Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade.
Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade.
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DOI：
10.1186/s40425-014-0042-0
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发表时间：
2014
影响因子：
10.9
通讯作者：
Diaz LA Jr
中科院分区：
文献类型：
--
作者：
Lipson EJ;Velculescu VE;Pritchard TS;Sausen M;Pardoll DM;Topalian SL;Diaz LA Jr
评估阻断免疫检查点（如CTLA-4和PD-1/PD-L1）的药物的治疗活性可能具有挑战性，因为由于肿瘤内炎症，肿瘤可能在消退前似乎会扩大或重新出现。我们评估了循环肿瘤DNA（ctDNA）水平是否可以作为接受这些药物治疗的患者肿瘤负荷真实变化的早期指标。对12例接受检查点阻断药物治疗的转移性黑色素瘤患者的肿瘤进行了分析，以确定BRAF、cKIT、NRAS和TERT中是否存在热点体细胞突变。从每个患者连续收集血浆，并将ctDNA水平与放射学和临床结果进行比较。在研究的10例患者中，有5例检测到BRAF（1例）、NRAS（2例）、TERT（1例）和ALK（1例）突变。5例患者中有4例的血浆分析鉴定出与肿瘤标本中发现的突变相同的突变。血浆ctDNA水平的范围为不可检测的（<0.01%）至总循环游离DNA的5.5%。在3例患者中，ctDNA水平升高与放射学评估的疾病进展相关。在一名患者中，ctDNA水平在接受肿瘤存款的针吸活检后增加。在另一名患者中，ctDNA水平最初随着检查淋巴结病的进展而增加，但随后在临床改善前3周变得不可检测。ctDNA水平与临床和放射学结果相关，并且在一个病例中，在最终肿瘤消退之前。需要进一步的前瞻性分析来评估ctDNA作为接受免疫检查点阻断药物的患者临床结果的早期生物标志物的效用。本文的在线版本（doi：10.1186/s40425-014-0042-0）包含补充材料，可供授权用户使用。
Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents. Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes. In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (<0.01%) to 5.5% of total circulating cell-free DNA. In 3 patients, increasing ctDNA levels correlated with progressive disease assessed by radiography. In one patient, ctDNA levels increased after undergoing a needle biopsy of a tumor deposit. In another patient, ctDNA levels increased initially as lymphadenopathy progressed by examination, but then became undetectable 3 weeks prior to clinical improvement. Levels of ctDNA correlated with clinical and radiologic outcomes, and, in one case, preceded eventual tumor regression. Further prospective analysis is required to assess the utility of ctDNA as an early biomarker of clinical outcomes in patients receiving immune checkpoint blocking drugs. The online version of this article (doi:10.1186/s40425-014-0042-0) contains supplementary material, which is available to authorized users.