Váraljai Renáta, Wistuba-Hamprecht Kilian, Seremet Teofila, Diaz Joey Mark S, Nsengimana Jérémie, Sucker Antje, Griewank Klaus, Placke Jan-Malte, Horn Peter A, von Neuhoff Nils, Shannan Batool, Chauvistré Heike, Vogel Felix C E, Horn Susanne, Becker Jürgen C, Newton-Bishop Julia, Stang Andreas, Neyns Bart, Weide Benjamin, Schadendorf Dirk, Roesch Alexander
University Hospital of Essen, University Duisburg-Essen and German Cancer Consortium partner site Essen/Düsseldorf, Essen, Germany.
University Medical Center Tübingen, Tübingen, Germany.
JCO Precis Oncol. 2019 Feb 15;3. doi: 10.1200/PO.18.00229. eCollection 2020.
Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma.
We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the and driver mutations as well as and promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase-targeted or immune checkpoint therapies.
Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for ctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans ( < .05), with a mean lead time of 3.5 months. -mutant ctDNA was detected in a significant proportion of patients with -mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of ctDNA in baseline samples of patients with mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; = .01).
Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastatic melanoma.
循环游离肿瘤DNA（ctDNA）反映了肿瘤特异性突变的异质性谱，尤其是在全身性疾病中。我们验证了基于血浆的检测方法，该方法可动态定量检测ctDNA，作为黑色素瘤肿瘤负荷的预后生物标志物和治疗反应的预测指标。
我们分析了来自一大群晚期黑色素瘤患者（n = 96）的血浆来源的ctDNA，采用检测 和 驱动基因突变以及 和 启动子突变的检测方法。一个独立的患者队列（n = 35）用于验证在丝裂原活化蛋白激酶靶向治疗或免疫检查点治疗下ctDNA监测的效用。
在多变量分析中，与血清S100和乳酸脱氢酶水平相比，基线时血浆ctDNA水平升高是疾病进展的独立预后因素（风险比[HR]，7.43；95%置信区间，1.01至55.19； = 0.05）。治疗期间ctDNA水平的变化与治疗反应相关，ctDNA升高预示无进展生存期较短（例如，对于 ctDNA，HR，3.70；95%置信区间，1.86至7.34； < 0.001）。ctDNA水平升高比常规放射学扫描显著更早地预测疾病进展（ < 0.05），平均提前时间为3.5个月。在接受治疗的 突变肿瘤患者中，很大一部分患者检测到 -突变ctDNA，但出乎意料的是在基线时也检测到。体外敏感性研究表明，这代表了高于预期的肿瘤内异质性。在接受丝裂原活化蛋白激酶抑制剂治疗的 突变患者的基线样本中检测到 ctDNA，与较短的无进展生存期（HR，3.18；95%置信区间，1.31至7.68； = 0.03）和较短的总生存期（HR，4.08；95%置信区间，1.57至10.58； = 0.01）显著相关。
我们的结果显示了ctDNA检测作为一种敏感的监测和预测工具在转移性黑色素瘤患者疾病进展和治疗反应早期评估中的潜在作用。
