Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Oncologist. 2019 Jun;24(6):820-828. doi: 10.1634/theoncologist.2018-0433. Epub 2019 Mar 13.
Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC).
A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length.
Higher ctDNA TMB was significantly correlated with smoking history ( < .05, chi-squared test). Among patients treated with immune checkpoint inhibitors ( = 20), higher ctDNA TMB was significantly correlated with shorter progressive free survival (PFS) and overall survival (OS; 45 vs. 355 days; hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.3-24.6; < .01, and OS 106 days vs. not reached; HR, 6.0; 95% CI, 1.3-27.1; < .01, respectively). In a small independent validation cohort ( = 12), there was a nonsignificant numerical difference for higher ctDNA TMB predicting shorter OS but not PFS. ctDNA TMB was not correlated with RECIST tumor burden estimation in the subset of patients treated with immune checkpoint blockade.
The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes.
Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
组织肿瘤突变负担（TMB）已成为预测抗程序性细胞死亡蛋白-1 受体（PD-1）/程序性细胞死亡蛋白配体（PD-L1）治疗反应的潜在生物标志物，但很少有研究探索使用非小细胞肺癌（NSCLC）中的循环肿瘤 DNA（ctDNA）TMB。
对一家机构的 136 名接受过 ctDNA 检测的 NSCLC 患者进行回顾性评估，并对第二家机构的验证队列进行评估。ctDNA TMB 是通过在 DNA 测序长度上检测到的突变数量得出的。
较高的 ctDNA TMB 与吸烟史显著相关（<0.05，卡方检验）。在接受免疫检查点抑制剂治疗的患者中（=20），较高的 ctDNA TMB 与较短的无进展生存期（PFS）和总生存期（OS）显著相关（45 天 vs. 355 天；危险比 [HR]，5.6；95%置信区间 [CI]，1.3-24.6；<0.01，和 OS 106 天 vs. 未达到；HR，6.0；95% CI，1.3-27.1；<0.01）。在一个小的独立验证队列中（=12），较高的 ctDNA TMB 预测 OS 较短，但 PFS 无显著差异。在接受免疫检查点阻断治疗的患者亚组中，ctDNA TMB 与 RECIST 肿瘤负担评估无相关性。
研究结果表明，目前商业测序长度下，较高的 ctDNA TMB 反映了更差的临床结局。寻找能识别出对免疫检查点阻断治疗有反应的患者的生物标志物至关重要。组织肿瘤突变负担（TMB）已成为预测抗 PD-1/PD-L1 治疗反应的可行生物标志物，但很少有研究探索非侵入性、基于血液的 TMB 的意义和潜在临床意义。在这里，我们研究了循环肿瘤 DNA（ctDNA）TMB，并提供了数据表明，目前的 ctDNA TMB 可能反映肿瘤负担，并且需要具有更多突变的 ctDNA 面板才能更准确地反映组织 TMB。
