Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Guardant Health, Inc., Redwood City, California.
J Thorac Oncol. 2021 Apr;16(4):601-609. doi: 10.1016/j.jtho.2020.12.011. Epub 2020 Dec 31.
Plasma-based circulating tumor DNA (ctDNA) is an established biomarker for molecular profiling with emerging applications in disease monitoring in multiple tumor types, including, NSCLC. However, determinants of ctDNA shedding and correlation with tumor burden are incompletely understood, particularly in advanced-stage disease.
We retrospectively analyzed ctDNA-based and tissue-based genomic data and imaging from 144 patients with NSCLC. Tumor burden was quantified with computed tomography (CT) and brain magnetic resonance imaging for the overall cohort and 18F-fludeoxyglucose positron emission tomography-CT in a subset of patients.
There was a moderate but statistically significant correlation between ctDNA variant allele frequency and multiple imaging measures of tumor burden such as CT volume (rho = 0.34, p ≤ 0.0001) and metabolic tumor volume (rho = 0.36, p = 0.003). This correlation was strongest in KRAS-mutant tumors (rho = 0.56, p ≤ 0.001), followed by TP53 mutants (rho = 0.43, p ≤ 0.0001), and weakest in EGFR-mutated (EGFR+) tumors (rho = 0.24, p = 0.077). EGFR+ tumors with EGFR copy number gain had significantly higher variant allele frequency than EGFR+ without copy number gain (p ≤ 0.00001). In multivariable analysis, TP53 and EGFR mutations, visceral metastasis, and tumor burden were independent predictors of increased ctDNA shedding.
Levels of detectable ctDNA were affected not only by tumor burden but also by tumor genotype. The genotype-specific differences observed may be due to variations in DNA shedding and cellular turnover. These findings have implications for the emerging use of ctDNA in NSCLC disease monitoring and early detection.
基于血浆的循环肿瘤 DNA（ctDNA）是一种已确立的分子谱分析生物标志物，在包括非小细胞肺癌（NSCLC）在内的多种肿瘤类型的疾病监测中具有新兴应用。然而，ctDNA 释放的决定因素及其与肿瘤负担的相关性尚不完全清楚，尤其是在晚期疾病中。
我们回顾性分析了 144 例 NSCLC 患者的 ctDNA 基于和组织基因组数据和影像学资料。对整个队列进行了计算机断层扫描（CT）和脑磁共振成像的肿瘤负担定量，对部分患者进行了 18F-氟脱氧葡萄糖正电子发射断层扫描-CT。
ctDNA 变异等位基因频率与多种影像学肿瘤负担指标（如 CT 体积[rho=0.34，p≤0.0001]和代谢肿瘤体积[rho=0.36，p=0.003]）之间存在中等但具有统计学意义的相关性。这种相关性在 KRAS 突变肿瘤中最强（rho=0.56，p≤0.001），其次是 TP53 突变肿瘤（rho=0.43，p≤0.0001），在 EGFR 突变（EGFR+）肿瘤中最弱（rho=0.24，p=0.077）。EGFR+肿瘤中存在 EGFR 拷贝数增益的患者，其变异等位基因频率明显高于无拷贝数增益的患者（p≤0.00001）。多变量分析显示，TP53 和 EGFR 突变、内脏转移和肿瘤负担是增加 ctDNA 释放的独立预测因素。
可检测到的 ctDNA 水平不仅受肿瘤负担影响，还受肿瘤基因型影响。观察到的基因型特异性差异可能是由于 DNA 释放和细胞周转率的差异所致。这些发现对 NSCLC 疾病监测和早期检测中新兴的 ctDNA 应用具有重要意义。
