HR] = 4.10, p = 6.58e-05)，可以单独根据肿瘤PD-L1表达改善PFS预测（HR = 2.70, p = 0.019）。在持续治疗中，残留的CNVs或ctDNA的异常片段可以根据随后的反应持续时间对患者进行分层（中位5.8 vs 47.0个月，p = 1.13e-06）。在多变量分析中，基线时的ctDNA片段特征、肿瘤PD-L1表达和持续治疗中残留的ctDNA的综合分析构成了PFS （p = 6.25e-05）和总生存（p = 1.3e-03）以及其他临床病理变量的最强独立预测因子。解释：本研究证明了lcWGS在PD-(L)1阻断下进行肿瘤不确定分层和监测的可行性和潜在的临床应用，基于CNV和片段组学分析。
Low-coverage whole genome sequencing of cell-free DNA to predict and track immunotherapy response in advanced non-small cell lung cancer.
Background: Outcomes under anti-PD-(L)1 therapy have been variable in advanced non-small cell lung cancer (NSCLC) without reliable predictive biomarkers so far. Targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) has demonstrated potential clinical utility to support clinical decisions, but requires prior tumor genetic profiling for proper interpretation, and wide adoption remains limited due to high costs.
Methods: Tumor-agnostic low-coverage ctDNA whole genome sequencing (lcWGS) was used to longitudinally track genome-wide copy number variations (CNVs) and fragmentation features in advanced NSCLC patients (n = 118 samples from 49 patients) and healthy controls (n = 57). Tumor PD-L1 expression was available for comparison.
Findings: Fragmentation features and CNVs were complementary indicators, whose combination significantly increased ctDNA detection compared to single-marker assessments (+ 20.3% compared to CNV analysis alone). Baseline fragment length alterations, but not CNVs, were significantly associated with subsequent progression-free survival (PFS; hazard ratio [HR] = 4.10, p = 6.58e-05) and could improve PFS predictions based on tumor PD-L1 expression alone (HR = 2.70, p = 0.019). Residual CNVs or aberrant fragmentation of ctDNA under ongoing therapy could stratify patients according to the subsequent response duration (median 5.8 vs. 47.0 months, p = 1.13e-06). The integrative analysis of ctDNA fragment characteristics at baseline, tumor PD-L1 expression, and residual ctDNA under ongoing treatment constituted the strongest independent predictor of PFS (p = 6.25e-05) and overall survival (p = 1.3e-03) in multivariable analyses along with other clinicopathologic variables.
Interpretation: This study demonstrates the feasibility and potential clinical utility of lcWGS for the tumor-agnostic stratification and monitoring of advanced NSCLC under PD-(L)1 blockade based on CNV and fragmentomic profiling.
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