Chang Gregory A, Tadepalli Jyothirmayee S, Shao Yongzhao, Zhang Yilong, Weiss Sarah, Robinson Eric, Spittle Cindy, Furtado Manohar, Shelton Dawne N, Karlin-Neumann George, Pavlick Anna, Osman Iman, Polsky David
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, USA; Department of Population Health, New York University School of Medicine, New York, NY, USA.
Mol Oncol. 2016 Jan;10(1):157-65. doi: 10.1016/j.molonc.2015.09.005. Epub 2015 Sep 25.
Melanoma lacks a clinically useful blood-based biomarker of disease activity to help guide patient management. To determine whether measurements of circulating, cell-free, tumor-associated BRAF(mutant) and NRAS(mutant) DNA (ctDNA) have a higher sensitivity than LDH to detect metastatic disease prior to treatment initiation and upon disease progression we studied patients with unresectable stage IIIC/IV metastatic melanoma receiving treatment with BRAF inhibitor therapy or immune checkpoint blockade and at least 3 plasma samples obtained during their treatment course. Levels of BRAF(mutant) and NRAS(mutant) ctDNA were determined using droplet digital PCR (ddPCR) assays. Among patients with samples available prior to treatment initiation ctDNA and LDH levels were elevated in 12/15 (80%) and 6/20 (30%) (p = 0.006) patients respectively. In patients with RECIST scores <5 cm prior to treatment initiation, ctDNA levels were elevated in 5/7 (71%) patients compared to LDH which was elevated in 1/13 (8%) patients (p = 0.007). Among all disease progression events the modified bootstrapped sensitivities for ctDNA and LDH were 82% and 40% respectively, with a median difference in sensitivity of 42% (95% confidence interval, 27%-58%; P < 0.001). In addition, ctDNA levels were elevated in 13/16 (81%) instances of non-RECIST disease progression, including 10/12 (83%) instances of new brain metastases. In comparison LDH was elevated 8/16 (50%) instances of non-RECIST disease progression, including 6/12 (50%) instances of new brain metastases. Overall, ctDNA had a higher sensitivity than LDH to detect disease progression, including non-RECIST progression events. ctDNA has the potential to be a useful biomarker for monitoring melanoma disease activity.
黑色素瘤缺乏一种临床上有用的基于血液的疾病活动生物标志物来帮助指导患者管理。为了确定循环游离肿瘤相关BRAF（突变型）和NRAS（突变型）DNA（ctDNA）的检测在治疗开始前和疾病进展时检测转移性疾病是否比乳酸脱氢酶（LDH）具有更高的敏感性，我们研究了接受BRAF抑制剂治疗或免疫检查点阻断治疗的不可切除IIIC/IV期转移性黑色素瘤患者，并在其治疗过程中获取了至少3份血浆样本。使用液滴数字PCR（ddPCR）检测法测定BRAF（突变型）和NRAS（突变型）ctDNA的水平。在治疗开始前有样本的患者中，ctDNA和LDH水平分别在12/15（80%）和6/20（30%）的患者中升高（p = 0.006）。在治疗开始前RECIST评分<5 cm的患者中，5/7（71%）的患者ctDNA水平升高，而LDH升高的患者为1/13（8%）（p = 0.007）。在所有疾病进展事件中，ctDNA和LDH的改良自展敏感性分别为82%和40%，敏感性的中位数差异为42%（95%置信区间，27%-58%；P < 0.001）。此外，在13/16（81%）的非RECIST疾病进展病例中ctDNA水平升高，包括10/12（83%）的新发脑转移病例。相比之下，在16例非RECIST疾病进展病例中有8例（50%）LDH升高，包括12例新发脑转移病例中的6例（50%）。总体而言，ctDNA在检测疾病进展（包括非RECIST进展事件）方面比LDH具有更高的敏感性。ctDNA有可能成为监测黑色素瘤疾病活动的有用生物标志物。
