Purpose: Liquid biopsy (LBx) for tumor profiling is increasingly used, but concerns remain regarding negative results. A lack of results may truly reflect tumor genomics, or it may be a false negative that would be clarified by tissue testing. A method of distinguishing between these scenarios could help clarify when follow-on tissue testing is valuable. Experimental Design: Here we evaluate circulating tumor DNA (ctDNA) tumor fraction (TF), a quantification of ctDNA in LBx samples, for utility in identifying true negative results.We assessed concordance between LBx and tissue-based results, stratified by ctDNA TF, in a real-world genomic data set of paired samples across multiple disease types. We also evaluated the frequency of tissue results identifying driver alterations in lung cancer patients after negative LBx in a real-world clinicogenomic database. Results: The positive percent agreement and negative predictive value between liquid and tissue samples for driver alterations increased from 63% and 66% for all samples to 98% and 97% in samples with ctDNA TF ≥1%. Among 505 lung cancer patients with no targetable driver alterations found by LBx who had subsequent tissue-based profiling, 37% had a driver, all of which had ctDNA TF <1%. Conclusions: Lung cancer patients with negative LBx and ctDNA TF ≥1% are unlikely to have a driver detected on confirmatory tissue testing; such informative negative results may benefit instead from prompt treatment initiation. Conversely, negative LBx with ctDNA TF <1% will commonly have a driver identified by follow-on tissue testing and should be prioritized for reflex testing.

中文翻译：

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ctDNA 肿瘤分数的测量可识别阴性液体活检结果并告知组织确认的价值

目的：越来越多地使用液体活检 (LBx) 进行肿瘤分析，但对阴性结果的担忧仍然存在。缺乏结果可能真正反映了肿瘤基因组学，也可能是假阴性，可以通过组织测试来澄清。区分这些情况的方法可以帮助澄清后续组织测试何时有价值。实验设计：在这里，我们评估循环肿瘤 DNA (ctDNA) 肿瘤分数 (TF)，即 LBx 样本中 ctDNA 的定量，用于识别真阴性结果。我们评估了 LBx 和基于组织的结果之间的一致性，按 ctDNA TF 分层，在跨多种疾病类型的配对样本的真实基因组数据集中。我们还在真实世界的临床基因组数据库中评估了 LBx 阴性后肺癌患者的驱动因素改变的组织结果的频率。结果：液体和组织样本之间驱动基因改变的阳性预测值和阴性预测值从所有样本的 63% 和 66% 增加到 ctDNA TF ≥1% 的样本中的 98% 和 97%。在 LBx 发现的 505 名未发现可靶向驱动基因改变且随后进行组织分析的肺癌患者中，37% 的患者有驱动基因，所有患者的 ctDNA TF 均小于 1%。结论：LBx 阴性且 ctDNA TF ≥1% 的肺癌患者在验证性组织检测中不太可能检测到驾驶员；这种信息丰富的阴性结果可能会受益于及时开始治疗。相反，ctDNA TF＜1％的阴性LBx通常会通过后续组织测试识别出驱动因素，并且应优先进行反射测试。